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We recently reported an association between low DNA repair capacity, measured through the host-cell reactivation assay, and melanoma risk in subjects with dysplastic naevi or low tanning ability. We investigated the genetic basis for these findings by analysing the Asp312Asn and Lys751Gln polymorphisms of the XPD (ERCC2) DNA repair gene in the same subjects. Similar to our previous report, no significant association between XPD polymorphisms and melanoma risk was found in 176 melanoma cases and 177 controls (odds ratio (OR)=1.5, 95% confidence interval (CI)=0.9-2.5 for 312Asn; OR=1.3, 95% CI=0.8-2.1 for 751Gln, adjusted for age, gender, dysplastic naevi and pigmentation characteristics). However, XPD variants were associated with increased risk in older (>50 years) subjects (OR=3.4, 95% CI=1.6-7.3 for 312Asn; OR=2.3, 95% CI=1.1-4.9 for 751Gln). The 751Gln allele was associated with elevated melanoma risk among subjects without dysplastic naevi (OR=2.6, 95% CI=1.1-6.4). Subjects with low tanning ability and XPD variants exhibited a nonsignificant increase of melanoma risk (OR=2.3, 95% CI=0.7-7.0 for 312Asn; OR=3.0, 95% CI=1.0-8.8 for 751Gln). DNA repair capacity was slightly decreased in subjects carrying 751Gln alleles. XPD variants may modify melanoma risk in subjects with specific host characteristics, such as older age, lack of dysplastic naevi or low tanning ability.

Background: Multiparity and the use of oral contraceptives reduce the risk of ovarian cancer, but their effects on this risk in women with a BRCA1 or BRCA2 mutation are unclear., Methods: We conducted a population-based case-control study of ovarian cancer among Jewish women in Israel. Women were tested for the two founder mutations in BRCA1 and the one founder mutation in BRCA2 that are known to be common among Jews. We estimated the effects of parity and oral-contraceptive use on the risk of ovarian cancer in carriers and noncarriers in separate analyses that included all control women, who did not have ovarian cancer., Results: Of 751 controls who underwent mutation analysis, 13 (1.7 percent) had a BRCA1 or BRCA2 mutation, whereas 244 of 840 women with ovarian cancer (29.0 percent) had a BRCA1 or BRCA2 mutation. Overall, each additional birth and each additional year of use of oral contraceptives were found to lower the risk of ovarian cancer, as expected. Additional births were protective in separate analyses of carriers and noncarriers, but oral-contraceptive use appeared to reduce the risk only in noncarriers; among carriers, the reduction in the odds of ovarian cancer was 12 percent per birth (95 percent confidence interval, 2.3 to 21 percent) and 0.2 percent per year of oral-contraceptive use (-4.9 to 5.0 percent)., Conclusions: The risk of ovarian cancer among carriers of a BRCA1 or BRCA2 mutation decreases with each birth but not with increased duration of use of oral contraceptives. These data suggest that it is premature to use oral contraceptives for the chemoprevention of ovarian cancer in carriers of such mutations.

Objective: The aim of this study was to define the prevalence, clinical characteristics, and BRCA1-2 mutation carrier status of ovarian cancer (OvC) patients with a previous primary malignancy in the breast (PPMBr)., Methods: The study population comprised 1240 consecutive Jewish Israeli women with pathologically confirmed epithelial OvC diagnosed between March 1, 1994, and December 31, 1997. Demographic and clinical data were obtained from medical files and from a detailed questionnaire taken through a nationwide epidemiological case-control study on OvC. Blood samples and tumor tissues were collected for analysis of the three predominant germline BRCA1-2 Jewish founder mutations (185delAG, 5382insC, and 6174delT)., Results: Fifty nine (4.7%) patients with OvC had a PPMBr. The median age at diagnosis of OvC was 60 years. The mean interval between the two diagnoses was 104 months (range 0-363 months). In the majority of the patients (n = 53), the diagnosis of breast cancer (BrC) preceded the OvC by more than 1 year. The ovarian tumors were diagnosed in 47% of the cases following investigation of patients' symptoms. In 41%, diagnosis was made as a consequence of check-up exams performed during the routine follow-up of BrC survivors. Patients with PPMBr were more likely to present with FIGO ovarian stage III-IV, compared to women with solitary OvC (73% vs 60. 3%, P < 0.05), and less likely to have borderline tumors (3.4% vs 17. 9%, P = 0.007). Family history of OvC/BrC was recorded in 26% of this group of patients compared to 10.5% among patients with solitary OvC (P = 0.003). Patients with PPMBr had an exceptionally high prevalence of BRCA1-2 mutations (57%), irrespective of family history., Conclusions: Patients with PPMBr present with more advanced disease and invasive-type epithelial ovarian tumors when compared to cases associated with solitary OvC. The rate of BRCA1-2 mutations in Jewish women with OvC who had PPMBr is at least twice as high as in Jewish women with OvC as the solitary disease., (Copyright 2000 Academic Press.)

