BRCA1 Penetrance Research Articles

21P Analysis of germline variants in the immune response-related genes in BRCA1 mutation carriers: Possible modifying effect on age-dependent BRCA1 penetrance

Most female carriers of germline BRCA1 mutation develop breast/ovarian cancer during the lifetime. However, the penetrance of BRCA1 pathogenic variants does not reach 100%, and the age of BRCA1-associated breast cancer (BC) onset varies widely. BRCA1-driven tumors are chromosomally unstable and may have excessive antigenicity. We hypothesized that hereditary variations in immune response pathways may contribute to the variability of BRCA1 penetrance. We evaluated whether genetic variations in the immune response-related genes contribute to this heterogeneity.

Penetrance estimates for BRCA1, BRCA2 (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk?

PurposeThe identification of BRCA1, BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall...

Prevalence and Penetrance of BRCA1 and BRCA2 Germline Mutations in Colombian Breast Cancer Patients

Pathogenic BRCA1/2 germline mutations confer high risks of breast and ovarian cancer to women of European ancestry. Characterization of BRCA1/2 mutations in other ethnic groups is also medically important. We comprehensively screened 68 Colombian breast/ovarian cancer families for small-range mutations, 221 families for large-genomic rearrangements, and 1,022 unselected breast cancer cases for Colombian founder mutations in BRCA1/2. The risk of cancer among relatives of mutation carriers and the mutation penetrance were estimated by survival analysis. Identified BRCA2 mutations included 6310delGA and the recurrent 1991del4 mutations. A novel large BRCA2 deletion was found in 0.9% of the screened families. Among unselected breast cancer cases, 3.3% tested positive for BRCA1/3450del4, 2.2% for BRCA1/A1708E, 1.1% for BRCA2/3034del4, and 0.4% for BRCA2/1991del4. Female relatives of carriers of BRCA1/2 founder mutations showed a 5.90 times higher risk of breast cancer, when the woman herself carried a BRCA1 mutation compared to a non-carrier (95% CI 2.01–17.3). The estimated cumulative risk of breast cancer by age 70 years for BRCA1 mutations carriers was 14% (95% CI 5–38) compared to 3% for the general Colombian population (relative risk of breast cancer 4.05). Together with known founder mutations, reported novel variants may ease a cost-effective BRCA1/2 screening in women with Colombian ancestry.

Abstract P3-09-02: Unhealthy lifestyle patterns are prevalent in unaffected BRCA mutation carriers & are associated with increased oxidative stress and telomere length alterations

The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes . Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication.The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes . Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication. Citation Format: McGarrigle SA, Guinan EM, Hussey J, O9Sullivan J, Boyle T, Hanhauser Y, Al-azawi D, Kennedy MJ, Gallagher DJ, Connolly EM. Unhealthy lifestyle patterns are prevalent in unaffected BRCA mutation carriers & are associated with increased oxidative stress and telomere length alterations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-09-02.

Ten modifiers of BRCA1 penetrance validated in a Norwegian series.

BackgroundCommon genetic variants have been shown to modify BRCA1 penetrance. The aim of this study was to validate these reports in a special cohort of Norwegian BRCA1 mutation carriers that were selected for their extreme age of onset of disease.MethodsThe ten variants rs13387042, rs3803662, rs8170, rs9397435, rs700518, rs10046, rs3834129, rs1045485, rs2363956 and rs16942 were selected to be tested on samples from our biobank. We selected female BRCA1 mutation carriers having had a diagnosis of breast or ovarian cancer below 40 years of age (young cancer group, N = 40), and mutation carriers having had neither breast nor ovarian cancer above 60 years of age (i.e., old no cancer group, N = 38). Relative risks and odd ratios of belonging to the young cancer versus old no cancer groups were calculated as a function of having or not having the SNPs in question.ResultsFive of the ten variants were found to be significantly associated with early onset cancer. Some of the variation between our results and those previously reported may be ascribed to stochastic effects in our limited number of patient studies, and/or genetic drift in linkage disequilibrium in the genetically isolated Norwegian population. This is in accordance with the understanding that the SNPs are markers in linkage disequilibrium with their respective disease-causing genetic variants, and that this may vary between different populations.ConclusionsThe results confirmed associations previously reported, with the notion that the degree of association may differ between other populations, which must be considered when discussing the clinical use of the associations described.Electronic supplementary materialThe online version of this article (doi:10.1186/s13053-015-0035-0) contains supplementary material, which is available to authorized users.

