BRCA1 Variations Research Articles

Effects of BRCA variation on prognosis in patients with nonmetastatic breast cancer.

To compare the clinicopathological characteristics of nonmetastatic breast cancer patients with and without BRCA variations and to investigate the impact of BRCA variations on prognosis. This retrospective single-center study involved an analysis of 938 patients with localized or locally advanced breast cancer who underwent BRCA variation testing. The patients were divided into three groups: 757 were without BRCA variation, 64 were with BRCA1 variation, and 117 were with BRCA2 variation. In patients with BRCA1 variation, the Ki67, grade, and frequency of triple-negative breast cancer were significantly higher than in patients without BRCA variation and with BRCA2 variation. The 5-year disease-free survival in patients with BRCA1 variation was significantly worse than the other two groups (without BRCA, BRCA1, and BRCA2; 87.7%, 69.9%, and 95.3%, respectively, p=0.049). Multivariate analysis detected no significant difference between groups. The pathological complete response rates with neoadjuvant therapy were significantly better in patients with BRCA variations than those without BRCA variations (49.2%vs. 29.6%, p=0.024). Patients with BRCA1 variation had more aggressive tumor characteristics, such as higher Ki67 and higher grade. Also, triple-negative breast cancer was more common. The presence of BRCA1 variation may worsen survival outcomes. Neoadjuvant treatment responses of patients with BRCA variations were significantly better, and neoadjuvant treatment may contribute to survival outcomes in nonmetastatic patients with BRCA variations.

Using species richness calculations to model the global profile of unsampled pathogenic variants: Examples from BRCA1 and BRCA2.

There have been many surveys of genetic variation in BRCA1 and BRCA2 to identify variant prevalence and catalogue population specific variants, yet none have evaluated the magnitude of unobserved variation. We applied species richness estimation methods from ecology to estimate "variant richness" and determine how many germline pathogenic BRCA1/2 variants have yet to be identified and the frequency of these missing variants in different populations. We also estimated the prevalence of germline pathogenic BRCA1/2 variants and identified those expected to be most common. Data was obtained from a literature search including studies conducted globally that tested the entirety of BRCA1/2 for pathogenic variation. Across countries, 45% to 88% of variants were estimated to be missing, i.e., present in the population but not observed in study data. Estimated variant frequencies in each country showed a higher proportion of rare variants compared to recurrent variants. The median prevalence estimate of BRCA1/2 pathogenic variant carriers was 0.64%. BRCA1 c.68_69del is likely the most recurrent BRCA1/2 variant globally due to its estimated prevalence in India. Modeling variant richness using ecology methods may assist in evaluating clinical targeted assays by providing a picture of what is observed with estimates of what is still unknown.

Ethnic-specificity, evolution origin and deleteriousness of Asian BRCA variation revealed by over 7500 BRCA variants derived from Asian population.

Pathogenic variation in BRCA1 and BRCA2 (BRCA) causes high risk of breast and ovarian cancer, and BRCA variation data are important markers for BRCA-related clinical cancer applications. However, comprehensive BRCA variation data are lacking from the Asian population despite its large population size, heterogenous genetic background and diversified living environment across the Asia continent. We performed a systematic study on BRCA variation in Asian population including extensive data mining, standardization, annotation and characterization. We identified 7587 BRCA variants from 685 592 Asian individuals in 40 Asia countries and regions, including 1762 clinically actionable pathogenic variants and 4915 functionally unknown variants (https://genemutation.fhs.um.edu.mo/Asian-BRCA/). We observed the highly ethnic-specific nature of Asian BRCA variants between Asian and non-Asian populations and within Asian populations, highlighting that the current European descendant population-based BRCA data is inadequate to reflect BRCA variation in the Asian population. We also provided archeological evidence for the evolutionary origin and arising time of Asian BRCA variation. We further provided structural-based evidence for the deleterious variants enriched within the functionally unknown Asian BRCA variants. The data from our study provide a current view of BRCA variation in the Asian population and a rich resource to guide clinical applications of BRCA-related cancer for the Asian population.

