The present study aimed to clarify the clinicopathological features, including the level of p53 protein expression and BRCA mutations, of primary fallopian tube cancer (PFTC) in Japanese women.

A multicenter clinical survey was conducted at three Japanese institutions. Clinical data in patients with PFTC between 1998 and 2016 were collected. Immunohistochemical staining of p53 and BRCA mutation analysis by exome sequence using paraffin-embedded surgical resected specimens were performed.

A total of 40 patients with PFTC were enrolled in the study. The median age was 58 years (range: 38-78 years); 31 patients were menopausal. Thirty-four (85.0%) patients were diagnosed with serous adenocarcinoma (high grade, 33; low grade, 1). PFTC was classified into ampulla type, fimbriae type and undeterminable type by tumor-occupying lesion; ampulla type and fimbriae type occurred with the same frequency. Among 30 patients with high-grade serous adenocarcinoma, 6 patients showed germline mutations of BRCA1 (stop-gain 4 and frameshift deletion 2) and 2 patients showed germline mutation of BRCA2 (stop-gain 1 and frameshift deletion 1). However, only 1 patient had familial history of breast or ovarian cancer. Patients with BRCA mutations in the germline were frequently observed in ampulla type and FIGO stage I/II cancers, but no significant difference in the frequency of p53 overexpression and overall survival was observed.

Among Japanese patients with PFTC, 26.7% presented with BRCA mutations in the germline. Additionally, p53 was important for the carcinogenesis in fallopian tubes, independent of the specific BRCA mutation.

As our technological capacities improve, genomic testing is increasingly integrating into patient care. The field of clinical hematology is no exception. Genomic testing carries great promise, but several ethical issues must be considered whenever such testing is performed. This review addresses these ethical considerations, including issues surrounding informed consent and the uncertainty of the results of genomic testing; the challenge of incidental findings; and possible inequities in access to and benefit from such testing. Genomic testing is likely to transform the practice of both benign and malignant hematology, but clinicians must carefully consider these core ethical issues in order to make the most of this exciting and evolving technology.

Cancers of the reproductive organs (i.e., ovaries, uterus and testes), like other cancers, occur as a result of a multi-stage interaction of genetic and environmental factors. A small proportion of cancers of the reproductive organs occur as part of a recognised cancer syndrome, as a result of inheritance of mutations in highly penetrant cancer susceptibility genes (e.g., BRCA1, BRCA2, MLH1 or MSH2). Recognition of individuals and families with inherited cancer predisposition syndromes and individuals at high risk due to familial cancer clustering is fundamentally important for the management and treatment of the current cancer and for future prevention of further cancers for the individual and their extended family.

Of all malignant neoplasias affecting women, breast cancer has the highest incidence rate in Brazil. The objective of the present study was to determine the frequency of genetic modifications in families with medium and high risk for breast and ovarian cancer from different regions of Brazil. An exploratory, descriptive study was carried out on the prevalence of the BRCA1 and BRCA2 mutations in case series of high-risk families for breast and/or ovarian cancer. After heredogram construction, a blood sample was taken and DNA extraction was performed in all index cases. The protein truncation test was used to screen for truncated mutations in exon 11 of the BRCA1 gene and in exons 10 and 11 of the BRCA2 gene. Of the 612 individuals submitted to genetic testing, 21 (3.4%), 19 women and 2 men, had mutations in the BRCA1 or BRCA2 genes. Of the 19 BRCA1 mutations found in the 18 participants, 7 consisted of ins6kb mutations, 4 were 5382insC, 3 were 2156delGinsCC, 2 were 185delAG, 1 was C1201G, 1 was C3522T, and 1 was 3450del4. With respect to the BRCA2 gene, 3 mutations were found: 5878del10, 5036delA and 4232insA (one case each). The prevalence of germline mutations in the BRCA1 and BRCA2 genes found in the present study was lower than reported by other studies on high-risk Brazilian populations. The inclusion of individuals with medium risk may have contributed to the lower prevalence observed.

A significant portion of ovarian cancer (OC) cases is caused by germ-line mutations in BRCA1 or BRCA2 genes. BRCA testing is cheap in populations with founder effect and therefore recommended for all patients with OC diagnosis. Recurrent mutations constitute the vast majority of BRCA defects in Russia, however their impact in OC morbidity has not been yet systematically studied. Furthermore, Russian population is characterized by a relatively high frequency of CHEK2 and NBS1 (NBN) heterozygotes, but it remains unclear whether these two genes contribute to the OC risk.

The study included 354 OC patients from 2 distinct, geographically remote regions (290 from North-Western Russia (St.-Petersburg) and 64 from the south of the country (Krasnodar)). DNA samples were tested by allele-specific PCR for the presence of 8 founder mutations (BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT, CHEK2 1100delC, CHEK2 IVS2+1G>A, NBS1 657del5). In addition, literature data on the occurrence of BRCA1, BRCA2, CHEK2 and NBS1 mutations in non-selected ovarian cancer patients were reviewed.

BRCA1 5382insC allele was detected in 28/290 (9.7%) OC cases from the North-West and 11/64 (17.2%) OC patients from the South of Russia. In addition, 4 BRCA1 185delAG, 2 BRCA1 4153delA, 1 BRCA2 6174delT, 2 CHEK2 1100delC and 1 NBS1 657del5 mutation were detected. 1 patient from Krasnodar was heterozygous for both BRCA1 5382insC and NBS1 657del5 variants.

