Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations.

BACKGROUND: Little is known regarding cancer risks for relatives of women with very early-onset breast cancer. METHODS: We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth. RESULTS: For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers. CONCLUSION: First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis.

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations.

Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2.

Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations.

In the general population, ovarian cancer risk is inversely associated with oral contraceptive use, tubal ligation, and childbearing. Among carriers of BRCA1 gene mutations, the data are conflicting. The authors identified women diagnosed with incident invasive epithelial ovarian cancer in the San Francisco Bay Area of California from March 1997 through July 2001. They compared the contraceptive and reproductive histories of 36 carrier cases and 381 noncarrier cases with those of 568 controls identified by random digit dialing who were frequency matched to cases on age and race/ethnicity. In both carriers and noncarriers, reduced risk was associated with ever use of oral contraceptives (odds ratio = 0.54 (95% confidence interval (CI): 0.26, 1.13) for carriers and 0.55 (95% CI: 0.41, 0.73) for noncarriers), duration of oral contraceptive use (risk reduction per year = 13% (p = 0.01) for carriers and 6% (p < 0.001) for noncarriers), history of tubal ligation (odds ratio = 0.68 (95% CI: 0.25, 1.90) for carriers and 0.65 (95% CI: 0.45, 0.95) for noncarriers), and increasing parity (risk reduction per childbirth = 16% (p = 0.26) for carriers and 24% (p < 0.001) for noncarriers). These data suggest that BRCA1 mutation carriers and noncarriers have similar risk reductions associated with oral contraceptive use, tubal ligation, and parity.

Classifying disease chromosomes arising from multiple founders, with application to fine-scale haplotype mapping.

The availability of high-density haplotype data has motivated several fine-scale linkage disequilibrium mapping methods for locating disease-causing mutations. These methods identify loci around which haplotypes of case chromosomes exhibit greater similarity than do those of control chromosomes. A difficulty arising in such mapping is the possibility that case chromosomes have inherited disease-causing mutations from different ancestral chromosomes (founder heterogeneity). Such heterogeneity dilutes measures of case haplotype similarity. This dilution can be mitigated by separating case chromosomes into subsets according to their putative mutation origin, and searching for an area with excessive haplotype similarity within each subset. We propose a nonparametric method for identifying subsets of case chromosomes likely to share a common ancestral progenitor. By simulation studies and application to published data, we show that the method accurately identifies relatively large subsets of chromosomes that share a common founder. We also show that the method allows more precise estimates of the disease mutation loci than obtained by other fine-scale mapping methods.

Iodine and thyroid cancer risk among women in a multiethnic population: the Bay Area Thyroid Cancer Study.

Research on the relationship between iodine exposure and thyroid cancer risk is limited, and the findings are inconclusive. In most studies, fish/shellfish consumption has been used as a proxy measure of iodine exposure. The present study extends this research by quantifying dietary iodine exposure as well as incorporating a biomarker of long-term (1 year) exposure, i.e., from toenail clippings. This study is conducted in a multiethnic population with a wide variation in thyroid cancer incidence rates and substantial diversity in exposure. Women, ages 20-74, residing in the San Francisco Bay Area and diagnosed with thyroid cancer between 1995 and 1998 (1992-1998 for Asian women) were compared with women selected from the general population via random digit dialing. Interviews were conducted in six languages with 608 cases and 558 controls. The established risk factors for thyroid cancer were found to increase risk in this population: radiation to the head/neck [odds ratio (OR), 2.3; 95% confidence interval (CI), 0.97-5.5]; history of goiter/nodules (OR, 3.7; 95% CI, 2.5-5.6); and a family history of proliferative thyroid disease (OR, 2.5; 95% CI, 1.6-3.8). Contrary to our hypothesis, increased dietary iodine, most likely related to the use of multivitamin pills, was associated with a reduced risk of papillary thyroid cancer. This risk reduction was observed in "low-risk" women (i.e., women without any of the three established risk factors noted above; OR, 0.53; 95% CI, 0.33-0.85) but not in "high-risk" women, among whom a slight elevation in risk was seen (OR, 1.4; 95% CI, 0.56-3.4). However, no association with risk was observed in either group when the biomarker of exposure was evaluated. In addition, no ethnic differences in risk were observed. The authors conclude that iodine exposure appears to have, at most, a weak effect on the risk of papillary thyroid cancer.