Racial and ethnic variation in BRCA1 and BRCA2 genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center.

The prevalence of pathogenic variants in BRCA1 and BRCA2 in populations other than Ashkenazi Jewish (AJ) is not well defined. We describe the racial and ethnic-specific prevalence of BRCA1/2 pathogenic variants and variants of uncertain significance (VUS) among individuals referred for genetic testing in a large urban comprehensive cancer center over a 20-year period. The population included 3,537 unrelated individuals who underwent genetic testing from January 1999 to October 2019 at the Karmanos Cancer Institute. We estimated the prevalence of pathogenic variants and VUS and evaluated associations with race and ethnicity for African American (AA), Arab, AJ and Hispanic individuals compared to Non-Hispanic Whites (NHW). We used multivariable models to adjust for other predictors of pathogenic variants. We also reported the most common pathogenic variants by racial and ethnic group. The racial and ethnic breakdown of our population was: NHW (68.9%), AA (20.3%), AJ (2.5%), Arab (2.2%), Hispanic (1.0%), Asian Pacific Islander, Native American/Alaskan Native (4.7%), and < 1% unknown. The overall prevalence of pathogenic variants in BRCA1/2 was 8.9% and the prevalence of VUS was 5.6%. Compared to NHW, there were no racial or ethnic differences in the rate of pathogenic variants. However, AA individuals were more likely to have VUS in BRCA1 (adjusted OR 2.43, 95% CI 1.38-4.28) and AJ weremore likely to have VUS in BRCA2 (adjusted OR 3.50, 95% CI 1.61-6.58). These results suggest the continued need for genetic testing and variant reclassification for individuals of all racial and ethnic groups.

Abstract P6-08-15: Racial and ethnic variation in BRCA1 and BRCA2 genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center

Abstract Background It is estimated that up to 10% of women diagnosed with breast cancer in the United States have a BRCA1 or BRCA2 inherited susceptibility, which accounts for approximately 125,000 women. There are racial and ethnic differences in the prevalence and types of pathogenic mutations and variants of uncertain significance (VUS) in BRCA1 and BRCA2. To better understand the prevalence of recurring pathogenic mutations and/or uncover novel mutations in specific racial and ethnic groups, we evaluated the mutational profile of individuals who had genetic counseling and testing at a large urban NCI designated Comprehensive Cancer Center. Methods Data was extracted from the Karmanos Cancer Institute (KCI) Cancer Genetic Counseling Service database over a 19 year period through 12/31/18. The cohort consisted of 5,929 individuals evaluated for high-risk of hereditary disease at 6 sites across Michigan including Detroit. We estimated the prevalence of BRCA1/2 pathogenic mutations and variants of uncertain significance (VUS) by race and ethnicity. Odds Ratios (OR) and 95% confidence intervals (CI) were calculated to compare the rate of pathogenic and VUS mutations in race and ethnic groups with non-Hispanic whites (NHW) indicated as the reference group. Results There were 3,114 (52.5%) unrelated individuals who underwent clinical BRCA1/2 testing. The racial/ethnic breakdown of the cohort included: 68.4% NHW, 21% African American (AA), 2.7% Ashkenazi Jewish (AJ), 2.2% Arab, 0.9% Hispanic (H), and 4.8% other. There were 290 individuals with pathogenic mutations (137 BRCA1 and 153 BRCA2) and 186 with VUS (61 BRCA1 and 125 BRCA2). For BRCA1, there were no differences by race and ethnicity in pathogenic mutations, however AA and Arab individuals were more likely to have VUS compared to NHW (OR &amp; 95% CI, 2.63, 1.53-4.54 and 3.39, 1.01-11.41) respectively. For BRCA2, AJ individuals were more likely to have pathogenic mutations compared to NHW (OR &amp; 95% CI, 2.51, 1.22-5.17) and both AA and AJ individuals were more likely to have VUS (OR &amp; 95% CI, 1.55, 1.02-2.35 and 3.15, 95% CI 1.46-6.79) respectively. The table lists the most common pathogenic mutations seen in BRCA1 and BRCA2 by race and ethnicity. All mutations are unique and seen in more than one person unless indicated. Conclusions AA, Arab and AJ individuals were more likely to have VUS in BRCA1&amp;BRCA2 than NHW suggesting the importance of variant reclassification in understanding cancer risk in racial and ethnic minority groups. Understanding the prevalence of BRCA1/2 mutations in specific racial and ethnic groups can potentially lead to customization of genetic testing and possible classification of new founder mutations. The most common pathogenic mutations by race and ethnicityRace/EthnicityBRCA1 (n)BRCA2 (n)% of Total MutationsNHWp.Glu1756Pro (14)p.Ile605Asn (7)p.Cys61Glu (5)p.Arg645Glu (2)p.Ser1253Arg (4)p.Ala938Pro (2)BRCA1: 28/102=27.5%p.Lys894Thr (3)p.Glu2198Asn (2)BRCA2: 17/103=16.5%p.Asp825Glu (2)2)p.Gln1886Ter (2)p.Asn312Ile (2)AA5296del4 (2)p.Gly1013Glu (2)IVS16+6T&amp;gt;C (2)p.Lys2496Ter (2)BRCA1: 6/23=26.1%p.Thr276Ala (2)p.Lys936Asn (2)BRCA2: 8/32=25%p.Lys1872Asn (2)AJp.Glu23Val (1)p.Ser1982Arg (5)BRCA1: 1/1=100%BRCA2: 5/9=55.6%Arabp.Gln12X(1)p.Ile1859Lys (2)BRCA1: 1/5=20%BRCA2: 2/3 = 66.7%Hispanicp.Arg71Gly (1)p.Glu1308Ter (1)BRCA1: 1/1=100%BRCA2: 1/1=100% Citation Format: Michael Steven Simon, Nadline Abdallah, Hadeel Assad, Rachel Reagle, Nancie Petrucelli, Kristen Purrington. Racial and ethnic variation in BRCA1 and BRCA2 genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-15.

Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants.

Testing for variation in BRCA1 and BRCA2 (commonly referred to as BRCA1/2), has emerged as a standard clinical practice and is helping countless women better understand and manage their heritable risk of breast and ovarian cancer. Yet the increased rate of BRCA1/2 testing has led to an increasing number of Variants of Uncertain Significance (VUS), and the rate of VUS discovery currently outpaces the rate of clinical variant interpretation. Computational prediction is a key component of the variant interpretation pipeline. In the CAGI5 ENIGMA Challenge, six prediction teams submitted predictions on 326 newly-interpreted variants from the ENIGMA Consortium. By evaluating these predictions against the new interpretations, we have gained a number of insights on the state of the art of variant prediction and specific steps to further advance this state of the art.

BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2.

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project’s outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases—Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)—as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

Variation of exon 11 of the BRCA1 gene in patients with familial breast cancer at Mohammed VI center for treatment of cancers

Breast cancer is predominantly sporadic, but familial aggregation has been found in 20% of cases. However, only 5 to 10% of breast cancers could be explained by hereditary predisposition. The objective of study determines the mutations of the BRCA1 gene in patients with familial breast cancer and to describe clinical and pathological features associated with these variations.In this study an analysis of exon 11 of BRCA1 gene in 27 Moroccan women with breast cancer family by Sanger sequencing.The mean age of patients was 41.3 ± 9.1 years. 14.8% of the cases were menopausal and oral contraceptives was found in 22.2% of cases. The stage at diagnosis was early (stage II and I) in the majority of cases (59.3%). The c.2612C>T (p.Pro871Leu) was found in 70.4% of the cases. The c.2596C>T (p.Arg866Cys) was present in only one case. The c.2884C>T (p.Glu962Lys) was found in only one case.A significant difference in the age of onset of cancer was observed. Patients with BRCA1 variation were younger compared to those with no change (40.3 ± 9.5 versus 43.6 ± 8.2 years p = 0.04).It should be noted that in our series studied, 7.4% of the cases present a genetic variation and seems to be involved in the carcinogenesis of the breast cancer. The results presented in this study are the first to determine the proportion of familial breast cancer in our center and that have the existence of molecular signatures associated with the presence of a mutation of BRCA1 gene.

