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Bonora E, Rizzato C, Diquigiovanni C, Oudot-Mellakh T, Campa D, Vargiolu M, Guedj M, McKay JD, Romeo G, Canzian F, Lesueur F. TheFOXE1locus is a major genetic determinant for familial nonmedullary thyroid carcinoma. Int J Cancer 2013; 134:2098-107. [DOI: 10.1002/ijc.28543] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 09/27/2013] [Indexed: 01/08/2023]
Affiliation(s)
- Elena Bonora
- Unit of Medical Genetics Department of Medical and Surgical Sciences; University of Bologna; Bologna Italy
| | - Cosmeri Rizzato
- Genomic Epidemiology Group; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - Chiara Diquigiovanni
- Unit of Medical Genetics Department of Medical and Surgical Sciences; University of Bologna; Bologna Italy
| | | | - Daniele Campa
- Genomic Epidemiology Group; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - Manuela Vargiolu
- Health Sciences and Technologies Interdepartmental Center for Industrial Research; University of Bologna; Bologna Italy
| | | | - James D. McKay
- Genetic Cancer Susceptibility, International Agency for Research on Cancer (IARC), Lyon; France
| | - Giovanni Romeo
- Unit of Medical Genetics Department of Medical and Surgical Sciences; University of Bologna; Bologna Italy
| | - Federico Canzian
- Genomic Epidemiology Group; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - Fabienne Lesueur
- Genetic Cancer Susceptibility, International Agency for Research on Cancer (IARC), Lyon; France
- INSERM, U900, Institut Curie, Mines ParisTech, 26 rue d'Ulm, 75248 Paris cedex 05; France
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Bevier M, Sundquist K, Hemminki K. Risk of breast cancer in families of multiple affected women and men. Breast Cancer Res Treat 2011; 132:723-8. [PMID: 22179927 DOI: 10.1007/s10549-011-1915-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 12/05/2011] [Indexed: 12/13/2022]
Abstract
Family history of first and second-degree relatives is known to increase the risk for breast cancer. Less data are available on the risks between defined multiple affected close and distant relatives for which the reliability of data may be an issue. Data on affected males are sparse. These questions and the probable genetic models were addressed in this study by means of a nationwide Swedish Family-Cancer Database. We estimated the effect of family history of breast cancer by Poisson regression for women of at least 30 years of age after adjusting for age, period, region, socioeconomic status, number of children, and age at first birth. The results of the study showed that relative risk (RR) for breast cancer was associated with a first degree as well as second-degree family history. Having at least two female affected first-degree relatives increased the RR at least to 2.8, favoring an additive interaction. The risk was increased around ten times in women with both parents affected. When either a father or a mother was affected, the RRs were nearly identical (RR = 1.73 and 1.74, respectively). The RR for a woman increased more when a brother was affected (RR = 2.48) compared to when a sister was affected (RR = 1.87). Having an affected grandmother showed lower familial excess risks than having an affected half sister (RR = 1.27, and 1.26; and RR = 1.39, and 1.50; respectively, for maternal and paternal relatives). We concluded that when both parents were diagnosed with breast cancer, the risk for the daughter was increased tenfold. Having an affected brother showed a somewhat higher risk than having an affected sister. The data suggest that male breast cancer has a higher genetic basis than female breast cancer, which invites further search of the underlying mechanisms.
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Affiliation(s)
- Melanie Bevier
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
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Stadler ZK, Thom P, Robson ME, Weitzel JN, Kauff ND, Hurley KE, Devlin V, Gold B, Klein RJ, Offit K. Genome-wide association studies of cancer. J Clin Oncol 2010; 28:4255-67. [PMID: 20585100 PMCID: PMC2953976 DOI: 10.1200/jco.2009.25.7816] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2009] [Accepted: 04/19/2010] [Indexed: 12/20/2022] Open
Abstract
Knowledge of the inherited risk for cancer is an important component of preventive oncology. In addition to well-established syndromes of cancer predisposition, much remains to be discovered about the genetic variation underlying susceptibility to common malignancies. Increased knowledge about the human genome and advances in genotyping technology have made possible genome-wide association studies (GWAS) of human diseases. These studies have identified many important regions of genetic variation associated with an increased risk for human traits and diseases including cancer. Understanding the principles, major findings, and limitations of GWAS is becoming increasingly important for oncologists as dissemination of genomic risk tests directly to consumers is already occurring through commercial companies. GWAS have contributed to our understanding of the genetic basis of cancer and will shed light on biologic pathways and possible new strategies for targeted prevention. To date, however, the clinical utility of GWAS-derived risk markers remains limited.