Age at natural menopause and the risk of epithelial ovarian cancer.

OBJECTIVE: To investigate the relationship between age at natural menopause and risk of developing epithelial ovarian cancer. METHODS: Using data from six population-based, case-control studies conducted in the United States, age at natural menopause among 1411 women with epithelial ovarian cancer and 6380 control subjects were analyzed using survival analysis methods, including Kaplan-Meier and proportional hazards models. Subjects ranged from 20 to 81 years of age. RESULTS: The median age at natural menopause was 50 years among cases compared with 51 years among controls, a difference of borderline statistical significance (P =.06). The hazard ratio for the relationship between case-control status and age at natural menopause was 1.09 (95% confidence interval 0.99, 1.20). Controlling for potential confounders including parity, oral contraceptive use, tubal ligation, smoking, and body mass index did not appreciably change this association. There was little evidence of an association between early age at natural menopause and early onset ovarian cancer (diagnosis age under 48 years). CONCLUSION: We observed a weak association between ovarian cancer risk and age at natural menopause and, among women with early onset disease, there was little evidence to suggest that early menopause is related to ovarian cancer. Thus, there seems little need for increased surveillance or screening for ovarian cancer among women with early natural menopause.

A genome screen of families with multiple cases of prostate cancer: evidence of genetic heterogeneity.

We conducted a genomewide screen for prostate cancer-susceptibility genes on the basis of data from 98 families from the United States and Canada that had three or more verified diagnoses of prostate cancer among first- and second-degree relatives. We found a statistically significant excess of markers for which affected relatives exhibited modest amounts of excess allele-sharing; however, no single chromosomal region contained markers with excess allele-sharing of sufficient magnitude to indicate unequivocal evidence of linkage. Positive linkage signals of nominal statistical significance were found in two regions (5p-q and 12p) that have been identified as weakly positive in other data sets and in region 19p, which has not been identified previously. All these signals were considerably stronger for analyses restricted to families with mean age at onset below the median than for analyses of families with mean age at onset above the median. The data provided little support for any of the putative prostate cancer-susceptibility genes identified in other linkage studies.

Lifestyle determinants of 5alpha-reductase metabolites in older African-American, white, and Asian-American men.

Men with higher endogenous 5alpha-reductase activity may have higher prostate cancer risk. This hypothesis raises two questions: (a) Could racial differences in 5alpha-reductase activity explain the observed racial differences in prostate cancer risk? and (b) Could a man reduce his activity level by modifying his lifestyle? To address these questions, we measured two hormonal indices of 5alpha-reductase activity [serum levels of androstane-3alpha-17beta-diol glucuronide (3alpha-diol G) and androsterone glucuronide (AG)] in healthy, older African-American, white, and Asian-American men, who are at high, intermediate, and low prostate cancer risk, respectively. We also examined associations between these metabolite levels and such lifestyle characteristics as body size and physical activity as well as select aspects of medical history and family history of prostate cancer. Men included in this cross-sectional analysis (n = 1054) had served as control subjects in a population-based case-control study of prostate cancer we conducted in California, Hawaii, and Vancouver, Canada and provided information on certain personal attributes and donated blood between March 1990 and March 1992. In this study, concentrations of 3alpha-diol G declined significantly with age and increased significantly with body mass index. Mean levels of 3alpha-diol G, adjusted for age and body mass index, were 6.1 ng/ml in African-Americans, 6.9 ng/ml in whites and 4.8 ng/ml in Asian-Americans. These differences were statistically significant (African-Americans versus whites: P < 0.01; whites versus Asian-Americans: P < 0.001). Concentrations of AG decreased significantly with age, but only in whites, and were unrelated to any of the reported personal attributes. Mean levels of AG, adjusted for age, were 44.1 ng/ml in African-Americans, 44.9 ng/ml in whites, and 37.5 ng/ml in Asian-Americans (Asian-Americans versus whites, P < 0.001). In conclusion, older African-American and white men have similar levels of these two indices of 5alpha-reductase activity, and these levels are higher than those of older Asian-American men. This difference may be related to the lower prostate cancer risk in Asian-Americans.