Cooperation between BRCA1 and vitamin D is critical for histone acetylation of the p21waf1 promoter and growth inhibition of breast cancer cells and cancer stem-like cells.

Carriers of germline mutations in the BRCA1 gene have a significant increased lifetime risk for being diagnosed with breast cancer. The incomplete penetrance of BRCA1 suggests that environmental and/or genetic factors modify the risk and incidence among mutation carriers. Nutrition and particular micronutrients play a central role in modifying the phenotypic expression of a given genotype by regulating chromatin structure and gene expression. The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is a potent inhibitor of breast cancer growth. Here we report that two non-calcemic analogues of 1α,25-dihydroxyvitamin D3, seocalcitol (EB1089) and QW-1624F2-2, collaborate with BRCA1 in mediating growth inhibition of breast cancer cells and breast cancer stem-like cells. EB1089 induces a G1/S phase growth arrest that coincides with induction of p21waf1 expression only in BRCA1-expressing cells. A complete knockdown of BRCA1 or p21waf1 renders the cells unresponsive to EB1089. Furthermore, we show that in the presence of ligand, BRCA1 associates with vitamin D receptor (VDR) and the complex co-occupies vitamin D responsive elements (VDRE) at the CDKN1A (p21waf1) promoter and enhances acetylation of histone H3 and H4 at these sites. Thus, BRCA1 expression is critical for mediating the biological impact of vitamin D3 in breast tumor cells.

Involvement of IGF-1R regulation by miR-515-5p modifies breast cancer risk among BRCA1 carriers

Several lines of evidence indicate that sequence alterations within microRNA (miRNA)-binding sites can modify the binding to its target gene resulting in altered expression patterns. We hypothesized that a single nucleotide polymorphism (SNP) located in the miR-515-5p binding site of igf-1r gene may alter IGF-1R regulation, with consequent effects on breast cancer risk in BRCA1 mutation carriers. Computational prediction revealed that the rs28674628 SNP in the igf-1r 3' UTR is located within a predicted binding site for miR-515-5p. The effect of this SNP on breast cancer risk was evaluated by genotyping 115 Jewish Ashkenazi carriers of the 185delAG mutation in the BRCA1 gene using the Sequenom platform followed by Kaplan-Meier analysis. Additional data set of 378 Jewish BRCA1 carriers was analyzed to validate our results. MiRNA transfection, Western blot analysis, luciferase reporter assay, real time PCR, and immunohistochemistry were performed to assess direct regulation of igf-1r by miR-515-5p. We show direct regulation of IGF-1R by miR-515-5p. We identified that disrupting miR-515-5p and igf-1r 3' UTR binding by SNP may cause elevated IGF-1R protein levels. Interestingly, miR-515-5p is downregulated in tumor tissue compared to its non-neoplastic surrounding tissue while IGF-1R levels are elevated. This igf-1r SNP was found to be significantly associated with age at diagnosis of breast cancer in Jewish Ashkenazi BRCA1 mutation carriers. These findings support the hypothesis that a SNP located in igf-1r gene may alter miRNA regulation of IGF-1R, with a putative effect on BRCA1 penetrance and breast cancer risk.

