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Pandey AS, Drogan C, Huo D, Postula K, Garg SM, Kupfer SS. Anticipation in families with MLH1-associated Lynch syndrome. Cancer 2025; 131:e35589. [PMID: 39435727 PMCID: PMC11694239 DOI: 10.1002/cncr.35589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 08/07/2024] [Accepted: 09/11/2024] [Indexed: 10/23/2024]
Abstract
BACKGROUND Lynch syndrome (LS) is an autosomal-dominant, hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in one of the mismatch-repair genes MLH1, MSH2/EPCAM, MSH6, or PMS2. Individuals who have MLH1 PVs have high lifetime risks of colorectal cancer (CRC) and endometrial cancer (EC). There is controversy regarding whether a younger age at diagnosis (or anticipation) occurs in MLH1-associated LS. The objective of this study was to assess anticipation in families with MLH1-associated LS by using statistical models while controlling for potential confounders. METHODS Data from 31 families with MLH1 PVs were obtained from an academic registry. Wilcoxon signed-rank tests on parent-child-pairs as well as parametric Weibull and semiparametric Cox proportional hazards and Cox mixed-effects models were used to calculate hazard ratios or to compare mean ages at CRC/EC diagnosis by generation. Models were also corrected for ascertainment bias and birth-cohort effects. RESULTS A trend toward younger ages at diagnosis of CRC/EC in successive generations, ranging from 3.2 to 15.7 years, was observed in MLH1 PV carrier families. A greater hazard for cancer in younger generations was not precluded by the inclusion of birth cohorts in the model. Individuals who had MLH1 variants with no Mlh1 activity were at a 78% greater hazard for CRC/EC than those who retained Mlh1 activity. CONCLUSIONS The current results demonstrated evidence in support of anticipation in families with MLH1-associated LS across all statistical models. Mutational effects on Mlh1 activity influenced the hazard for CRC/EC. Screening based on the youngest age of cancer diagnosis in MLH1-LS families is recommended.
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Affiliation(s)
- Arti S. Pandey
- Graduate Program in Genetic CounselingFeinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
- Division of Cancer Predisposition, OncologySt Jude Children’s HospitalMemphisTennesseeUSA
| | - Christine Drogan
- Section of Gastroenterology, Hepatology and NutritionDepartment of MedicineThe University of ChicagoChicagoIllinoisUSA
| | - Dezheng Huo
- Public Health SciencesThe University of ChicagoChicagoIllinoisUSA
| | - Kristen Postula
- Clinical Service Liaison OperationsGeneDxCrystal LakeIllinoisUSA
| | - Shreshtha M. Garg
- Graduate Program in Genetic CounselingFeinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
- HelixSan MateoCaliforniaUSA
| | - Sonia S. Kupfer
- Section of Gastroenterology, Hepatology and NutritionDepartment of MedicineThe University of ChicagoChicagoIllinoisUSA
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von Salomé J, Boonstra PS, Karimi M, Silander G, Stenmark-Askmalm M, Gebre-Medhin S, Aravidis C, Nilbert M, Lindblom A, Lagerstedt-Robinson K. Genetic anticipation in Swedish Lynch syndrome families. PLoS Genet 2017; 13:e1007012. [PMID: 29088233 PMCID: PMC5681299 DOI: 10.1371/journal.pgen.1007012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 11/10/2017] [Accepted: 09/08/2017] [Indexed: 12/15/2022] Open
Abstract
Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a nationwide cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990–2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM–MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller. Genetic anticipation is a phenomenon where symptoms of a hereditary disease appear at an earlier age and/or are more severe in successive generations. In genetic disorders such as Fragile X syndrome, Myotonic dystrophy type 1 and Huntington disease, anticipation is caused by the expansion of unstable trinucleotide repeats during meiosis. Anticipation is also reported to occur in some hereditary cancers though the underlying mechanism behind this observation is unknown. Several studies have investigated anticipation in Lynch syndrome, the most common hereditary colorectal cancer syndrome, yet there is a debate concerning whether anticipation occurs and what underlying mechanism there is. The objective of this project is to study if anticipation is part of the clinical picture in Swedish families with LS, with the long term goal to enable better prediction of age at onset in family members. Our results suggest that anticipation occurs in families with mutation in MSH2 and PMS2, while the evidence is equivocal for MLH1 and MSH6.
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Affiliation(s)
- Jenny von Salomé
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, Solna, Stockholm, Sweden
- * E-mail:
| | - Philip S. Boonstra
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Masoud Karimi
- Department of Oncology, Radiumhemmet, Karolinska University Hospital, Solna, Stockholm, Sweden
| | - Gustav Silander
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Marie Stenmark-Askmalm
- Department of Oncology, Linköping University, Linköping, Sweden
- Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden
| | - Samuel Gebre-Medhin
- Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Christos Aravidis
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Mef Nilbert
- Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden
- Clinical Research Centre, Hvidovre Hospital, Copenhagen University, Hvidovre, Denmark
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, Solna, Stockholm, Sweden
| | - Kristina Lagerstedt-Robinson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, Solna, Stockholm, Sweden
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Vasen HFA, Velthuizen ME, Kleibeuker JH, Menko FH, Nagengast FM, Cats A, van der Meulen-de Jong AE, Breuning MH, Roukema AJ, van Leeuwen-Cornelisse I, de Vos Tot Nederveen Cappel WH, Wijnen JT. Hereditary cancer registries improve the care of patients with a genetic predisposition to cancer: contributions from the Dutch Lynch syndrome registry. Fam Cancer 2017; 15:429-35. [PMID: 26973060 PMCID: PMC4901115 DOI: 10.1007/s10689-016-9897-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria. Since 2000 the registry has focused on family follow-up, and ensuring the quality of surveillance programs and appropriate clinical management. Since its founding, the registry has identified over 10,000 high-risk individuals with a diverse array of hereditary cancer syndromes. All were encouraged to participate in prevention programmes. The registry has published a number of studies that evaluated the outcome of surveillance protocols for colorectal cancer (CRC) in Lynch syndrome, as well as in familial colorectal cancer. In 2006, evaluation of the effect of registration and colonoscopic surveillance on the mortality rate associated with colorectal cancer (CRC) showed that the policy led to a substantial decrease in the mortality rate associated with CRC. Following discovery of MMR gene defects, the first predictive model that could select families for genetic testing was published by the Leiden group. In addition, over the years the registry has produced many cancer risk studies that have helped to develop appropriate surveillance protocols. Hereditary cancer registries in general, and the Lynch syndrome registry in particular, play an important role in improving the clinical management of affected families.