Founder BRCA1 mutations, especially BRCA1 5382insC variant, are responsible for substantial share of OC morbidity in Russia, therefore DNA testing has to be considered for every OC patient of Russian origin. Taken together with literature data, this study does not support the contribution of CHEK2 in OC risk, while the role of NBS1 heterozygosity may require further clarification.

The objective of the study was to compare chemotherapy response and survival of patients with advanced primary peritoneal carcinoma (PPC) vs those with epithelial ovarian carcinoma (EOC).

From 1998 to 2004, 43 PPC patients were identified and matched to 129 patients with International Federation of Gynecology and Obstetrics stage IIIC-IV EOC by criteria abstracted from medical records. Primary endpoints were chemotherapy response, platinum resistance, progression-free survival (PFS), and overall survival (OS).

All patients received primary platinum-taxane chemotherapy. There was no significant difference in achieving a clinical complete response. PPC patients were more likely to be platinum resistant at 6 months and had significantly impaired PFS and OS. After multivariate analysis, PPC was independently associated with a worse prognosis for both survival endpoints.

PPC was associated with a similar initial response but a higher rate of platinum resistance and shorter PFS and OS. Consideration of these results may be useful for patient counseling, trial stratification, and molecular comparisons.

The incidence of breast cancer (BC) in Arab women is lower compared to the incidence in the Jewish population in Israel; still, it is the most common malignancy among Arab women. There is a steep rise in breast cancer incidence in the Arab population in Israel over the last 10 years that can be attributed to life style changes. But, the younger age of BC onset in Arab women compared with that of the Jewish population is suggestive of a genetic component in BC occurrence in that population.

We studied the family history of 31 women of Palestinian Arab (PA) origin affected with breast (n = 28), ovarian (n = 3) cancer. We used denaturing high performance liquid chromatography (DHPLC) to screen for mutations of BRCA1/2 in 4 women with a personal and family history highly suggestive of genetic predisposition.

A novel BRCA1 mutation, E1373X in exon 12, was found in a patient affected with ovarian cancer. Four of her family members, 3 BC patients and a healthy individual were consequently also found to carry this mutation. Of the other 27 patients, which were screened for this specific mutation none was found to carry it.

We found a novel BRCA1 mutation in a family of PA origin with a history highly compatible with BRCA1 phenotype. This mutation was not found in additional 30 PA women affected with BC or OC. Therefore full BRCA1/2 screening should be offered to patients with characteristic family history. The significance of the novel BRCA1 mutation we identified should be studied in larger population. However, it is likely that the E1373X mutation is not a founder frequent mutation in the PA population.

In this study, the genetic polymorphisms associated with breast cancer in southern Taiwan were investigated. Two categories of genes were analyzed: (1) BRCA1, BRCA2, and Rad51, the DNA repair factors involved in homologous recombinational repair; and (2) CYP1A1, COMT, GST, and NAT2, the xenobiotic-metabolizing enzymes (XME) involved in estrogen metabolism. We found that the number of deletions and/or mutations in the GST genes was highly correlated with the occurrence of breast cancer. These data suggest that the GST enzymes, which detoxify the catechol estrogen quinones, are important target molecules for screening in populations at high risk of breast cancer.

Using a specially constructed questionnaire, the effect of BRCA test results for the Jewish founder mutations and genetic counseling on women's attitudes towards and acceptance of preventive surgeries was evaluated. The subjects consisted of 99 women 43% of whom were found to be carriers as opposed to 57%--non-carriers. After learning of their genetic status, 94% of the carriers and 28% of the non-carriers declared having positively considered the option of preventive oophorectomy. However, only about 25% of the carriers and 4.5% of the non-carriers had positively considered the option of preventive mastectomy. In practice, 78% of the carriers and 18% of the non-carriers who proved to be eligible for these procedures underwent preventive oophorectomy compared with 19% of carriers and 1.8% of non-carriers who underwent preventive mastectomy. Almost all carriers, as well as a majority of the non-carriers, who finally opted for the preventive surgeries did so after learning the result of their genetic test. The different attitudes toward the two surgeries were found to be based on varied beliefs regarding the two procedures. Preventive oophorectomy was perceived as being more acceptable to women than preventive mastectomy both from an attitudinal as well as practical aspect. These differences may be the result of cultural factors, of women's trust in the ability of screening tests to prevent morbidity and/or mortality, of the effect of the surgeries on body image and of different counseling protocols.

Mutation detection plays an increasingly significant role in clinical diagnostic testing, posing formidable challenges for laboratories. The expanding indications for clinical molecular testing and the nuances of interpreting test results are discussed. Methods for screening mutation detection platforms and monitoring assay reliability are presented, and results of platform comparisons are described. The potential for irrevocable medical interventions following a positive mutation analysis is highlighted to stress the imperative for accuracy in mutation detection and vigilance in the clinical arena.

Russian Jews, particularly men, have a large mortality advantage compared with the general Russian population. We consider possible explanations for this advantage using data on 445,000 deaths in Moscow, 1993-95. Log-linear analysis of the distribution of deaths by sex, age, ethnic group, and cause of death reveals a relatively high concentration of endogenous causes and a relatively low concentration of exogenous and behaviourally induced causes among Jews. There is also a significant concentration of deaths from breast cancer among Jewish women. Mortality estimates using the 1994 micro-census population as the denominator reveal an 11-year Russian-Jewish gap in the life expectancy of males at age 20, but only a 2-year life-expectancy gap for women. Only 40 per cent of the Russian-Jewish difference for men, but the entire difference for women, can be eliminated by adjustment for educational differences between the two ethnic groups. Similarities with other Jewish populations and possible explanations are discussed.

Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. Approximately 80%-90% of hereditary breast cancer cases are caused by mutations in the BRCA1 and BRCA2 genes. Other important clinical genetic predispositions include Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia. The key to identifying women who are at risk for a hereditary breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus, but there are limitations to these models. Other quantitative models predict the likelihood that a patient is carrying a mutated gene. Genetic testing is available at selected laboratories for each of the hereditary syndromes described, and there are three possible outcomes to testing. These outcomes and their management implications are described in detail. Clinical management options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery. Application of these principles can reduce morbidity in women with genetic predispositions to breast cancer.

In recent years, testing for cancer susceptibility genes has entered the clinical setting. The practicing physician needs to be familiar with this evolving area of medicine to be able to counsel and/or refer high-risk patients such as those with a strong personal or family history of cancer. The following is a review of the clinically pertinent information regarding hereditary breast and ovarian cancers resulting from mutations in BRCA genes. A special emphasis is placed on the different options available for BRCA mutation carriers, because many interventions have already proven to be highly efficacious. The increased risk of cancer seen in hereditary nonpolyposis colorectal cancer (HNPCC) is not part of this review but is mentioned briefly.

Our recent study determined the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma (USPC). The purpose of this study was to determine the incidence of these mutations in an enlarged series of USPC.

We screened DNA from 27 women with USPC for BRCA1 and BRCA2 germline mutations common in the Jewish population (BRCA1-185delAG and 5382 insC,BRCA2-6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity (LOH) at the appropriate loci.

Women (20) were of Jewish Ashkenazi origin and seven were non-Ashkenazi. Four of 20 (20%) Ashkenazi women were carriers of germline mutations: three 185delAG mutation and one 5382insC mutation. All carriers had strong family histories of breast-ovarian carcinoma. Seven out of 20 (35%) women had been diagnosed for breast carcinoma before diagnosis of USPC. Family histories of 12 women (60%) showed at least one first-degree relative with breast, ovarian, or colon carcinoma. Loss of heterozygosity analysis found a loss of the wild-type BRCA1 allele in three of the four primary uterine tumors that were examined.

Our findings further support our previous published data suggesting a high incidence of BRCA carriers among USPC Ashkenazi Jewish patients. The loss of heterozygosity in the tumor tissue of carriers coupled with the high frequency of patient and family history of breast and ovarian malignancies suggest that USPC might be part of the manifestation of familial breast-ovarian cancer in Ashkenazi Jewish patients.

Women from families with multiple cases of breast and ovarian cancer, specifically those who carry cancer-associated mutations of BRCA1 or BRCA2 are at increased life-time risk for peritoneal carcinoma, even after previous surgery to remove the ovaries, fallopian tubes and uterus. Hereditary breast-ovarian cancer (HBOC) syndrome and the associated BRCA1 and BRCA2 mutations are particularly prevalent in women of Jewish lineage, and specific BRCA1 and BRCA2 germline mutations have been linked with peritoneal carcinoma and HBOC syndrome in Jewish populations, especially those of Ashkenazi descent. This review presents the currently available data and looks forward toward further and better understanding of peritoneal carcinoma in women with inherited susceptibility. Over 90% of peritoneal cancer in patients from HBOC syndrome kindreds and associated with BRCA1 and BRCA2 mutations are serous carcinomas, which is equivalent with the proportion of ovarian cancers that are serous carcinomas in similar patients. The best indications are that while many peritoneal carcinomas in genetically susceptible women may arise directly from malignant transformation of the peritoneum, others might represent metastases from primary ovarian or fallopian tube carcinomas. Although the incidence of borderline ovarian tumors may not be increased in HBOC syndrome kindreds and those who carry cancer-associated BRCA1 and BRCA2 mutations, these individuals could be susceptible to malignant transformation of borderline lesions of the ovaries and peritoneum. Moreover, recent reports raise the question of possibly increased risk in Jewish carriers of germline BRCA1 mutations for uterine papillary serous carcinoma, which could be the source of metastasis to the peritoneum in some cases. The penetrance of cancer-associated BRCA1 mutations for ovarian cancer is estimated to be 11%-54%, and for BRCA2 mutations the penetrance for ovarian cancer is 11%-23%. So far, available screening methods appear to be insufficient for early detection of many ovarian cancers. Prophylactic oophorectomy has been found to reduce the risk for ovarian cancer in women from HBOC kindreds and those who carry cancer-associated BRCA1 and BRCA2 mutations, leaving a residual risk for peritoneal carcinomatosis of well less than 5%. Therefore, surgical removal of the ovaries, fallopian tubes and uterus, after child-bearing has been completed and by early in the fifth decade of life, are appropriate prophylactic procedures in women whose genetic susceptibility puts them at increased risk for cancers of mullerian tract origin, including ovarian and fallopian tube carcinomas and possibly serous carcinoma of the uterus. Hysterectomy, as well as salpingo-oophorectomy, removes the gynecologic organs targeted for malignant transformation in genetically susceptible women and simplifies decisions regarding hormone replacement therapy and chemical prophylaxis and treatment of breast cancer. Unless a transabdominal operative approach is otherwise indicated, laparoscopic-assisted transvaginal techniques are well suited for intra-abdominal exploration, cytology, biopsies and prophylactic salpingo-oophorectomy and hysterectomy in women with hereditary susceptibility to gynecologic cancer.