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Affiliation(s)
- Zsofia K. Stadler
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
| | - Peter Thom
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
| | - Mark E. Robson
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
| | - Jeffrey N. Weitzel
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
| | - Noah D. Kauff
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
| | - Karen E. Hurley
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
| | - Vincent Devlin
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
| | - Bert Gold
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
| | - Robert J. Klein
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
| | - Kenneth Offit
- From the Clinical Genetics Service and the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, NY, NY; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; and the Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD
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Brandt A, Bermejo JL, Sundquist J, Hemminki K. Age-specific risk of incident prostate cancer and risk of death from prostate cancer defined by the number of affected family members. Eur Urol 2010; 58:275-80. [PMID: 20171779 DOI: 10.1016/j.eururo.2010.02.002] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Accepted: 02/03/2010] [Indexed: 11/15/2022]
Abstract
BACKGROUND The thorough assessment of familial prostate cancer (PCa) risk is as important as ever to provide a basis for clinical counselling and screening recommendations. OBJECTIVE Our aim was to determine the age-specific risks of PCa and the risk of death from PCa according to the number and the age of affected first-degree relatives. DESIGN, SETTING, AND PARTICIPANTS The nationwide Swedish Family-Cancer Database includes a record of >11.8 million individuals and their cancers from 1958 to 2006. All men from the database with identified parents (>3.9 million individuals) were followed between 1961 and 2006. The study included 26 651 PCa patients, of whom 5623 were familial. MEASUREMENTS The age-specific hazard ratios (HRs) of PCa and the HRs of death from PCa were calculated according to the number and age of affected fathers and brothers. RESULTS AND LIMITATIONS The HRs of PCa diagnosis increased with the number of affected relatives and decreased with increasing age. The highest HRs were observed for men <65 yr of age with three affected brothers (HR: approximately 23) and the lowest for men between 65 and 74 yr of age with an affected father (HR: approximately 1.8). The HRs increased with decreasing paternal or fraternal diagnostic age. The pattern of the risk of death from familial PCa was similar to the incidence data. CONCLUSIONS The present results should guide clinical counselling and demonstrate the vast increases in risk when multiple first-degree relatives are affected.
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Affiliation(s)
- Andreas Brandt
- Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, Heidelberg, Germany.
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Germline mutations and polymorphisms in the origins of cancers in women. JOURNAL OF ONCOLOGY 2010; 2010:297671. [PMID: 20111735 PMCID: PMC2810468 DOI: 10.1155/2010/297671] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2009] [Accepted: 11/14/2009] [Indexed: 12/18/2022]
Abstract
Several female malignancies including breast, ovarian, and endometrial cancers can be characterized based on known somatic and germline mutations. Initiation and propagation of tumors reflect underlying genomic alterations such as mutations, polymorphisms, and copy number variations found in genes of multiple cellular pathways. The contributions of any single genetic variation or mutation in a population depend on its frequency and penetrance as well as tissue-specific functionality. Genome wide association studies, fluorescence in situ hybridization, comparative genomic hybridization, and candidate gene studies have enumerated genetic contributors to cancers in women. These include p53, BRCA1, BRCA2, STK11, PTEN, CHEK2, ATM, BRIP1, PALB2, FGFR2, TGFB1, MDM2, MDM4 as well as several other chromosomal loci. Based on the heterogeneity within a specific tumor type, a combination of genomic alterations defines the cancer subtype, biologic behavior, and in some cases, response to therapeutics. Consideration of tumor heterogeneity is therefore important in the critical analysis of gene associations in cancer.
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Kilpivaara O, Mukherjee S, Schram AM, Wadleigh M, Mullally A, Ebert BL, Bass A, Marubayashi S, Heguy A, Garcia-Manero G, Kantarjian H, Offit K, Stone RM, Gilliland DG, Klein RJ, Levine RL. A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat Genet 2009; 41:455-9. [PMID: 19287384 PMCID: PMC3676425 DOI: 10.1038/ng.342] [Citation(s) in RCA: 272] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2009] [Accepted: 02/02/2009] [Indexed: 02/03/2023]
Abstract
Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2(V617F)) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis, there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci. We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2(V617F)-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2(V617F) is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.
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Affiliation(s)
- Outi Kilpivaara
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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