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Affiliation(s)
- Hans F A Vasen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. .,Hereditary Cancer Registry, Leiden, The Netherlands.
| | - Mary E Velthuizen
- Department of Clinical Genetics, University Medical Centre, Utrecht, The Netherlands
| | - Jan H Kleibeuker
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Fred H Menko
- Cancer Family Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Fokke M Nagengast
- Department of Gastroenterology and Hepatology, Slingerland Ziekenhuis, Doetinchem, The Netherlands
| | - Annemieke Cats
- Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Andrea E van der Meulen-de Jong
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Martijn H Breuning
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Anne J Roukema
- Department of Surgery, Elizabeth Hospital, Tilburg, The Netherlands
| | | | | | - Juul T Wijnen
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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Stupart D, Goldberg P, Algar U, Vorster A, Ramesar R. No evidence of genetic anticipation in a large family with Lynch syndrome. Fam Cancer 2015; 13:29-34. [PMID: 23771324 DOI: 10.1007/s10689-013-9669-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Lynch syndrome is the commonest inherited cause of colorectal cancer (CRC). Genetic anticipation occurs when the age of onset of a disorder decreases in successive generations. It is controversial whether this occurs in Lynch syndrome. Previous studies have included heterogenous groups of subjects from multiple families, including subjects with a clinical diagnosis (based on family history) as well as those with proven germline mismatch repair gene mutations. The purpose of this study was to determine whether genetic anticipation occurs in mismatch repair gene carriers from a single Lynch syndrome family. This study includes members of a single family known to carry an MLH1 gene mutation who are proven germline mutation carriers or obligate carriers (based on their offspring's mutation status). Evidence of genetic anticipation (determined by age of onset of first CRC) was sought in two ways: Firstly, subjects were grouped as parent-child pairs and individuals were compared with their own offspring; secondly they were grouped by generation within the family tree. The Kaplan-Meier technique was used to adjust for variable follow up times. The family tree consisted of 714 subjects. Ninety-two subjects over five generations were included in the study. There was no evidence of genetic anticipation over the generations. (P = 0.37). Similarly, in the 75 parent-child pairs identified, age of onset of CRC was similar for parents and children (P = 0.51). We could not identify any evidence of genetic anticipation in mutation carriers from a single family with Lynch syndrome.
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Affiliation(s)
- D Stupart
- Department of Surgery, Deakin University, Geelong, Australia,
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Stupart D, Win AK, Jenkins M, Winship IM, Goldberg P, Ramesar R. Fertility and apparent genetic anticipation in Lynch syndrome. Fam Cancer 2014; 13:369-74. [PMID: 24677027 DOI: 10.1007/s10689-014-9714-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Genetic anticipation is the phenomenon in which age of onset of an inherited disorder decreases in successive generations. Inconsistent evidence suggests that this occurs in Lynch syndrome. A possible cause for apparent anticipation is fecundity bias, which occurs if the disease adversely affects fertility. The purpose of this study was to determine the effect of age of diagnosis of colorectal cancer (CRC) on lifetime fertility in Lynch syndrome, and whether this can falsely create the appearance of genetic anticipation. A computer model simulated age of diagnosis of CRC in hypothetical Lynch syndrome carriers and their offspring. The model assumed similar age distribution of CRC across generations (i.e. that there was no true anticipation). Age distribution of CRC diagnosis, and lifetime fertility rates (grouped by age of diagnosis of CRC) were determined from the Australasian Colorectal Cancer Family Registry (ACCFR). Apparent anticipation was calculated by comparing ages of diagnosis of CRC in affected parent-child pairs. A total of 1,088 patients with CRC were identified from the ACCFR. Total lifetime (cohort) fertility was related to age of diagnosis of CRC (correlation coefficient 0.13, P = 0.0001). In the simulation, apparent anticipation was 1.8 ± 0.54 years (P = 0.0044). Observed apparent anticipation in the ACCFR cohort was 4.8 ± 1.73 years (P = 0.0064). There was no difference in apparent anticipation between the simulate d and observed parent-child pairs (P = 0.89). The appearance of genetic anticipation in Lynch syndrome can be falsely created due to changes in fertility.
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Affiliation(s)
- Douglas Stupart
- Deakin University Department of Surgery, Geelong Hospital, Ryrie Street, Geelong, VIC, 3227, Australia,
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Seguí N, Pineda M, Guinó E, Borràs E, Navarro M, Bellido F, Moreno V, Lázaro C, Blanco I, Capellá G, Valle L. Telomere length and genetic anticipation in Lynch syndrome. PLoS One 2013; 8:e61286. [PMID: 23637804 PMCID: PMC3634050 DOI: 10.1371/journal.pone.0061286] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 03/08/2013] [Indexed: 02/02/2023] Open
Abstract
Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.
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Affiliation(s)
- Nuria Seguí
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Marta Pineda
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Elisabet Guinó
- Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Barcelona, Spain
| | - Ester Borràs
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Matilde Navarro
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Fernando Bellido
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Victor Moreno
- Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain
| | - Conxi Lázaro
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Ignacio Blanco
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- * E-mail:
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Bozzao C, Lastella P, Stella A. Anticipation in lynch syndrome: where we are where we go. Curr Genomics 2012; 12:451-65. [PMID: 22547953 PMCID: PMC3219841 DOI: 10.2174/138920211797904070] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 07/08/2011] [Accepted: 07/20/2011] [Indexed: 02/06/2023] Open
Abstract
Lynch syndrome (LS) is the most common form of inherited predisposition to develop cancer mainly in the colon and endometrium but also in other organ sites. Germline mutations in DNA mismatch repair (MMR) gene cause the transmission of the syndrome in an autosomal dominant manner. The management of LS patients is complicated by the large variation in age at cancer diagnosis which requires these patients to be enrolled in surveillance protocol starting as early as in their second decade of life. Several environmental and genetic factors have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Although the presence of genetic anticipation in Lynch syndrome has been suspected since 15 years, only recently the phenomenon has been increasingly reported to be present in different cancer genetic syndromes including LS. While the biological basis of earlier cancer onset in successive generations remains poorly known, recent findings point to telomere dynamics as a mechanism significantly contributing to genetic anticipation in Lynch syndrome and in other familial cancers. In this review, we summarize the clinical and molecular features of Lynch syndrome, with a particular focus on the latest studies that have investigated the molecular mechanisms of genetic anticipation.