The aims of this study were to determine the incidence of BRCA mutations among Ashkenazi Jewish patients with fallopian tube carcinoma (FTC) or primary peritoneal carcinoma (PPC), to study the clinicopathologic features of these cancers, and to estimate the risks of these cancers in association with a BRCA mutation.

A retrospective review at two institutions identified 29 Jewish patients with FTC and 22 Jewish patients with PPC. These patients were genotyped for the three Ashkenazi Jewish BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). Surgical and pathologic information, family history, and survival data were obtained from hospital records. All statistical tests were two sided.

Germline BRCA mutations were identified in five of 29 patients with FTC (17%) and nine of 22 patients with PPC (41%). Mutation carriers had a younger mean age at diagnosis than patients without a mutation (60 v 70 years; P =.002). The overall median survival was 148 months for mutation carriers and 41 months for patients without a mutation (P =.04). For BRCA mutation carriers, the lifetime risks of FTC and PPC were 0.6% and 1.3%, respectively.

Substantial proportions of Ashkenazi Jewish patients with FTC or PPC are BRCA mutation carriers. Patients with BRCA-associated FTC or PPC are younger at diagnosis and have improved survival compared with patients without a BRCA mutation. Although the lifetime risks of FTC or PPC for patients with BRCA heterozygotes are greater than those for the general population, the absolute risks seem relatively low.

The objective was to evaluate the prevalence of BRCA1/2 mutations in selected categories of ovarian cancer patients in Israel.

Blood samples and specimens of ovarian tumors were obtained in the course of a national case control study of women with ovarian cancer in Israel. Eight hundred ninety-six patients with epithelial ovarian cancer, 40 cases with nonepithelial ovarian cancer, and 68 with primary peritoneal cancer were tested for the BRCA mutations. Analysis of the three common BRCA mutations in Israel (185delAG, 5382insC in BRCA1, and 6174delT in BRCA2) was done using a multiplex polymerase chain reaction assay. A multivariate logistic regression model was used to assess the association of mutation carrier status and other factors (age, origin, family history, and clinical variables).

Of the 779 invasive epithelial ovarian cancer cases, 29.4% were mutation carriers. The prevalence of the mutations was higher among women below age 60 and in more advanced cases. The prevalence was low in mucinous tumors. There was almost a twofold excess of mutations among women with positive family history (45.7%), but still 26.5% of the family history negative cases were carriers. As expected, we found a higher rate of mutation carriers among the Ashkenazi group (34.2%) and 55% among Ashkenazi women with positive family history. No subjects born in North Africa were mutation positive.

BRCA mutations are strongly associated with ovarian cancer and they are present in variable rates in distinct age, ethnic, and histopathologic categories.

Breast cancer risk assessment provides an estimation of disease risk that can be used to guide management for women at all levels of risk. In addition, the likelihood that breast cancer risk is due to specific genetic susceptibility (such as BRCA1 or BRCA2 mutations) can be determined. Recent developments have reinforced the clinical importance of breast cancer risk assessment. Tamoxifen chemoprevention as well as prevention studies such as the Study of Tamoxifen and Raloxifene are available to women at increased risk of developing breast cancer. In addition, specific management strategies are now defined for BRCA1 and BRCA2 mutation carriers. Risk may be assessed as the likelihood of developing breast cancer (using risk assessment models) or as the likelihood of detecting a BRCA1 or BRCA2 mutation (using prior probability models). Each of the models has advantages and disadvantages, and all need to be interpreted in context. We review available risk assessment tools and discuss their application. As illustrated by clinical examples, optimal counseling may require the use of several models, as well as clinical judgment, to provide the most accurate and useful information to women and their families.

The characterization of specific genes responsible for the hereditary risk of common cancers has enabled the development of clinical tests designed to identify at-risk individuals and to significantly improve the clinical outcome of such individuals. Two of the most important syndromes associated with a hereditary risk of cancer in women are hereditary breast and ovarian cancer, resulting from the BRCA1 and BRCA2 genes, and hereditary non-polyposis colorectal cancer, caused primarily by the MLH1 and MSH2 genes. As testing for the hereditary risk of breast, ovarian, endometrial and colorectal cancer enters the clinical mainstream, physicians responsible for the health care of women are increasingly required to assess and provide guidance to healthy patients with a strong family history, cancer survivors who may be at risk of a second cancer and women who discover that a family member carries a specific mutation identified through genetic testing. Obstetricians and gynaecologists must therefore become familiar with the principles of assessing the family history for specific hereditary cancer syndromes, with the appropriate use of tests to confirm such syndromes and with the management options for women who have inherited a greatly increased risk of cancer.

Successful investigation of common diseases requires advances in our understanding of the organization of the genome. Linkage disequilibrium provides a theoretical basis for performing candidate gene or whole-genome association studies to analyze complex disease. However, to constructively interrogate SNPs for these studies, technologies with sufficient throughput and sensitivity are required. A plethora of suitable and reliable methods have been developed, each of which has its own unique advantage. The characteristics of the most promising genotyping and polymorphism scanning technologies are presented. These technologies are examined both in the context of complex disease investigation and in their capacity to face the unique physical and molecular challenges (allele amplification, loss of heterozygosity and stromal contamination) of solid tumor research.