A prospective investigation of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2gene carriers

BackgroundBreast cancer is the most common female cancer worldwide. The lifetime risk of a woman being diagnosed with breast cancer is approximately 12.5%. For women who carry the deleterious mutation in either of the BRCA genes, BRCA1 or BRCA2, the risk of developing breast or ovarian cancer is significantly increased. In recent years there has been increased penetrance of BRCA1 and BRCA2 associated breast cancer, prompting investigation into the role of modifiable risk factors in this group. Previous investigations into this topic have relied on participants recalling lifetime weight changes and subjective methods of recording physical activity. The influence of obesity-related biomarkers, which may explain the link between obesity, physical activity and breast cancer risk, has not been investigated prospectively in this group. This paper describes the design of a prospective cohort study investigating the role of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene mutation carriers.Methods/designParticipants will be recruited from breast cancer family risk clinics and genetics clinics. Lifestyle risk factors that will be investigated will include body composition, metabolic syndrome and its components, physical activity and dietary intake. PBMC telomere length will be measured as a potential predictor of breast cancer occurrence. Measurements will be completed on entry to the study and repeated at two years and five years. Participants will also be followed annually by questionnaire to track changes in risk factor status and to record cancer occurrence. Data will be analysed using multiple regression models. The study has an accrual target of 352 participants.DiscussionThe results from this study will provide valuable information regarding the role of modifiable lifestyle risk factors for breast cancer in women with a deleterious mutation in the BRCA gene. Additionally, the study will attempt to identify potential blood biomarkers which may be predictive of breast cancer occurrence.

Breast cancer risk factors differ between Asian and white women with BRCA1/2 mutations

The prevalence and penetrance of BRCA1 and BRCA2 (BRCA1/2) mutations may differ between Asians and whites. We investigated BRCA1/2 mutations and cancer risk factors in a clinic-based sample. BRCA1/2 mutation carriers were enrolled from cancer genetics clinics in Hong Kong and California according to standardized entry criteria. We compared BRCA mutation position, cancer history, hormonal and reproductive exposures. We analyzed DNA samples for single-nucleotide polymorphisms reported to modify breast cancer risk. We performed logistic regression to identify independent predictors of breast cancer. Fifty Asian women and forty-nine white American women were enrolled. BRCA1 mutations were more common among whites (67 vs. 42%, p=0.02), and BRCA2 mutations among Asians (58 vs. 37%, p=0.04). More Asians had breast cancer (76 vs. 53%, p=0.03); more whites had relatives with breast cancer (86 vs. 50%, p=0.0003). More whites than Asians had breastfed (71 vs. 42%, p=0.005), had high BMI (median 24.3 vs. 21.2, p=0.04), consumed alcohol (2 drinks/week vs. 0, p<0.001), and had oophorectomy (61 vs. 34%, p=0.01). Asians had a higher frequency of risk-associated alleles in MAP3K1 (88 vs. 59%, p=0.005) and TOX3/TNRC9 (88 vs. 55%, p=0.0002). On logistic regression, MAP3K1 was associated with increased breast cancer risk for BRCA2, but not BRCA1 mutation carriers; breast density was associated with increased risk among Asians but not whites. We found significant differences in breast cancer risk factors between Asian and white BRCA1/2 mutation carriers. Further investigation of racial differences in BRCA1/2 mutation epidemiology could inform targeted cancer risk-reduction strategies.

Breast Cancer Screening inBRCA1Mutation Carriers: Effectiveness of MR Imaging—Markov Monte Carlo Decision Analysis

To project intermediate and long-term clinical outcomes of magnetic resonance (MR) imaging screening for breast cancer in women with BRCA1 gene mutations. A microsimulation model was developed to compare three annual screening strategies versus clinical surveillance: (a) mammography, (b) MR imaging, and (c) combined MR imaging and mammography. Input parameters were obtained from the published medical literature, existing databases, and expert opinion. The model was calibrated to targets from the Surveillance Epidemiology and End Results database (1975-1980) compiled during a period prior to the onset of widespread mammographic screening. Sensitivity analysis was performed to evaluate the effect of uncertainty in parameter estimates. With clinical surveillance, the estimated median diameter of invasive breast cancers at presentation was 2.6 cm. Average life expectancy was 71.15 years. With annual screening with mammography, MR imaging, or combined mammography and MR imaging, median invasive tumor diameters at diagnosis decreased to 1.9, 1.3, and 1.1 cm, respectively. Annual screening with mammography, MR imaging, or combined mammography and MR imaging increased average life expectancy by 0.80 year, 1.10 years, and 1.38 years, respectively, and decreased relative mortality from breast cancer (16.8%, 17.2%, and 22.0%, respectively). Program sensitivity was greater than 50% only with MR imaging screening strategies. The majority of women undergoing screening had one or more false-positive screening examinations (53.8%, 80.2%, and 84.0% for mammography, MR imaging, and combined mammography and MR imaging, respectively). Many women also underwent one or more biopsies for benign disease (11.3%, 26.3%, and 30.3%, respectively). Results were sensitive to BRCA1 penetrance estimates and to MR imaging sensitivity in the detection of ductal carcinoma in situ. Annual screening with combined mammography and MR imaging provides BRCA1 mutation carriers with the greatest life expectancy gain and breast cancer mortality reduction. However, an important trade-off of this strategy is an increased rate of false-positive screening results and biopsies performed for benign disease.