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Affiliation(s)
- Cristina Bozzao
- Medical Genetics Unit, Department of Biomedicine in Childhood, Università degli Studi di Bari "Aldo Moro", Bari, Italy
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van Vliet CM, Dowty JG, van Vliet JL, Smith L, Mead LJ, Macrae FA, St John DJB, Giles GG, Southey MC, Jenkins MA, Velan GM, Hopper JL. Dependence of colorectal cancer risk on the parent-of-origin of mutations in DNA mismatch repair genes. Hum Mutat 2011; 32:207-12. [PMID: 21120946 DOI: 10.1002/humu.21408] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Accepted: 10/31/2010] [Indexed: 11/08/2022]
Abstract
Genetic diseases associated with dynamic mutations in microsatellite DNA often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Carriers of germline mutations in mismatch repair (MMR) genes have high risks of colorectal carcinoma (CRC). We investigated whether these risks depend on the parent-of-origin of the mutation. We studied 422 subjects, including 89 MMR gene mutation carriers, from 17 population-based families who were each recruited via a CRC case diagnosed before age 45 years and found to carry a MMR gene mutation. The POE hazard ratio (HR(POE)), defined to be the CRC incidence for carriers with maternally derived mutations divided by the corresponding paternal incidence, was estimated using a novel application of modified segregation analysis. HR(POE) (95% confidence interval) was estimated to be 3.2 (1.1-9.8) for males (P = 0.03) and 0.8 (0.2-2.8) for females (P = 0.5) and the corresponding cumulative risks to age 80 years were 88% (54%-100%) for male carriers with maternally derived mutations and 38-48% for all other carriers. If confirmed by larger studies, these results will have important implications for the etiology of CRC and for the clinical management of MMR gene mutation carriers.
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Affiliation(s)
- Christine M van Vliet
- Centre for Molecular, Environmental, Genetic, Analytic Epidemiology, The University of Melbourne, Victoria 3010, Australia
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Boonstra PS, Gruber SB, Raymond VM, Huang SC, Timshel S, Nilbert M, Mukherjee B. A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome. Genet Epidemiol 2010; 34:756-68. [PMID: 20878717 PMCID: PMC3894615 DOI: 10.1002/gepi.20534] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Anticipation, manifested through decreasing age of onset or increased severity in successive generations, has been noted in several genetic diseases. Statistical methods for genetic anticipation range from a simple use of the paired t-test for age of onset restricted to affected parent-child pairs to a recently proposed random effects model which includes extended pedigree data and unaffected family members [Larsen et al., 2009]. A naive use of the paired t-test is biased for the simple reason that age of onset has to be less than the age at ascertainment (interview) for both affected parent and child, and this right truncation effect is more pronounced in children than in parents. In this study, we first review different statistical methods for testing genetic anticipation in affected parent-child pairs that address the issue of bias due to right truncation. Using affected parent-child pair data, we compare the paired t-test with the parametric conditional maximum likelihood approach of Huang and Vieland [1997] and the nonparametric approach of Rabinowitz and Yang [1999] in terms of Type I error and power under various simulation settings and departures from the modeling assumptions. We especially investigate the issue of multiplex ascertainment and its effect on the different methods. We then focus on exploring genetic anticipation in Lynch syndrome and analyze new data on the age of onset in affected parent-child pairs from families seen at the University of Michigan Cancer Genetics clinic with a mutation in one of the three main mismatch repair (MMR) genes. In contrast to the clinic-based population, we re-analyze data on a population-based Lynch syndrome cohort, derived from the Danish HNPCC-register. Both datasets indicate evidence of genetic anticipation in Lynch syndrome. We then expand our review to incorporate recently proposed statistical methods that consider family instead of affected pairs as the sampling unit. These prospective censored regression models offer additional flexibility to incorporate unaffected family members, familial correlation and other covariates into the analysis. An expanded dataset from the Danish HNPCC-register is analyzed by this alternative set of methods.
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Affiliation(s)
| | - Stephen B. Gruber
- Departments of Epidemiology and Human Genetics, University of Michigan, Ann Arbor
- Department of Internal Medicine, University of Michigan, Ann Arbor
| | | | - Shu-chen Huang
- Department of Internal Medicine, University of Michigan, Ann Arbor
| | - Susanne Timshel
- Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
| | - Mef Nilbert
- The Danish HNPCC-register, Hvidovre University Hospital, Hvidovre, Denmark
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Wang CW, Hui EC. Ethical, legal and social implications of prenatal and preimplantation genetic testing for cancer susceptibility. Reprod Biomed Online 2010; 19 Suppl 2:23-33. [PMID: 19891845 DOI: 10.1016/s1472-6483(10)60274-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
With the progress in cancer genetics and assisted reproductive technologies, it is now possible for cancer gene mutation carriers not only to reduce cancer mortality through the targeting of surveillance and preventive therapies, but also to avoid the birth of at-risk babies through the choice of different means of reproduction. Thus, the incidence of hereditary cancer syndromes may be decreased in the future. The integration of cancer genetic testing and assisted reproductive technologies raises certain ethical, legal and social issues beyond either genetic testing or assisted reproductive technology itself. In this paper, the reproductive decisions/choices of at-risk young couples and the ethical, legal and social concerns of prenatal genetic testing and preimplantation genetic diagnosis for susceptibility to hereditary cancer syndromes are discussed. Specifically, three ethical principles related to the integration of cancer genetic testing and assisted reproductive technologies, i.e. informed choice, beneficence to children and social justice, and their implications for the responsible translation of these medical techniques into common practice of preventive medicine are highlighted.