A family history of ovarian cancer confers an increased risk of ovarian cancer. We review the literature quantifying the familial risks associated with ovarian cancer and assess the evidence that the familial clustering of ovarian cancer is genetically determined. We then describe the known high-penetrance genes, the ovarian cancer risks attached to them and their contribution to ovarian cancer in families and in the general population. The evidence for the existence of other ovarian cancer genes is then considered.

Ovarian cancer is a clinically important cancer in Turkey. The contribution of BRCA1 and BRCA2 to ovarian cancer in Turkish patients has not previously been described. In this study we investigated the presence of BRCA1 and BRCA2 mutations in 102 consecutively ascertained, hospital-based, ovarian cancer cases. Four out of 15 (26.7%, 95% confidence interval (CI), 7.8%-55.1%) familial cases were found to carry mutations in BRCA1. Thirteen of the 87 (14.9%, 95% CI, 7.5%-22.4%) non-familial cases had BRCA1 and BRCA2 mutations, six in BRCA1, and seven in BRCA2. We have further studied the non-familial ovarian cancer cases to determine which subgroups have a likelihood of carrying clinically important mutations. Our study shows that those Turkish ovarian cancer patients with serous histopathology harbor a high proportion of mutations (12/58, 20.7%, 95% CI, 10.3%-31.1%) compared to all non-familial cases (14.9%) regardless of pathology. Within the serous sub-group, those that were also diagnosed below age 50 have an even greater percentage of mutations (8/28, 28.6%, 95% CI, 11.8%-45.3%). Our findings demonstrate that a substantial proportion of Turkish ovarian cancer patients, both with and without a family history, carry BRCA1 and BRCA2 mutations, demonstrating the importance of BRCA1 and BRCA2 in the development of ovarian cancer in this population.

A great number of physiological and anthropological studies have investigated Andean and Himalayan populations native to high altitude (HA). A non-scientific survey of the extant literature reveals a relatively liberal tradition of inferring genetic (evolutionary) adaptation to HA in these groups, often based on limited evidence and/or based on study designs insufficient to fully address the issue. Rather than review the evidence for or against genetic adaptation, and in order to provide some perspective, this paper will review relevant conceptual, methodological, and statistical issues that are germane to the study of HA native human groups. In particular, focus will be on the limitations of the most common research approach which bases evolutionary inference on the comparison of phenotypic mean differences between highland and lowland native populations. The migrant study approach is discussed, as is a relatively new approach based on genetic admixture in hybrid populations.

Sequencing an amplification product of the terminal segment of BRCA2 exon 11 showed apparent homozygosity for the 6174delT mutation in two healthy sisters. Subsequent sequencing of an alternate overlapping amplicon revealed the presence of the 5972C >T polymorphism, which is within the standard upstream amplification primer. This mismatch was responsible for the failure to amplify the normal (5972T) allele in both sisters who were heterozygous for the 6174delT mutation. Though the unexpected finding of apparent homozygosity for the 6174delT mutation prompted re-evaluation of the assay, the potential for false negative results due to masking of a mutation-bearing allele by such a circumstance should be a cautionary note for the testing and also in the interpretation of the results published under such assay conditions.

Ovarian cancer is the fifth most common cause of cancer death in women in Western countries and family history is one of the strongest known risk factors. Approximately 5 to 13% of all ovarian cancer cases are caused by the inheritance of cancer predisposing genes with an autosomal pattern of transmission. The inherited fraction of ovarian cancer may differ between populations. Based on analysis of familial ovarian cancer pedigrees and other epidemiological studies, three hereditary ovarian cancer syndromes have been defined. The identification of the genes responsible for most hereditary ovarian cancers has open a new area of early detection methods and preventive procedures specifically dedicated to women identified as carrying ovarian cancer predisposing genes. Predictive oncology is best performed by a dedicated unit with professionals aware of all the issues surrounding genetic testing.

To assess the characteristics that correlate best with the presence of mutations in BRCA1 and BRCA2 in individuals tested in a clinical setting.

The results of 10,000 consecutive gene sequence analyses performed to identify mutations anywhere in the BRCA1 and BRCA2 genes (7,461 analyses) or for three specific Ashkenazi Jewish founder mutations (2,539 analyses) were correlated with personal and family history of cancer, ancestry, invasive versus noninvasive breast neoplasia, and sex.

Mutations were identified in 1,720 (17.2%) of the 10,000 individuals tested, including 968 (20%) of 4,843 women with breast cancer and 281 (34%) of 824 with ovarian cancer, and the prevalence of mutations was correlated with specific features of the personal and family histories of the individuals tested. Mutations were as prevalent in high-risk women of African (25 [19%] of 133) and other non-Ashkenazi ancestries as those of European ancestry (712 [16%] of 4379) and were significantly less prevalent in women diagnosed before 50 years of age with ductal carcinoma in situ than with invasive breast cancer (13% v 24%, P =.0007). Of the 74 mutations identified in individuals of Ashkenazi ancestry through full sequence analysis of both BRCA1 and BRCA2, 16 (21.6%) were nonfounder mutations, including seven in BRCA1 and nine in BRCA2. Twenty-one (28%) of 76 men with breast cancer carried mutations, of which more than one third occurred in BRCA1.