Hereditary breast and ovarian cancer.

Familial breast cancer was first recognized in the Roman medical literature of 100 AD [1]. The first documentation of familial clustering of breast cancer in modern times was published by Broca, who reported 10 cases of breast cancer in 4 generations of his wife's family [2]. In the middle of the nineteen nineties it was proven at the molecular level that a substantial number of breast and ovarian cancers has hereditary monogenic aetiology [3,4]. Evaluation of frequency of pedigree-clinical signs characteristic for strong aggregations of breast/ovarian cancers among consecutive cases of cancers of these organs as well as analyses of cancer incidence in monozygotic twins indicate that about 30% of breast and ovarian cancers develop because of a strong genetic predisposition [5]. In other breast/ovarian cancers the significance of genetic factors was underestimated. However, recently it has been possible to show the characteristic constitutional background influencing development of cancer also in patients sporadic neoplasms. Therefore now scientists think that in almost all patients cancer a certain genetic background should be detectable, although influencing cancer risk to a various degree. Genetic abnormalities strongly related to cancer are called high risk changes (genes) and abnormalities influencing cancer development to a lower degree are called moderate risk changes (genes). Most frequently strong genetic predisposition to breast/ovarian cancers are related to mutations in the BRCA1 and BRCA2 genes and most often it appears as syndromes of hereditary breast cancer -site-specific (HBC-ss), hereditary breast-ovarian cancer (HBOC) and hereditary ovarian cancer (HOC). In family members of families HBC-ss syndrome only breast cancers but not ovarian cancers are observed. In HBOC syndrome families both breast and ovarian cancers are diagnosed, and in HOC syndrome only ovarian but not breast cancers are detected. Operational clinical-pedigree criteria which we use in order to diagnose definitively or with high probability the discussed syndromes are summarized in Table ​Table1.1. In the vast majority of cancer cases related to moderate risk genes family history is negative. HBC-ss, HBOC and HOC syndromes are clinically and molecularly heterogeneous. Mutations in the BRCA1 and BRCA2 genes are the most frequent cause of these syndromes. Table 1 Pedigree-clinical diagnostic criteria of HBC-ss, HBOC and HOC syndromes [6] BRCA1 syndrome In this syndrome women carry a germline mutation in the BRCA1 gene. Carriers of a BRCA1 mutation have approximately 50-80% lifetime risk of breast cancer and 40% risk of ovarian cancer [7]. We estimate that these risks are 66% for breast cancer and 44% for ovarian cancer in the Polish population (Table ​(Table2).2). Both risks appear to be dependent on the type and localization of the mutation [8-10]. Our findings suggest that the risk of breast cancer in women 5382insC is two times higher than in women 4153delA. Table 2 Risk of breast and ovarian cancer in BRCA1 mutation carriers in Poland [8] Incomplete penetrance of BRCA1 suggests that other factors, genetic and non-genetic modifiers, are important in carcinogenesis in the mutation carriers. The risk of ovarian cancer is modified by VNTR locus for HRAS 1 and is increased 2-fold in BRCA1 carriers harbouring one or two rare alleles of HRAS 1 [11]. We reported that the 135G>C variant in the RAD51 gene is strongly protective (OR = 0.5) against both ovarian and breast cancer [12,13]. Carriers of a BRCA1 mutation are also at about 10% lifetime risk of fallopian tube and peritoneal cancers [14]. These data about the frequency of ovarian cancer in BRCA1 carriers appear to reflect the combined frequency of ovarian, fallopian tube and peritoneal cancers, because these tumours were diagnosed as ovarian cancers in the past, and because they share similar morphology and cause elevated levels of the marker CA 125. The risk of cancer at other sites may be increased in carriers of a BRCA1 mutation as well, but the evidence is controversial and needs further studies. Breast and ovarian cancer in BRCA1 carriers have particular clinical characteristics. The mean age at onset of breast cancer is about 42-45 years [15,16] and of ovarian cancer is about 54 years [17,18]. 18-32% of breast cancers are bilateral [19,20]. These are rapidly growing tumours: >90% of cases have G3 grade at the time of diagnosis and almost all ovarian cancers in women a BRCA1 mutation are diagnosed in FIGO stage III°/IV°. Medullary, atypical medullary, ducal and oestrogen receptor negative (ER) breast tumours are common in BRCA1 carriers. BRCA1 mutation-positive tumours constitute about 10-15% of all ER-breast cancers [21-23]. Most carriers of a BRCA1 mutation report a positive family history of breast or ovarian cancer (Figure ​(Figure1).1). However, 45% of BRCA1 carriers report a negative family history, mainly because of paternal inheritance and incomplete penetrance (Figure ​(Figure3)3) [20]. Figure 1 Family HOC syndrome and diagnosed constitutional 4153delA BRCA1 gene mutation. Figure 3 Patient ovarian cancer and detected 5382insC BRCA1 mutation from family negative family history.