Allele-sharing among affected relatives: non-parametric methods for identifying genes.

Non-parametric linkage analysis examines similarities among affected relatives in alleles of one or more genetic markers (pieces of DNA at known locations on a chromosome). The objective is to evaluate departures from the null hypothesis that the markers are not near a disease gene. Under the null hypothesis, Mendel's laws give the probabilities that a set of relatives exhibits a particular allele-sharing pattern, and the null hypothesis is rejected if the extent of allele sharing among affected relatives exceeds Mendelian expectation. Because the rationale for allele-sharing methods is intuitively plausible and easily grasped, geneticists have used these methods for more than 30 years, well before the advent of the large sets of polymorphic markers that have made linkage analysis so fruitful today. Here we describe methods for assessing whether the extent of marker allele sharing among affected relatives exceeds Mendelian expectation. We first quantify the notion of allele sharing and the probabilities of allele sharing in various sets of relatives. Then we describe allele sharing methods for affected sibs and more general sets of relatives. We also discuss related issues of test size and power. We conclude with a brief discussion of areas in need of further research.

Problems in the definition, interpretation, and evaluation of genetic heterogeneity.

Suppose that we wish to classify families with multiple cases of disease into one of three categories: those that segregate mutations of a gene of interest, those which segregate mutations of other genes, and those whose disease is due to nonhereditary factors or chance. Among families in the first two categories (the hereditary families), we wish to estimate the proportion, p, of families that segregate mutations of the gene of interest. Although this proportion is a commonly accepted concept, it is well defined only with an unambiguous definition of "family." Even then, extraneous factors such as family sizes and structures can cause p to vary across different populations and, within a population, to be estimated differently by different studies. Restrictive assumptions about the disease are needed, in order to avoid this undesirable variation. The assumptions require that mutations of all disease-causing genes (i) have no effect on family size, (ii) have very low frequencies, and (iii) have penetrances that satisfy certain constraints. Despite the unverifiability of these assumptions, linkage studies often invoke them to estimate p, using the admixture likelihood introduced by Smith and discussed by Ott. We argue against this common practice, because (1) it also requires the stronger assumption of equal penetrances for all etiologically relevant genes; (2) even if all assumptions are met, estimates of p are sensitive to misspecification of the unknown phenocopy rate; (3) even if all the necessary assumptions are met and the phenocopy rate is correctly specified, estimates of p that are obtained by linkage programs such as HOMOG and GENEHUNTER are based on the wrong likelihood and therefore are biased in the presence of phenocopies. We show how to correct these estimates; but, nevertheless, we do not recommend the use of parametric heterogeneity models in linkage analysis, even merely as a tool for increasing the statistical power to detect linkage. This is because the assumptions required by these models cannot be verified, and their violation could actually decrease power. Instead, we suggest that estimation of p be postponed until the relevant genes have been identified. Then their frequencies and penetrances can be estimated on the basis of population-based samples and can be used to obtain more-robust estimates of p for specific populations.

Primary ovarian dysgerminoma in a patient with a germline BRCA1 mutation.

Germline mutations in the BRCA1 tumor suppressor gene are associated with increased risk for the development of ovarian cancer. All such cancers thus far reported have been of the epithelial histologic type. We identified an ovarian dysgerminoma in a 16-year-old woman (proband) with a family history of ovarian cancer during a review of histopathologic characteristics of ovarian cancers from women enrolled in the Gilda Radner Familial Ovarian Cancer Registry. Mutation analysis of DNA from this patient's peripheral blood leukocytes revealed a germline BRCA1 mutation (3312insG). The mutation was also present in the mother with breast cancer, a maternal aunt and a distant cousin with ovarian cancer, and a maternal grandfather and an uncle with skin cancer. The development of the proband's dysgerminoma may be unrelated to her germline BRCA1 mutation. Alternatively, such dysgerminomas may be caused by BRCA1 mutations, but occur so infrequently compared with epithelial cancers that they are seldom identified. Analysis of a larger series of ovarian germ cell tumors may resolve this question.