Specific features of personal and family history can be used to assess the likelihood of identifying a mutation in BRCA1 or BRCA2 in individuals tested in a clinical setting.

Knowledge of inherited and sporadic mutations in known and candidate cancer genes may influence clinical decisions. We have developed a mutation scanning method that combines thermostable EndonucleaseV (Endo V) and DNA ligase. Variant and wild-type PCR amplicons are generated using fluorescently labeled primers, and heteroduplexed. Thermotoga maritima (Tma) EndoV recognizes and primarily cleaves heteroduplex DNA one base 3' to the mismatch, as well as nicking matched DNA at low levels. Thermus species (Tsp.) AK16D DNA ligase reseals the background nicks to create a highly sensitive and specific assay. The fragment mobility on a DNA sequencing gel reveals the approximate position of the mutation. This method identified 31/35 and 8/8 unique point mutations and insertions/deletions, respectively, in the p53, VHL, K-ras, APC, BRCA1, and BRCA2 genes. The method has the sensitivity to detect K-ras mutations diluted 1 : 20 with wild-type DNA, a p53 mutation in a 1.7 kb amplicon, and unknown p53 mutations in pooled DNA samples. EndoV/Ligase mutation scanning combined with PCR/LDR/Universal array proved superior to automated DNA sequencing for detecting p53 mutations in colon tumors. This technique is well suited for scanning low-frequency mutations in pooled samples and for analysing tumor DNA containing a minority of the unknown mutation.

Many physiological and anthropological studies have investigated the unique Andean and Himalayan populations that have resided for many hundreds of generations at high altitude (HA). A nonscientific survey of the extant literature reveals a relatively liberal tradition of inferring genetic (evolutionary) adaptation to HA in these groups, often based on limited evidence and/or based on study designs insufficient to fully address the issue. In order to provide some perspective, I review relevant methodological issues that should be considered before evolutionary inference is made. On the whole, this paper takes a conservative stance and cautions against evolutionary inference based on the serious limitations of currently applied research approaches.

The lack of information regarding the effectiveness of screening strategies, chemoprevention, or surgical prophylaxis, and the uncertainty regarding penetrance and risk modification has led many experts to recommend that genetic testing for BRCA1, BRCA2, and other cancer susceptibility genes be performed only in a research setting. Patients, however, are likely to increasingly request access to genetic testing and deserve up-to-date counseling about recent advancements in our knowledge. The primary care physician should concentrate on identifying women likely to be at high-risk for cancer for further referral, allowing the cancer genetics specialist to track down medical records, clarify the pedigree, discuss genetic testing, and provide access to the appropriate cancer specialist to discuss risk reduction.

To compare the clinical characteristics and survival of Ashkenazi Jewish ovarian cancer patients with and without BRCA1 and BRCA2 mutations.

An unselected series of 118 Ashkenazi Jewish ovarian cancer patients were screened for the three common founder mutations in BRCA1 and BRCA2. Patient survival and other clinical characteristics of the tumours were compared in patients with BRCA1 or BRCA2 mutations and those without mutations.

Twenty-seven individuals with invasive carcinomas were found to have mutations (14 with 185delAG and one with 5382insC in BRCA1 and 12 with 6174delT in BRCA2). No mutations were identified in the 20 patients with borderline tumours. For the invasive carcinomas, there was a survival advantage for BRCA1 and BRCA2 patients compared to patients without mutations, though the differences were not statistically significant. There were no significant differences in the histopathological characteristics of the tumours between the patient groups.

These results are similar to those of other studies and suggest that ovarian cancer in BRCA1 and BRCA2 mutation carriers may have a distinct clinical behaviour.

In the past, all women with a family history of breast or ovarian cancer were considered to be at increased risk of cancer themselves. The discovery of BRCA1 and BRCA2 demonstrated that susceptibility to breast and ovarian cancer can be inherited by women as a single-gene autosomal dominant disorder. For such women, evaluation of family history is an important screening tool to identify the possibility of hereditary cancer risk but only genetic testing can provide definitive, individualized risk assessment. Women who have inherited mutations in BRCA1 or BRCA2 now have several medical management options to address their increased risk of cancer. A well-educated community of health care providers and patients can use hereditary risk assessment, including genetic testing, to improve health care.

To investigate whether polymorphic p53 and WAF1 alleles are associated with clinical, demographic and histopathological features and BRCA mutation in women with ovarian cancer.

A cross-sectional study.

Two hundred and twenty-one nonselected Israeli women with epithelial ovarian cancer.

DNA was analysed for known polymorphisms in intron 3 (a 16 nucleotide single repeat) and intron 6 (a G to A change at nucleotide 13,494) of the p53 gene, the S31R polymorphism in the WAF1 gene, and for three predominant Jewish mutations in the BRCA genes (185delAG and 5382insC in BRCA1, and 6174delT in BRCA2).

The rate of polymorphic p53 and WAF1 alleles and their association with BRCA mutation, ethnic origin, age and stage at diagnosis, and family history of cancer.

Of the tested women, 72 (32.6%) were either BRCA1 (n = 57) or BRCA2 (n = 15) mutation carriers. Sixty-eight of 213 (31.9%) were heterozygous for intron 3 polymorphism, 67/193 (34.7%) for intron 6 polymorphism, and 22/154 (14.3%) for S31R of the WAF1 gene. The p53 and WAF1 polymorphism rate did not differ between BRCA mutation carriers and noncarriers. No significant association between specific p53 or WAF1 genotypes, and clinical, histopathological or demographic variables was observed.