Genetic Mapping in Mice Identifies DMBT1 as a Candidate Modifier of Mammary Tumors and Breast Cancer Risk

Low-penetrance breast cancer susceptibility alleles seem to play a significant role in breast cancer risk but are difficult to identify in human cohorts. A genetic screen of 176 N2 backcross progeny of two Trp53(+/-) strains, BALB/c and C57BL/6, which differ in their susceptibility to mammary tumors, identified a modifier of mammary tumor susceptibility in an approximately 25-Mb interval on mouse chromosome 7 (designated SuprMam1). Relative to heterozygotes, homozygosity for BALB/c alleles of SuprMam1 significantly decreased mammary tumor latency from 70.7 to 61.1 weeks and increased risk twofold (P = 0.002). Dmbt1 (deleted in malignant brain tumors 1) was identified as a candidate modifier gene within the SuprMam1 interval because it was differentially expressed in mammary tissues from BALB/c-Trp53(+/-) and C57BL/6-Trp53(+/-) mice. Dmbt1 mRNA and protein was reduced in mammary glands of the susceptible BALB/c mice. Immunohistochemical staining demonstrated that DMBT1 protein expression was also significantly reduced in normal breast tissue from women with breast cancer (staining score, 1.8; n = 46) compared with cancer-free controls (staining score, 3.9; n = 53; P < 0.0001). These experiments demonstrate the use of Trp53(+/-) mice as a sensitized background to screen for low-penetrance modifiers of cancer. The results identify a novel mammary tumor susceptibility locus in mice and support a role for DMBT1 in suppression of mammary tumors in both mice and women.

Partnering in Oncogenetic Research – The INHERIT BRCAs Experience: Opportunities and Challenges

Today it is common to conduct research in collaboration with colleagues from different disciplines and institutions. The INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility (INHERIT BRCAs), involves Canadian and international experts from diverse fields working with health service providers, patients and collaborators from the World Health Organization and other European networks. Evidence-based information and knowledge transfer drive our efforts to advance genomic research to understand the genetic basis of cancer susceptibility and treatment response. Several goals reveal the interdisciplinary team approach: (a) to estimate the prevalence and penetrance of BRCA1 and BRCA2 mutations and their deleterious impact upon different populations; (b) to pinpoint novel breast cancer susceptibility loci; (c) to assess the efficacy of clinical interventions; (d) to address changes in quality of life and health-related behaviour from the decision to undergo genetics testing and during follow-up; (e) to evaluate legal, social and ethical implications; and, finally; (f) to promote professional and public education by facilitating the transfer of research findings to clinical practice and informing policy makers. The lessons learned by the INHERIT research team and future challenges are presented.