Although BRCA1/2 testing has increasingly entered clinical practice, much is to be learned about the most effective ways to provide counseling to persons potentially interested in receiving test results. The purpose of this study was to identify factors affecting genetic testing decisions in a cohort of hereditary breast and ovarian cancer (HBOC) families presented with the choice to undergo testing. Relatives in these families are known to carry BRCA1 or BRCA2 mutations. Sociodemographics, personality traits, and family functioning were self-assessed using validated psychometric instruments at baseline. Among 172 individuals who participated in pretest education and counseling, 135 (78%) chose to undergo genetic testing and 37 (22%) chose not to be tested. Individuals who chose to undergo genetic testing were more likely to be older (> or =40 years), to have lower levels of optimism, and to report higher levels of cohesiveness in their families. A better understanding of factors that influence interest in predictive testing may help to inform the counseling that occurs prior to genetic testing.

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.

Background: Estimates of an 80-90% risk of breast cancer for carriers of germline mutations in the BRCA1 and BRCA2 genes are based on studies of families at high risk of breast cancer. Risk estimates for a population are possible if the mutation status of a representative sample of that population can be assessed. In Iceland, one common founder BRCA2 mutation occurs in 0.6% of the population. Iceland has a population-based cancer registry and a large collection of pedigrees, and estimation of cancer risk in mutation carriers is therefore possible., Methods: We studied 575 breast-cancer patients, 541 women and 34 men unselected for family history of breast cancer. Data on cancer in first-degree relatives were available from the cancer registry. Risk of cancer was estimated by comparing the history of cancer in first-degree relatives of carriers and non-carriers., Findings: 56 (10.4%) of the 541 women and 13 (38%) of the 34 men carried the 999del5 mutation. The estimated risk of breast cancer at age 50 for all female carriers of the 999del5 mutation was 17.0% (95% CI 9.1-25.9) and 37.2% (22.4-53.9) at age 70., Interpretation: The results of our population-based study show that the mean risk of breast cancer in carriers of mutation in BRCA2 is lower than previously suggested. Individual risk assessment will, however, have to take account of family history.

Background: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors., Methods: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided., Results: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers., Conclusions: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

Background: Carriers of germ-line mutations in BRCA1 and BRCA2 from families at high risk for cancer have been estimated to have an 85 percent risk of breast cancer. Since the combined frequency of BRCA1 and BRCA2 mutations exceeds 2 percent among Ashkenazi Jews, we were able to estimate the risk of cancer in a large group of Jewish men and women from the Washington, D.C., area., Methods: We collected blood samples from 5318 Jewish subjects who had filled out epidemiologic questionnaires. Carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 were identified with assays based on the polymerase chain reaction. We estimated the risks of breast and other cancers by comparing the cancer histories of relatives of carriers of the mutations and noncarriers., Results: One hundred twenty carriers of a BRCA1 or BRCA2 mutation were identified. By the age of 70, the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval, 40 to 73 percent); of ovarian cancer, 16 percent (95 percent confidence interval, 6 to 28 percent); and of prostate cancer, 16 percent (95 percent confidence interval, 4 to 30 percent). There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated., Conclusions: Over 2 percent of Ashkenazi Jews carry mutations in BRCA1 or BRCA2 that confer increased risks of breast, ovarian, and prostate cancer. The risks of breast cancer may be overestimated, but they fall well below previous estimates based on subjects from high-risk families.