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Affiliation(s)
- C-W Wang
- Medical Ethics Unit, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong
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Nilbert M, Timshel S, Bernstein I, Larsen K. Role for genetic anticipation in Lynch syndrome. J Clin Oncol 2008; 27:360-4. [PMID: 19075283 DOI: 10.1200/jco.2008.16.1281] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
PURPOSE Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum. PATIENTS AND METHODS In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290 parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were used to assess a possible role of anticipation. RESULTS Both methods revealed anticipation with children developing cancer mean 9.8 years (P < .001) earlier than parents using the paired t-test and 5.5 years (P < .001) earlier using the bivariate model. Birth cohort effects were excluded since anticipation with 7.2 years earlier age at onset was identified also in the oldest cohort, in which the children were observed until they were older than 80 years. The effect remained when cancers diagnosed at surveillance were excluded, applied to maternal as well as paternal inheritance, and was independent of the MMR gene mutated. CONCLUSION The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need to initiate surveillance programs at young age. It should also stimulate research into the genetic mechanisms that determine age at onset and whether the genetic instability that characterizes Lynch syndrome can be linked to anticipation.
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Affiliation(s)
- Mef Nilbert
- Copenhagen University, Clinical Research Centre, Hvidovre, Denmark.
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12
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Hereditary Nonpolyposis Colorectal Cancer in Lower Silesia. POLISH JOURNAL OF SURGERY 2007. [DOI: 10.2478/v10035-007-0028-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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13
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High Risk Premalignant Colorectal Conditions. Surg Oncol 2006. [DOI: 10.1007/0-387-21701-0_38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Johnson PM, Gallinger S, McLeod RS. Surveillance colonoscopy in individuals at risk for hereditary nonpolyposis colorectal cancer: an evidence-based review. Dis Colon Rectum 2006; 49:80-93; discussion 94-5. [PMID: 16284887 DOI: 10.1007/s10350-005-0228-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Surveillance colonoscopy plays an important role in the management of asymptomatic patients known to carry and suspected of carrying hereditary nonpolyposis colorectal cancer gene mutations. Although the shortest interval between surveillance examinations may seem to offer the most benefit to patients, excessive use of this procedure may have unwanted consequences. This study was designed to evaluate the evidence and make recommendations regarding the optimal frequency of surveillance colonoscopy and the age at which to initiate surveillance based on the best available evidence. METHODS MEDLINE was searched for all articles assessing surveillance colonoscopy from 1966 to 2004 by using the MESH terms "hereditary nonpolyposis colorectal cancer" and "screening." The evidence was systematically reviewed and a critical appraisal of the evidence was performed. RESULTS There are no randomized, controlled, clinical trials examining the frequency of surveillance colonoscopy in hereditary nonpolyposis colorectal cancer. Three cohort studies were identified for review. There is one cohort study of good quality that provides evidence that surveillance colonoscopy every three years in patients with hereditary nonpolyposis colorectal cancer reduces the risk of developing colorectal cancer and the risk of death. The two remaining cohort studies provide poor evidence on which to make a recommendation. CONCLUSIONS The best available evidence supports surveillance with complete colonoscopy to the cecum every three years in patients with hereditary nonpolyposis colorectal cancer (B recommendation). There is no evidence to support or refute more frequent screening. Further research is required to examine the potential harms and benefits of more frequent screening. However, given the potential for rapid progression from adenoma to carcinoma and missing lesions at colonoscopy, there is consensus that screening more frequently than every three years is required.
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Affiliation(s)
- Paul M Johnson
- IBD Research Unit, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
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15
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Jass JR. A new entity of hereditary colorectal cancer. Gut 2005; 54:1819. [PMID: 16284296 PMCID: PMC1774810 DOI: 10.1136/gut.2005.078790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
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Westphalen AA, Russell AM, Buser M, Berthod CR, Hutter P, Plasilova M, Mueller H, Heinimann K. Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer. Hum Genet 2005; 116:461-5. [PMID: 15772852 DOI: 10.1007/s00439-005-1272-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2004] [Accepted: 01/14/2005] [Indexed: 10/25/2022]
Abstract
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited, colorectal cancer (CRC) predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 and MSH2. Thus far, only limited data exist on the occurrence of genetic anticipation in HNPCC, i.e. the earlier age at diagnosis of CRC in successive generations. Performing nonparametric distribution-free statistical analyses, we investigated 55 parent-child pairs who had been diagnosed with CRC and who came from 21 Swiss HNPCC families with characterised MMR germline mutation (15 in MLH1 and 6 in MSH2). The overall median age at diagnosis was 43 years, with an interquartile range (IQR) of 14 and incidence ages ranging from 18 to 62 years. Descendants of HNPCC patients (median age at diagnosis 39 years, IQR=12) were found to be diagnosed with CRC significantly earlier than their parents (47 years, IQR=10), with the median of the paired age difference amounting to 8 years (IQR=15; P<0.0001). Birth cohort effects could be excluded, since the same, statistically significant, age difference was also observed in the oldest offspring birth cohort (birth year <1916; P=0.01). Genetic anticipation appeared to be more pronounced when the disease allele was transmitted through the father than through the mother (median age difference 11 vs. 4 years, respectively; both P<0.01). If confirmed in larger, ideally prospective studies, these results may have important implications for genetic counselling and clinical management of HNPCC families.
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Affiliation(s)
- Alexander A Westphalen
- Research Group Human Genetics, Division of Medical Genetics, Centre for Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland
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Abstract
Cancer genetics is increasingly becoming integrated into the practice of modern medical oncology. The ability to distinguish a growing proportion of the 5% to 10% of all cancers that develop in individuals who have inherited a genetic mutation conferring heightened susceptibility to specific cancers may permit targeted efforts in cancer surveillance and prevention. While these individuals comprise a small proportion of the overall burden of cancer, strategies successful in reducing their remarkable cancer risks may be generalizable to the broader population. In this review, we highlight the most common hereditary cancer syndromes, most attributable to genes inherited in an autosomal dominant manner with incomplete penetrance, and a number of rare syndromes in which particular progress has been made. The prevalence, penetrance, tumor spectrum, and underlying genetic defects are discussed and summarized in a large table in which a more comprehensive enumeration of syndromes is provided.
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Affiliation(s)
- Judy E Garber
- Dana-Farber Cancer Institute, 44 Binney Street, SM 209, Boston, MA 02115, USA.