Characterization ofBRCA1andBRCA2Mutations in a Large United States Sample

An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families. We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family. In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling. The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.

BRCA1 and BRCA2 mutation predictions using the BOADICEA and BRCAPRO models and penetrance estimation in high-risk French-Canadian families

IntroductionSeveral genetic risk models for breast and ovarian cancer have been developed, but their applicability to specific populations has not been evaluated. We used data from French-Canadian families to evaluate the mutation predictions given by the BRCAPRO and BOADICEA models. We also used this data set to estimate the age-specific risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers.MethodsA total of 195 families with multiple affected individuals with breast or ovarian cancer were recruited through the INHERIT (INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility) BRCAs research program. Observed BRCA1 and BRCA2 mutation status was compared with predicted carrier probabilities under the BOADICEA and BRCAPRO models. The models were assessed using Brier scores, attributes diagrams and receiver operating characteristic curves. Log relative risks for breast and ovarian cancer in mutation carriers versus population risks were estimated by maximum likelihood, using a modified segregation analysis implemented in the computer program MENDEL. Twenty-five families were eligible for inclusion in the BRCA1 penetrance analysis and 27 families were eligible for the BRCA2 penetrance analysis.ResultsThe BOADICEA model predicted accurately the number of BRCA1 and BRCA2 mutations for the various groups of families, and was found to discriminate well at the individual level between carriers and noncarriers. BRCAPRO over-predicted the number of mutations in almost all groups of families, in particular the number of BRCA1 mutations. It significantly overestimated the carrier frequency for high predicted probabilities. However, it discriminated well between carriers and noncarriers. Receiver operating characteristic (ROC) curves indicate similar sensitivity and specificity for BRCAPRO and BOADICEA. The estimated risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers were consistent with previously published estimates.ConclusionThe BOADICEA model predicts accurately the carrier probabilities in French-Canadian families and may be used for counselling in this population. None of the penetrance estimates was significantly different from previous estimates, suggesting that previous estimates may be appropriate for counselling in this population.

Genetics in Clinical Cancer Care: A Promise Unfulfilled among Minority Populations

Genetics in Clinical Cancer Care: A Promise Unfulfilled among Minority Populations

Prediction of pathogenic mutations in patients with early-onset breast cancer by family history

We aimed to assess frequency and penetrance of BRCA1, BRCA2,and TP53 mutations in women diagnosed with breast cancer aged 30 years or younger, and then correlate this frequency with family history. 17 of 36 familial cases had a BRCA1, BRCA2, or TP53 mutation, compared with three of 63 non-familial cases. The calculated population frequency of TP53 mutations was one in 5000, substantially greater than previous estimates. This finding underlines the importance of accurate elucidation of a family history from young women diagnosed with breast cancer. Establishment of family history could help with development of patient-specific management and tumour surveillance protocols.

CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q.

Women with germline mutations in BRCA1 have a greatly elevated risk of breast and ovarian cancer. However, considerable variation in the degree of breast cancer risk associated with a BRCA1 mutation has been observed, suggesting that modifiers of BRCA1 penetrance may exist. We hypothesized that the modifier genes might be located in regions of allelic imbalance in the tumors of BRCA1 mutation carriers, as have been reported on chromosomes 4p, 4q and 5q. In order to determine whether novel genetic modifiers of BRCA1-associated breast cancer penetrance in these regions exist, we used non-parametric linkage analysis methods to determine whether allele sharing of chromosomes 4p, 4q and 5q was observed preferentially within BRCA1 mutation families in women with BRCA1 mutations and breast cancer. No significant linkage on chromosome 4p or 4q was observed associated with breast cancer risk in BRCA1 mutation carriers. However, we observed a significant linkage signal at D5S1471 on chromosome 5q (P = 0.009) in all the families analyzed together. The significance of this observation increased in the subset of families with an average of breast cancer diagnosis less than 45 years (P = 0.003). These results suggest the presence of one or more genes on chromosome 5q33-34 that modify breast cancer risk in BRCA1 mutation carriers. The approach described here may be utilized to identify penetrance modifiers in other autosomal dominant syndromes.