In Jewish-Israeli women with sporadic and familial ovarian cancer, p53 or WAF1 polymorphisms do not seem to affect the phenotype.

The identification of the BRCA genes, and their possible etiologic relationship with various forms of inherited cancer, has been recognized universally as a cornerstone in the search of cancer's genetic susceptibility. Female BRCA gene mutation carriers are found to carry an increased risk of developing breast or ovarian cancer and to a lesser degree, colon cancer, and male BRCA mutation carriers are also related to an increased risk of breast, colon, or prostate cancer. Although genetic testing promises a possible future presymptomatic determination and treatment of women who are genetically susceptible to cancer, current data reveal certain dilemmas and uncertainties regarding our ability to interpret the results from testing and offer effective management options. In addition, several complex ethical, legal, and social issues have been revealed with the advent of this new information, which also confirm the need for additional research regarding the most effective use of this genetic information and for the establishment of appropriate clinical management strategies.

Breast and ovarian cancers account for approximately 210000 newly diagnosed cases per year. More than half a million American women are estimated to be carriers of a breast cancer susceptibility gene. The purpose of this study was to assess the association of characteristics such as, age at diagnosis, race/ethnicity and family history of cancer with inherited BRCA1 mutations in a population-based sample of breast and ovarian cancer cases. No selection was made by race, age at diagnosis or positive family history of breast or ovarian cancer. The population under study was all breast cancer cases diagnosed in Orange County, CA, during the 1-year period beginning 1 March 1994 and all ovarian cancer cases diagnosed in Orange County during the 2-year period beginning 1 March 1994. This report focuses on the first consecutively ascertained 802 participating probands enrolled in the study, of which 9 were male breast cancer probands, 673 were female breast cancer probands and 120 were ovarian cancer probands. We observed 11 BRCA1 mutations or 1.6% (95% CI: 0.8-2.9) among the 673 female breast cancer probands and 4 BRCA1 mutations or 3.3% (95% CI: 0.8-8. 3) among the 120 ovarian cancer probands. No BRCA1 mutations were identified among the 98 non-white breast and ovarian cancer probands. The prevalence of BRCA1 mutations in non-Hispanic-white breast cancer cases below the age of 50 years was 2%. Positive family history of breast or ovarian cancers was significantly associated with BRCA1 mutation status among breast cancer probands. Similarly, positive family history of breast or ovarian cancer was significantly associated with BRCA1 mutation status among the ovarian cancer probands. In summary, we present results on the prevalence of BRCA1 mutations in a significantly larger sample of population-based breast and ovarian cancer cases than previously reported. The results indicate that, using a conservative approach to targeted genotyping of BRCA1, the frequency of mutations was consistent with those reported using similar methods of population-based case ascertainment.

Although most solid tumors are treated surgically, determining the genetic changes present in the tumor of an individual patient is becoming increasingly important for managing the oncology patient. Our knowledge of the genetic alterations that characterize and predispose to solid tumors continues to expand. Concurrently, the advent of newer technologies such as DNA chips has the potential to enable a more rapid and comprehensive assessment of these changes. The ultimate goal of this new information and technology is to provide sensitive and specific tests that reduce unnecessary procedures and optimize therapy. This review addresses the utility of molecular testing in evaluating cancer. A review of the current technology and hereditary cancer syndromes is also presented.

Ovarian cancer is a component of the autosomal-dominant hereditary breast-ovarian cancer syndrome and may be due to a mutation in either the BRCA1 or BRCA2 genes. Two mutations in BRCA1 (185delAG and 5382insC) and one mutation in BRCA2 (6174delT) are common in the Ashkenazi Jewish population. One of these three mutations is present in approximately 2% of the Jewish population. Each mutation is associated with an increased risk of ovarian cancer, and it is expected that a significant proportion of Jewish women with ovarian cancer will carry one of these mutations. To estimate the proportion of ovarian cancers attributable to founding mutations in BRCA1 and BRCA2 in the Jewish population and the familial cancer risks associated with each, we interviewed 213 Jewish women with ovarian cancer at 11 medical centers in North America and Israel and offered these women genetic testing for the three founder mutations. To establish the presence of nonfounder mutations in this population, we also completed the protein-truncation test on exon 11 of BRCA1 and exons 10 and 11 of BRCA2. We obtained a detailed family history on all women we studied who had cancer and on a control population of 386 Ashkenazi Jewish women without ovarian or breast cancer. A founder mutation was present in 41.3% of the women we studied. The cumulative incidence of ovarian cancer to age 75 years was found to be 6.3% for female first-degree relatives of the patients with ovarian cancer, compared with 2.0% for the female relatives of healthy controls (relative risk 3.2; 95% CI 1.5-6.8; P=.002). The relative risk to age 75 years for breast cancer among the female first-degree relatives was 2.0 (95% CI 1.4-3.0; P=.0001). Only one nonfounder mutation was identified (in this instance, in a woman of mixed ancestry), and the three founding mutations accounted for most of the observed excess risk of ovarian and breast cancer in relatives.