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18
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Rijcken FEM, Mourits MJE, Kleibeuker JH, Hollema H, van der Zee AGJ. Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2003; 91:74-80. [PMID: 14529665 DOI: 10.1016/s0090-8258(03)00371-8] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE In hereditary nonpolyposis colorectal cancer (HNPCC), women with a mismatch repair (MMR) gene mutation have a cumulative lifetime risk of 25-50% for endometrial cancer and 8-12% for ovarian cancer. Therefore, female members of HNPCC families are offered an annual gynecologic and transvaginal ultrasound (TVU) examination and serum level CA 125 analysis. The aim of the present study was to evaluate our 10-year experience with this screening program. METHODS Women who are MMR gene mutation carriers or who fulfil the Amsterdam criteria were identified from our HNPCC database. Information concerning the screening program was retrospectively collected from patient files. RESULTS Forty-one women, 35 premenopausal and 6 postmenopausal, were enrolled in the program with a median follow-up of 5 years (range 5 months-11 years). In 197 patient years at risk, 17 of 179 TVUs gave reason for endometrial sampling. Three premalignant lesions, with complex atypical hyperplasia, were discovered. One interval endometrial cancer was detected as a result of clinical symptoms. No abnormal CA 125 levels were measured and no ovarian cancers were detected. CONCLUSIONS These results demonstrate that gynecologic screening allows the detection of premalignant lesions of the endometrium but also illustrate that recognition and reporting of clinical symptoms by the women themselves is of utmost importance.
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Affiliation(s)
- Fleur E M Rijcken
- Department of Gastroenterology, University Hospital Groningen, Groningen, The Netherlands.
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19
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Voskuil DW, Kampman E, Grubben MJAL, Kok FJ, Nagengast FM, Vasen HFA, van 't Veer P. Meat consumption and meat preparation in relation to colorectal adenomas among sporadic and HNPCC family patients in The Netherlands. Eur J Cancer 2002; 38:2300-8. [PMID: 12441267 DOI: 10.1016/s0959-8049(02)00455-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Meat consumption and meat preparation methods are thought to be associated with the risk of sporadic colorectal cancer, and possibly adenomas. As the same somatic mutations occur in sporadic adenomas and hereditary non-polyposis colorectal cancer (HNPCC)-related adenomas, similar exogenous factors may play a role in the development of both types of adenoma. In a case control study among 57 sporadic colorectal adenoma cases and 62 adenoma cases from HNPCC families (and 148 adenoma-free controls) from the Netherlands, we examined whether meat consumption and preparation are similarly associated with sporadic and suspected HNPCC colorectal adenomas. Frequency of meat consumption was not significantly associated with adenoma risk in our population of sporadic and HNPCC family cases and controls (Odds Ratios (OR) for high versus low consumption were 1.0 and 0.6, respectively). Interestingly, consumption of red meat and specific preparation methods (i.e., "not adding any water" and " closed lid with most meat types") slightly, but non-significantly, increased the risk of adenomas in the sporadic group only (OR, 95% Confidence Interval (CI): 4.1, 0.7-23.0, 2.0, 0.6-6.5 and 2.6, 0.9-7.2, respectively). This is the first study to examine possible differences or similarities in risk factors for sporadic and HNPCC colorectal carcinogenesis. Our results do not provide support for meat consumption as a risk factor for adenoma formation in HNPCC family members. Some characteristics of habitual meat preparation in the Netherlands may, however, increase the risk of sporadic adenomas.
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Affiliation(s)
- D W Voskuil
- Division of Human Nutrition and Epidemiology, Wageningen University, PO Box 8129, 6700 EV, Wageningen, The Netherlands
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20
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Bisgaard ML, Jäger AC, Myrhøj T, Bernstein I, Nielsen FC. Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation. Hum Mutat 2002; 20:20-7. [PMID: 12112654 DOI: 10.1002/humu.10083] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Affected members of hereditary non-polyposis colorectal cancer (HNPCC) families develop colorectal cancer at an early age (mean 45 yr) and frequently get extracolonic cancers particularly in the uterus, urinary tract, and small intestine. They have a high risk of developing more than one primary colorectal cancer if not treated with subtotal colectomy at first operation and have more frequent right-sided colon cancers and less frequent rectum cancers, compared to patients with sporadic colorectal cancer. We have screened 31 families fulfilling the Amsterdam criteria and 54 families with a colorectal cancer clustering but not fulfilling the Amsterdam criteria for mutations in MLH1 and MSH2 by direct sequencing, and detected a mutation in 61% of the Amsterdam positive families but only in 15% of the Amsterdam negative families. Genotype-phenotype correlation was compared between 141 affected individuals with an identified mutation and 78 affected individuals from Amsterdam positive families in which a mutation was not identifiable in MLH1 or MSH2. In the affected persons with identified mutations, all expected phenotypic traits were represented, whereas affected persons in whom no mutation was detected fell into two clearly distinguishable subgroups. The minor subgroup, in which no mutation was identified, generally had the same characteristics as found in affected persons with identified mutations. The major subgroup differed significantly in clinical features and exhibited phenotypic traits similar to those found in late-onset families, including abundance of rectal cancer, few HNPCC-related cancers, lower frequency of multiple colorectal cancers, and later age at onset. Finally, for six missense mutations and one single codon deletion, the pathogenic potential was evaluated by domain localization, lod score calculation or segregation analysis when possible, and mutation-induced biochemical change. The results indicate that the majority of missense mutations are pathogenic, although further characterization by functional assays is necessary before implementation in predictive testing programs.
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Zhao B, Wang ZJ, Xu YF, Wan YL, Li P, Huang YT. Report of 16 kindreds and one kindred with hMLH1 germline mutation. World J Gastroenterol 2002; 8:263-6. [PMID: 11925604 PMCID: PMC4658363 DOI: 10.3748/wjg.v8.i2.263] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the diagnosis and treatment of 16 hereditary nonpolyposis colorectal cancer (HNPCC) kindreds, and to report the first kindred with hMLH1 germline mutation in Mainland China.
METHODS: The diagnosis, treatment and follow-up study of 16 HNPCC kindreds were retrospectively reviewed. Data concerning site of the malignant tumor, age at the diagnosis, history of synchronous and/or metachronous cancer, and histopathology of tumors were recorded. All treatments had won formal consent. PCR and SSCP were used to screen the coding region of hMLH1 and hMSH2 genes. Variant bands were sequenced by a 377 DNA sequencer.
RESULTS: Among sixteen kindreds, sixty-eight patients had a mean age of 50.8 years, including twenty-one multiple cancer patients and forty-six colorectal cancer patients (metachronous colorectal cancers in sixteen). A total of one hundred and one malignant neoplasms were found in these sixty-eight patients, including 50 colonic, 17 rectal, 11 gastric, 7 endometrial, and 4 esophageal cancers. 39.5% colorectal patients had metachronous cancers within ten years who needed reoperations. A germline G265T nonsense mutation was found in the third exon of hMLH1, resulting in a stop codon and truncated protein. Three phenotypically normal family members were also found to carry the mutated gene.