Histopathology of familial ovarian tumors in women from families with and without germline BRCA1 mutations.

Breast cancers from patients with germline BRCA1 mutations show characteristic histopathologic features. However, similar studies of BRCA1-associated ovarian cancers have reported inconsistent findings. Interobserver differences in histopathologic classification are a significant source of variation, and most studies have obtained histopathologic information from pathology reports rather than from review of histopathology slides. We therefore reviewed the histopathology slides and pathology reports to determine histologic type, grade, and stage for cancers of the ovary or peritoneum in 217 women from 126 families enrolled in the Gilda Radner Familial Ovarian Cancer Registry. Peripheral blood DNA from at least 1 affected member of each family was analyzed for BRCA1 mutations, and tumors from BRCA1 mutation-positive families were compared with those from BRCA1-negative families. Of 66 patients from 36 BRCA1-positive families, 64 had ovarian carcinoma, 1 had an ovarian carcinoma in situ, and 1 had a dysgerminoma. Of 151 patients from 90 BRCA1-negative families, 135 had ovarian carcinoma, 10 had ovarian borderline tumors, 3 had ovarian sex cord/stromal tumors, and 3 had primary peritoneal carcinoma. There were fewer grade 1 (P <.001) and stage I (P =.10) cancers in patients from BRCA1-positive families than in patients from BRCA1-negative families. Neither mucinous nor borderline tumors were found in the BRCA1-positive families. Ovarian cancers arising in women from BRCA1-positive families are more likely to be high grade and nonmucinous than cancers arising in women from BRCA1-negative families. The absence of borderline tumors in patients from BRCA1-positive families adds to accumulating evidence that BRCA1 mutations do not play a role in the development of these tumors. HUM PATHOL 31:1420-1424.

Declining ovarian cancer rates in U.S. women in relation to parity and oral contraceptive use.

Ovarian cancer incidence and mortality rates have declined among U.S. women age 35-59 years during the period 1970-1995. Epidemiologic studies have shown that ovarian cancer risk decreases with increasing parity and increasing duration of oral contraceptive use. During this period, parity has declined while oral contraceptive use has increased. We compared temporal trends in observed ovarian cancer incidence rates with rates predicted by changes in parity and duration of oral contraceptive use to determine whether the changes in these characteristics could explain the declining rates in younger women. In addition, we wished to examine whether oral contraceptive use continues to be protective to postmenopausal women. To predict changes in rates between 1970 and 1995, we assumed that increases in parity and duration of oral contraceptive use induce proportional decreases in incidence rates. We found that the rates predicted by these assumptions agreed well with observed rates in young women (age 30-49) but were substantially lower than observed rates in older women (age 50-64). The data indicate that the relative decrease in incidence rates due to the protective effect of oral contraceptive use declines with age.

Survival in epithelial ovarian cancer patients with prior breast cancer.

Ovarian cancer patients who carry germ-line BRCA1 mutations may have improved survival compared with ovarian cancer patients without these mutations. To evaluate this hypothesis, the authors compared survival in ovarian cancer patients who had a history of prior breast cancer with that of patients without such a history. Specifically, they used data from the population-based US Surveillance, Epidemiology, and End Results (SEER) Program to assess time to death from ovarian cancer among ovarian cancer patients with and without a prior breast cancer. All 25,637 White women diagnosed with invasive epithelial ovarian cancer in SEER registries between 1973 and 1995 were included. Of these, 824 women had had a prior breast cancer diagnosis. The ovarian cancer death rate among women with prior breast cancer was significantly lower than that of women with ovarian cancer only, adjusted for age and stage at ovarian cancer diagnosis. The survival advantage was most pronounced among older women and among those whose ovarian cancers were more advanced at the time of diagnosis. These results lend indirect support to prior findings of improved ovarian cancer survival in BRCA1 mutation carriers.