Inherited mutations in the genes BRCA1 and BRCA2 are associated with a significantly increased risk of breast cancer, particularly before the age of 50 years, as well as an increased risk of ovarian cancer. Patients with early-onset breast cancer or ovarian cancer at any age with a family history of either disease are at higher risk of carrying a mutation in BRCA1 or BRCA2. Laboratory analysis of these genes can determine whether a patient has inherited an increased risk of breast and ovarian cancer. In the absence of a mutation that has been previously identified in a family member, most tests for hereditary breast-ovarian cancer risk analyze the entire coding sequences of BRCA1 and BRCA2. The gene sequencing process itself can be automated, but the data must be interpreted by an individual with training in molecular diagnostics. Management options generally available to individuals with hereditary susceptibility to breast and ovarian cancer include heightened surveillance, prophylactic surgery, and chemoprevention. The use of genetic techniques to identify women with increased risk of cancer demonstrates the application of recent advances in the understanding of the genetic basis of malignancy to laboratory medicine and clinical care.

BACKGROUND: Approximately one out of every 10 ovarian cancers is caused by inherited mutations in identified genes. The characterization of hereditary ovarian cancer as an autosomal dominant disorder of specific gene mutations is more specific and useful than descriptive clinical syndromes such as "Lynch II," "site-specific ovarian cancer," or "breast-ovarian cancer." METHODS: The author reviewed recent studies of the biology, epidemiology, and medical management of hereditary ovarian cancer risk. RESULTS: Most hereditary ovarian cancer is attributable to two genes, BRCA1 and BRCA2, with other genes accounting for a smaller fraction. Women who inherit a mutation in any of these genes are far more likely than the general population to develop an epithelial malignancy of the ovary. Appropriate evaluation of family history can identify women most likely to have hereditary cancer risk, and genetic testing can definitively identify women with germline mutations that place them and their family at increased risk of ovarian cancer. CONCLUSIONS: Hereditary risk assessment, including genetic testing, can enhance medical management when used appropriately and should be accompanied by patient education and counseling.

The breast cancer susceptibility genes, BRCA1 and BRCA2, differ in their contribution to ovarian cancer. Recently, founder mutations in each of these genes were identified in Canadian breast cancer and breast ovarian cancer families of French ancestry. We have examined the prevalence of the founder mutations in a series of 113 French Canadian women with ovarian cancer unselected for family history. Germline mutations were found in eight of 99 invasive carcinomas and in none of the 14 tumors of borderline malignancy. Five cases carried the BRCA1 C4446T mutation and two cases carried the BRCA2 8765delAG mutation which are the most common mutations that have been described in French Canadian breast cancer and breast ovarian cancer families. All of these cases reported a family history of at least one first-degree relative with breast cancer, diagnosed below age 60 years, or with ovarian cancer. The identification of founder BRCA1 and BRCA2 mutations in ovarian cancer cases unselected for family history can facilitate carrier detection when the expected yield of a comprehensive screen may be low.

Three founder mutations in the cancer-associated genes BRCA1 and BRCA2 occur frequently enough among Ashkenazi Jews to warrant consideration of genetic testing outside the setting of high-risk families with multiple cases of breast or ovarian cancer. We estimated the prevalence of these founder mutations in BRCA1 and BRCA2 in the general population of Ashkenazi Jews according to age at testing, personal cancer history, and family cancer history. We compared the results of anonymous genetic testing of blood samples obtained in a survey of >5,000 Jewish participants from the Washington, DC, area with personal and family cancer histories obtained from questionnaires completed by the participants. In all subgroups defined by age and cancer history, fewer mutations were found in this community sample than in clinical series studied to date. For example, 11 (10%) of 109 Jewish women who had been given a diagnosis of breast cancer in their forties carried one of the mutations. The most important predictor of mutation status was a previous diagnosis of breast or ovarian cancer. In men and in women never given a diagnosis of cancer, family history of breast cancer before age 50 years was the strongest predictor. As interest in genetic testing for BRCA1 and BRCA2 in the Jewish community broadens, community-based estimates such as these help guide those seeking and those offering such testing. Even with accurate estimates of the likelihood of carrying a mutation and the likelihood of developing cancer if a mutation is detected, the most vexing clinical problems remain.

Following the genomic localization and subsequent identification of the breast cancer susceptibility genes, BRCA1 and BRCA2, the basic patterns of cancer risk associated with mutations in these genes have been defined. In addition, preliminary insights into the prevalence of mutations and their contributions to cancer incidence have been acquired. Features of breast and other cancers that develop in these genetic syndromes have now been investigated and shown to differ from sporadic versions of the same neoplasms. However, several areas are complex and require further clarification. There remain discrepancies between published cancer risk estimates. Furthermore, there may be variation in cancer risk between different mutations in the same gene and there is preliminary evidence that genetic and nongenetic influences may modify risks. Finally, it is probable that the genes underlying a substantial component of susceptibility to breast cancer remain to be identified.

Numerous case-control, cohort studies, case reports and reviews have been published during the last 5 years regarding the association between infertility and induction of ovulation and epithelial ovarian cancer. Despite this amount of published material, final conclusions regarding direct linkage between these different aspects of infertility and ovarian cancer, as well as any data relating to a putative pathogenetic mechanism, cannot be drawn. In this review we summarize the available data as well as update a previous review by Shoham published in 1994. We outline some of the information that has become available from basic research which may help to direct investigators to suitable clinical research models that may eventually serve to clarify this enigma. Finally we share ideas that focus on specific high-risk cohorts.