CONCLUSION: HNPCC is a typical auto-dominant hereditary disease, the main characteristics include early onset and frequency of cancers; predominance of colorectal, especially right-sided colon cancers; frequency of multiple primary cancers (especially colorectal cancers). Segmental resection for colorectal cancers is not eligible for colorectal cancer patient in HNPCC kindreds. Intensive follow-up is essential for all patients and possible gene carriers. The first HNPCC kindred with hMLH1 gene germline mutation was identified in Mainland China, and three phenotypically normal family members were found to be carriers of the mutated gene. The G265T germline (nonsense) mutation in the third exon of hMLH1 found here had not been reported previously in the literature.
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Affiliation(s)
- Bo Zhao
- Department of Surgery, Peking University First Hospital, No. 8 Xishiku Street, Western Distract, Beijing 100034, China
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22
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Berends MJ, Wu Y, Sijmons RH, Hofstra RM, van der Zee AG, Buys CH, Kleibeuker JH. Clinical definition of hereditary non-polyposis colorectal cancer: a search for the impossible? SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 2002:61-7. [PMID: 11768563 DOI: 10.1080/003655201753265127] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Hereditary non-polyposis colorectal cancer is an autosomal dominant inherited disorder that predisposes its carriers to an almost 100% lifetime risk of cancer, in particular colorectal and endometrial cancer. Germline mutations, resulting in a deficient DNA mismatch repair system, are responsible for the disease. Because of the lack of specific phenotypical features, clinical diagnosis in an individual patient is impossible and relies heavily on family history. Genetic diagnosis by mismatch detection is now possible in a substantial proportion of families. Thus there is a great need for reliable but simple criteria that will help clinicians to recognize patients and families who can be referred for genetic diagnostics. In this article the different criteria that have been formulated and published in recent years are reviewed and the results, in terms of the proportions of subjects satisfying the criteria who were found to have a germline mutation, are discussed. In most studies the criteria were evaluated in only a small number of subjects. A population-based study is currently being carried out in the north of The Netherlands that aims to include 400 patients fulfilling one of a few simple criteria. Mutation analysis will be performed in all patients. The results of this study will help in the formulation of accurate and simple criteria for use in clinical practice.
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Affiliation(s)
- M J Berends
- Dept. of Gastroenterology, University Hospital, Groningen, The Netherlands
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23
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Tsai YY, Petersen GM, Booker SV, Bacon JA, Hamilton SR, Giardiello FM. Evidence against genetic anticipation in familial colorectal cancer. Genet Epidemiol 2000; 14:435-46. [PMID: 9271715 DOI: 10.1002/(sici)1098-2272(1997)14:4<435::aid-gepi8>3.0.co;2-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Anecdotal reports of hereditary colorectal cancer suggest that genetic anticipation (earlier appearance in successive generations) occurs, but ascertainment bias and cohort effects confound this interpretation. Using approaches that correct for such biases, we examined the age at diagnosis of colorectal cancer from family history questionnaires completed by subjects in the Johns Hopkins Hereditary Colorectal Cancer Registry; 475 parent-offspring pairs in 308 pedigrees were studied. We observed the expected cohort effect among offspring, in that the mean ages at diagnosis of those born before 1921, between 1921 and 1930, and after 1930 were 63 +/- 13 (SD), 57 +/- 10, and 42 +/- 10 years, respectively, while their parents' mean ages were 65 +/- 14, 66 +/- 14, and 58 +/- 15 years, respectively. In the cohort born before 1921, in which observation periods for both parents and offspring were comparable, there was no difference in age at diagnosis by pairwise comparison or life table analysis (P = 0.15 and 0.23, respectively; r = 0.32). Subgroup analysis of 67 pairs from 38 families that met the International Collaborative Group (ICG) criteria for hereditary nonpolyposis colorectal cancer (HNPCC) and of 14 pairs from 7 families with known germline mutations of DNA mismatch repair genes also showed no significant differences (mean age at diagnosis: 56 +/- 14 years for parents and 57 +/- 16 years for offspring from ICG families, and 45 +/- 10 years for parents and 44 +/- 12 years for offspring in families with known mutations). We also found no evidence for effect of parental gender on age at diagnosis in offspring of either gender, nor a secular trend toward younger onset colorectal cancer in this sample. In conclusion, there is no evidence for genetic anticipation or genomic imprinting of age at diagnosis in this sample of colorectal cancer families. Apparent anticipation appears to reflect a birth cohort bias of ascertainment.
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Affiliation(s)
- Y Y Tsai
- Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205-2179, USA
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24
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de Leon MP, Pedroni M, Benatti P, Percesepe A, Di Gregorio C, Foroni M, Rossi G, Genuardi M, Neri G, Leonardi F, Viel A, Capozzi E, Boiocchi M, Roncucci L. Hereditary colorectal cancer in the general population: from cancer registration to molecular diagnosis. Gut 1999; 45:32-8. [PMID: 10369701 PMCID: PMC1727564 DOI: 10.1136/gut.45.1.32] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited disorders predisposing to cancer. The genes responsible for the disease have recently been cloned and characterised; their mutations induce a generalised genomic instability which is particularly evident at microsatellite loci (replication error (RER)+ phenotype). AIMS To investigate how to select individuals and families in the general population who should be screened for constitutional mutations predisposing to colorectal cancer. PATIENTS/METHODS Between 1984 and 1995, 1899 colorectal malignancies in 1831 patients were registered, and in 1721 of these (94%), family trees could be obtained. Patients and families were classified into five categories according to a more or less likely genetic basis: HNPCC; "suspected" HNPCC; juvenile cases; aspecific cancer aggregation; sporadic cases. In 18 families with HNPCC as well as in 18 with suspected HNPCC, microsatellite instability in tumour tissues and constitutional mutations of two DNA mismatch repair genes (MSH2 and MLH1) could be evaluated. RER status was studied with five markers (BAT40, D2S123, D18S57, D17S787, and BAT26) in paraffin embedded tissues. Germline mutations of MSH2 or MLH1 genes were assessed on DNA and RNA extracted from lymphomonocytic cells, using reverse transcription polymerase chain reaction, single strand conformation polymorphism analysis, and direct DNA sequencing. RESULTS HNPCC represented 2.6% and suspected HNPCC 4.6% of all registered colorectal neoplasms. Eleven out of 18 HNPCC families (61%) showed microsatellite instability as opposed to four (of 18) suspected HNPCC (22%; p<0.02). Three germline mutations (two in MSH2 and one in MLH1 gene) were found in three different large HNPCC families, whereas no mutations were detected in suspected HNPCC. CONCLUSIONS In this study of cancer genetic epidemiology, data from a tumour registry were analysed and this ultimately led to the identification and selection of families that should be tested for mutator gene mutations. With the use of a population based approach, the incidence of mutations was appreciably lower than previously reported and limited to families with full blown HNPCC. It is possible that in most families with a clinical spectrum of HNPCC (or suspected HNPCC) other DNA mismatch repair genes are involved in the pathogenesis of the disease.