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer.

Mutations of the BRCA1 or BRCA2 genes have been shown to strongly predispose towards the development of contralateral breast cancer in patients from large multi-case families. In order to test the hypothesis that BRCA1 and BRCA2 mutations are more frequent in patients with bilateral breast cancer, we have investigated a hospital-based series of 75 consecutive patients with bilateral breast cancer and a comparison group of 75 patients with unilateral breast cancer, pairwise matched by age and family history, for mutations in the BRCA1 and BRCA2 genes. Five frameshift deletions (517delGT in BRCA1; 4772delA, 5946delCT, 6174delT and 8138del5 in BRCA2) were identified in patients with bilateral disease. No further mutations, apart from polymorphisms and 3 rare unclassified variants, were found after scanning the whole BRCA1 and BRCA2 coding sequence. Three pathogenic BRCA1 mutations (Cys61Gly, 3814del5, 5382insC) were identified in the group of patients with unilateral breast cancer. The frequencies of common BRCA1 and BRCA2 missense variants were not different between the 2 groups. In summary, we did not find a significantly increased prevalence of BRCA1 and BRCA2 mutations in a hospital-based cohort of German patients with bilateral breast cancer. We conclude that bilaterality of breast cancer on its own is not strongly associated with BRCA1 and BRCA2 mutations when adjusted for age and family history. The high frequency of bilateral disease in multi-case breast cancer families may be due to a familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 and BRCA2 mutations. © 2001 Cancer Research Campaignhttp://www.bjcancer.com

CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriers.

Variation in the penetrance estimates for BRCA1 and BRCA2 mutations carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. A previous study has suggested that BRCA1 carriers with longer lengths of the CAG repeat in the androgen receptor (AR) gene are at increased risk of breast cancer (BC). We genotyped 188 BRCA1/2 carriers (122 affected and 66 unaffected with breast cancer), 158 of them of Ashkenazi origin, 166 BC cases without BRCA1/2 mutations and 156 Ashkenazi control individuals aged over 56 for the AR CAG and GGC repeats. In carriers, risk analyses were conducted using a variant of the log-rank test, assuming two sets of risk estimates in carriers: penetrance estimates based on the Breast Cancer Linkage Consortium (BCLC) studies of multiple case families, and lower estimates as suggested by population-based studies. We found no association of the CAG and GGC repeats with BC risk in either BRCA1/2 carriers or in the general population. Assuming BRCA1/2 penetrance estimates appropriate to the Ashkenazi population, the estimated RR per repeat adjusted for ethnic group (Ashkenazi and non-Ashkenazi) was 1.05 (95%CI 0.97–1.17) for BC and 1.00 (95%CI 0.83–1.20) for ovarian cancer (OC) for CAG repeats and 0.96 (95%CI 0.80–1.15) and 0.90 (95%CI 0.60–1.22) respectively for GGC repeats. The corresponding RR estimates for the unselected case–control series were 1.00 (95%CI 0.91–1.10) for the CAG and 1.05 (95%CI 0.90–1.22) for the GGC repeats. The estimated relative risk of BC in carriers associated with ≥28 CAG repeats was 1.08 (95%CI 0.45–2.61). Furthermore, no significant association was found if attention was restricted to the Ashkenazi carriers, or only to BRCA1 or BRCA2 carriers. We conclude that, in contrast to previous observations, if there is any effect of the AR repeat length on BRCA1 penetrance, it is likely to be weak. © 2001 Cancer Research Campaign http://www.bjcancer.com