Mutations in the genes BRCA1 and BRCA2 account for 5%-10% of familial early onset breast cancer. Identification of these mutations allows molecular diagnosis for breast cancer susceptibility. A high through-put automated PCR allelic discrimination assay (ADA) was developed to detect the prevalent mutations in these genes. Two allele specific oligonucleotides (ASO) are directly used in the PCR reaction, in both of which the fluorescent reporter and quencher dyes are attached to the 5' and 3' ends, respectively. During PCR, fluorescence is generated after cleavage of the annealed ASO by the 5' nuclease activity of Taq polymerase. The wild-type BRCA sequence is distinguished from the mutant sequence by the differential fluorescence emission of two different reporter dyes. The sensitivity of ADA is at the level of a single cell following a nested PCR. Eighty-six patient samples can be analyzed for each mutation in 15-min post-PCR without the need for radioactivity, gel electrophoresis, or membrane blotting/hybridization.

Certain germline mutations in either BRCA1 or BRCA2 confer a lifetime risk of developing breast cancer that may approach 90%. The BRCA1 185delAG mutation was found in 20% and the BRCA2 6174delT mutation in 8% of Ashkenazi Jewish women with early-onset breast cancer. The 185delAG mutation was observed in 0.9% of 858 Ashkenazi Jews unselected for a personal or family history of cancer. Assuming comparable age-specific penetrances, a carrier frequency of 0.3% was estimated for the 6174delT BRCA2 mutation. To test this hypothesis, we performed a population survey of 1,255 Jewish individuals. In two independent groups, a prevalence of approximately 1% (C.I. 0.6-1.5) was observed for the 6174delT mutation. The relative risk of developing breast cancer by age 42 was estimated to be 9.3 (C.I. 2.5-22.5) for 6174delT, compared to 31 (C.I. 11-77) for 185delAG. Analysis of 107 Ashkenazi Jewish women with breast cancer and a family history of breast or ovarian cancer confirmed a four-fold greater prevalence for the BRCA1 185delAG mutation compared to the BRCA2 6174delT mutation. Our findings suggest a difference in cumulative life-time penetrance for the two mutations. Genetic counseling for the one in 50 Ashkenazi Jewish individuals harbouring specific germline mutations in BRCA1 or BRCA2 must be tailored to reflect the different risks associated with the two mutations.

Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations. Tests of both mutations and family-specific differences in age at diagnosis were not significant. A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P = .069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1. For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago. In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events.

Since BRCA1, the first major gene responsible for inherited breast cancer, was cloned, more than 50 unique mutations have been detected in the germline of individuals with breast and ovarian cancer. In high-risk pedigrees, female carriers of BRCA1 mutations have an 80-90% lifetime risk of breast cancer, and a 40-50% risk of ovarian cancer. However, the mutation stats of individuals unselected for breast or ovarian cancer has not been determined, and it is not known whether mutations in such individuals confer the same risk of cancer as in individuals from the high-risk families studied so far. Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families, we have determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference individuals not selected for ethnic origin. We observed the 185delAG mutation in 0.9% of Ashkenazim (95% confidence limit, 0.4-1.8%) and in none of the reference samples. Our results suggest that one in a hundred women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer.

Genetic epidemiological evidence suggests that mutations in BRCA1 may be responsible for approximately one half of early onset familial breast cancer and the majority of familial breast/ovarian cancer. The recent cloning of BRCA1 allows for the direct detection of mutations, but the feasibility of presymptomatic screening for cancer susceptibility is unknown. We analyzed genomic DNA from one affected individual from each of 24 families with at least three cases of ovarian or breast cancer, using SSCP assays. Variant SSCP bands were subcloned and sequenced. Allele-specific oligonucleotide hybridization was used to verify sequence changes and to screen DNA from control individuals. Six frameshift and two missense mutations were detected in 10 different families. A frameshift mutation was detected in a male proband affected with both breast and prostate cancer. A 40-bp deletion was detected in a patient who developed intra-abdominal carcinomatosis 1 year after prophylactic oophorectomy. Mutations were detected throughout the gene, and only one was detected in more than a single family. These results provide further evidence that inherited breast and ovarian cancer can occur as a consequence of a wide array of BRCA1 mutations. These results suggests that development of a screening test for BRCA1 mutations will be technically challenging. The finding of a mutation in a family with male breast cancer, not previously thought to be related to BRCA1, also illustrates the potential difficulties of genetic counseling for individuals known to carry mutations.