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Affiliation(s)
- M P de Leon
- Dipartimento di Medicina Interna, Università di Modena, Italy
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Wijnen JT, Vasen HF, Khan PM, Zwinderman AH, van der Klift H, Mulder A, Tops C, Møller P, Fodde R. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998; 339:511-8. [PMID: 9709044 DOI: 10.1056/nejm199808203390804] [Citation(s) in RCA: 275] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing. METHODS We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families. RESULTS Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1. CONCLUSIONS Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.
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Affiliation(s)
- J T Wijnen
- Department of Human Genetics, Leiden University Medical Center, The Netherlands
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26
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Menko FH, Wijnen JT, Vasen HF, Sijmons RH, Khan PM. Familial and hereditary non-polyposis colorectal cancer: issues relevant for surgical practice. Recent Results Cancer Res 1998; 146:20-31. [PMID: 9670246 DOI: 10.1007/978-3-642-71967-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
About 15% of patients with colorectal cancer report a family history of this disease. An estimated 1%-5% of patients have hereditary non-polyposis colorectal cancer (HNPCC). Recently, DNA mismatch repair genes associated with this syndrome were identified. For about 50% of families in which HNPCC occurs, DNA-based diagnosis and presymptomatic DNA testing are now feasible. Diagnosis of a hereditary tumour syndrome is relevant for both the patient with cancer and his or her close relatives. The complexities of family studies warrant the forming of a multidisciplinary team which may choose to work within a specialized cancer family clinic.
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Affiliation(s)
- F H Menko
- Department of Clinical Genetics, University Hospital Vrije Universiteit, Amsterdam, The Netherlands
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Voskuil DW, Vasen HF, Kampman E, van't Veer P. Colorectal cancer risk in HNPCC families: development during lifetime and in successive generations. National Collaborative Group on HNPCC. Int J Cancer 1997; 72:205-9. [PMID: 9219821 DOI: 10.1002/(sici)1097-0215(19970717)72:2<205::aid-ijc1>3.0.co;2-v] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Members of hereditary non-polyposis colorectal cancer (HNPCC) families develop colorectal cancer at a much higher rate, and at a much younger age, than the general population. To quantify lifetime colorectal cancer risk in HNPCC family members, we calculated the cumulative incidence (CI) in different age categories, and compared this to the general population. Furthermore, we investigated whether successive generations of HNPCC families had earlier onset of disease. In 51 HNPCC families, selected according to the "Amsterdam criteria", the CI of colorectal cancer at age 75 was 40%, compared to only 4% in the general population. The CI ratio (CIR) of HNPCC family members relative to the general population was 148 at age 40, 79 at age 50 and 11 at age 75. Comparing successive generations of HNPCC families, the CI at age 75 increases from 19% in the ancestors to 32% in the first generation and 55% in the second generation. However, Cox proportional hazard analysis showed that this generation effect (RR per generation: 1.8, 95% CL = 1.4-2.2) largely disappears after adjustment for year of birth. In summary, at young ages, HNPCC family members experience an up-to-150 times higher risk for colorectal cancer than the general population. This risk difference declines from age 60 onwards. The earlier age of onset in successive HNPCC generations does not appear to be a biological feature of HNPCC, but reflects a secular time trend in cancer occurrence in these families, similar to that in the general population.
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Affiliation(s)
- D W Voskuil
- Department of Epidemiology and Public Health, Wageningen Agricultural University, The Netherlands.
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29
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Ponz de Leon M, Benatti P, Roncucci L. Inheritance and susceptibility to tumours of the large bowel: a new classification of colorectal malignancies. Eur J Cancer 1996; 32A:2206-11. [PMID: 9038601 DOI: 10.1016/s0959-8049(96)00352-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- M Ponz de Leon
- Department of Internal Medicine, University of Modena, Italy
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30
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Jass JR. Screening for familial colorectal cancer. Gut 1996; 39:497. [PMID: 8949666 PMCID: PMC1383371 DOI: 10.1136/gut.39.3.497-a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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31
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Maes B, Hastier P, Delmont JP. Acute idiopathic pancreatitis. Gut 1996; 39:496-7. [PMID: 8949665 PMCID: PMC1383369 DOI: 10.1136/gut.39.3.496-b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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32
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Jass JR, Pokos V, Arnold JL, Cottier DS, Jeevaratnam P, Van de Water NS, Browett PJ, Winship IM, Lane MR. Colorectal neoplasms detected colonoscopically in at-risk members of colorectal cancer families stratified by the demonstration of DNA microsatellite instability. J Mol Med (Berl) 1996; 74:547-51. [PMID: 8892060 DOI: 10.1007/bf00204981] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
This study compared colonoscopic findings in families meeting the Amsterdam criteria (A) for hereditary non-polyposis colorectal cancer (HNPCC) but stratified according to whether the familial cancers showed DNA microsatellite instability. DNA was extracted from paired samples of normal and cancer, and microsatellite instability was analysed at up to six loci. Families were termed replication error positive (RER+) when at least 50% of tumours tested per family were positive. Of 26 families studied 17 were RER+ and 9 were RER-. Cancers in the A/RER- families showed no right-sided predilection (P < 0.001). Colonoscopies have been performed on 182 at-risk members of A/RER+ families and 60 members of A/RER- families. More of the at-risk members of A/RER-families were found to have adenomas at colonoscopy (P = 0.095), but these were smaller than those of A/RER+ families (P = 0.19). The adenoma:carcinoma ratio was twice as high in A/RER- families (13:1) as in A/RER+ families (7:1). One of the A/RER- families had hyperplastic polyposis. The others do not appear to have attenuated familial adenomatous polyposis and are similar to the adenoma families or late-onset colorectal cancer families described by others. This study illustrates the importance of molecular technology in separating HNPCC from syndromes with overlapping phenotypes.
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Affiliation(s)
- J R Jass
- Department of Pathology, Medical School, University of Queensland, Herston, Brisbane, Australia
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Affiliation(s)
- M A Rodríguez-Bigas
- Division of Surgical Oncology and Endoscopy, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
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Rodríguez-Bigas MA, Lee PH, O'Malley L, Weber TK, Suh O, Anderson GR, Petrelli NJ. Establishment of a hereditary nonpolyposis colorectal cancer registry. Dis Colon Rectum 1996; 39:649-53. [PMID: 8646951 DOI: 10.1007/bf02056944] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition characterized by early age of onset colorectal cancer, right-sided predominance, excess of synchronous and metachronous colonic neoplasms, and extracolonic cancers. The purpose of this study is to report clinical characteristics of HNPCC families in our registry. METHODS This is a retrospective review of medical records of patients with a significant history of colorectal cancer and interviews with their families. RESULTS Three hundred one people with cancer in 40 HNPCC families were identified. In 284 of 301 (94 percent) people, 363 cancers were identified. Colorectal cancer only was identified in 182 people (64 percent) and, in conjunction with extracolonic tumors, in another 31 people (11 percent). Extracolonic cancer alone was noted in 71 people (25 percent). Median age at diagnosis of colorectal cancer was 48 (range, 17-92) years. In patients with documented pathology, right-sided tumors predominated (55 percent), synchronous and metachronous tumors were noted in 53 percent, and synchronous of metachronous adenomas were documented in 51 percent of people. Generational anticipation was also noted. CONCLUSION This study demonstrates and confirms characteristics that have been described in HNPCC. Namely, early age of onset of colorectal cancer, right-sided predominance, multiple synchronous and metachronous neoplasms, increased extracolonic cancers, and generational anticipation.
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Affiliation(s)
- M A Rodríguez-Bigas
- Division of Surgical Oncology and Endoscopy, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
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Abstract
Mutations in 4 genes associated with DNA repair have been shown to be associated with hereditary non-polyposis colon cancer (HNPCC) in families which display unusually high risk for colorectal cancer. Laboratory tests for mutations in these genes will soon be commercially available, raising the possibility that population-wide gene testing to identify individuals with an inherited susceptibility to colorectal cancer could be conducted. The purpose of our report is to explore the economic implications of conducting a program of population-wide screening for HNPCC compared with alternative programs which would be restricted to families already known to be at high risk for HNPCC. Rather than provide a definitive answer to these questions, our purpose is to indicate priority areas of research which need to be conducted before such a definitive analysis can be done. An exploratory analysis has been conducted to determine which factors are most important in determining the cost-effectiveness of a genetic testing program for HNPCC. The base case analysis focuses on current uncertainty about the population prevalence of the HNPCC genotype and phenotype, factors which are central to the cost-effectiveness of population-wide screening. Uncertainty in parameters related to the cost and effectiveness of screening and preventive interventions for HNPCC were explored using additional sensitivity analyses. Favorable levels of cost-effectiveness for population-wide screening are achieved only when the most favorable assumptions about HNPCC prevalence and the cost and effectiveness of screening and preventive interventions are made.
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Affiliation(s)
- M L Brown
- Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, MD, 20892 USA
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Green SE, Chapman PD, Burn J, Bishop DT, Varma JS. Clinical impact of colonoscopic screening in first-degree relatives of patients with hereditary non-polyposis colorectal cancer. Br J Surg 1995; 82:1338-40. [PMID: 7489157 DOI: 10.1002/bjs.1800821013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Sixty-one asymptomatic individuals with an affected first-degree relative from five large hereditary non-polyposis colorectal cancer (HNPCC) kindreds were screened by colonoscopy. Neoplasms were found in nine (15 per cent) of 61 individuals on the first screen. Five subjects had a single adenoma while two had two adenomas each. There were two patients (3 per cent) with malignant neoplasms: one with a Dukes B adenocarcinoma and one with synchronous Dukes C adenocarcinomas in the caecum and ascending colon. These findings support the hypothesis that adenomas do not occur in large numbers in HNPCC families but, because of the high malignant conversion rate, biennial colonoscopy with removal of polyps seen is recommended.
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Affiliation(s)
- S E Green
- Department of Surgery, University of Newcastle Upon Tyne, UK
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Vasen HF, Taal BG, Nagengast FM, Griffioen G, Menko FH, Kleibeuker JH, Offerhaus GJ, Meera Khan P. Hereditary nonpolyposis colorectal cancer: results of long-term surveillance in 50 families. Eur J Cancer 1995; 31A:1145-8. [PMID: 7577010 DOI: 10.1016/0959-8049(95)00249-i] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
A surveillance programme comprising either colonoscopy of sigmoidoscopy plus barium enema every 2-3 years was instituted in 50 hereditary nonpolyposis colorectal cancer (HNPCC) families. The families included 238 patients with colorectal cancer (CRC) (mean age at diagnosis: 43.7 years; range: 16-86 years). These patients had 597 first-degree relatives of whom 493 could be traced and 388 (79%) accepted the invitation for screening. The control group were relatives (index patients) with symptomatic CRC. The average follow-up duration was 5 years (1-20 years). Screening led to the detection of adenomas in 33 patients and CRC in 11 patients. Pathological examination revealed 1 Dukes' A, 7 Dukes' B and 3 Dukes' C cancers. In contrast, among the control group 47% had advanced CRC (Dukes' C or distant metastases). The 5-year survival of the screen-detected cases was 87% versus 63% in the control group. Of the 11 CRC cases in the screening group, 4 were detected within 1-4 years after a negative colonic examination. A large proportion of the polyps found in the screening and control groups showed a villous growth pattern and/or a high degree of dysplasia. We conclude that periodic examination of HNPCC families allows the detection of cancer at an earlier stage than in patients not under surveillance. Because of the possibly more aggressive nature of polyps associated with HNPCC, we recommend a screening interval of 1-2 years.
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Affiliation(s)
- H F Vasen
- The Netherlands Foundation, Leiden, The Netherlands
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