Common variation in BRCA1 may have a role in progression to lethal prostate cancer after radiation treatment.

To evaluate whether single-nucleotide polymorphisms (SNPs) reflecting common variation in the tumor suppressor BRCA1 affect prostate cancer outcomes. Because radiation therapy (RT) induces DNA damage, we hypothesized that common variation in BRCA1 has a role in progression to lethal prostate cancer, particularly in patients receiving RT. We followed 802 men diagnosed with localized prostate cancer (cT1-T3/N0/M0) who were treated with RT in the US Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS), for progression to lethal prostate cancer. Six SNPs (rs3737559, rs1799950, rs799923, rs915945, rs4474733 and rs8176305) were genotyped in HPFS to capture common variation across BRCA1. rs4474733 and rs8176305 were also evaluated in the PHS cohort. Cox proportional hazards models were used to estimate per-allele hazard ratios (HR) and 95% confidence intervals (CI) stratified by primary treatment. In the RT group (n=802), 71 men progressed to lethal disease during a mean follow-up of 12 years. We found that two SNPs, rs4473733 (HR: 0.65; 95% CI 0.42-0.99) and rs8176305 (HR: 2.03; 95% CI 1.33-3.10), were associated with lethal prostate cancer in men receiving RT. Common variation in BRCA1 may influence clinical outcomes in patients receiving RT for localized prostate cancer by modifying the response to RT. Our findings merit further follow-up studies to validate these SNPs and better understand their functional and biological significance.

Evaluation of genetic variations in miRNA-binding sites of BRCA1 and BRCA2 genes as risk factors for the development of early-onset and/or familial breast cancer.

Although genetic markers identifying women at an increased risk of developing breast cancer exist, the majority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron- exon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/ BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphisms were identified. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3'UTR region of the BRCA1/2 genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship between the BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher's Exact Test. SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.

PD31-05 BRCA1 SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) MAY HELP IDENTIFY PATIENTS AT RISK FOR LETHAL PROSTATE CANCER OR RECURRENCE AFTER TREATMENT WITH RADIATION THERAPY (RT)

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History I1 Apr 2014PD31-05 BRCA1 SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) MAY HELP IDENTIFY PATIENTS AT RISK FOR LETHAL PROSTATE CANCER OR RECURRENCE AFTER TREATMENT WITH RADIATION THERAPY (RT) Alejandro Sanchez, Irene M. Shui, Jonathan Schoenfeld, Paul Nguyen, Kathryn Penney, Michelangelo Fiorentino, Dipanjan Choudhury, Meir Stampfer, Edward Giovannucci, and Lorelei Mucci Alejandro SanchezAlejandro Sanchez More articles by this author , Irene M. ShuiIrene M. Shui More articles by this author , Jonathan SchoenfeldJonathan Schoenfeld More articles by this author , Paul NguyenPaul Nguyen More articles by this author , Kathryn PenneyKathryn Penney More articles by this author , Michelangelo FiorentinoMichelangelo Fiorentino More articles by this author , Dipanjan ChoudhuryDipanjan Choudhury More articles by this author , Meir StampferMeir Stampfer More articles by this author , Edward GiovannucciEdward Giovannucci More articles by this author , and Lorelei MucciLorelei Mucci More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2264AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The tumor suppressor BRCA1 regulates the maintenance of genome integrity through its DNA repair role. While rare BRCA1 mutations have been associated with familial prostate cancer (PCa) risk, few studies have assessed how common variation predicts PCa outcomes. We assessed whether common genetic variation in BRCA1 was associated with PCa progression. Moreover, we hypothesized that due to the relevance of the DNA repair pathway with radiosensitivity, the associations with BRCA1 SNPs and PCa outcomes would be stronger in patients treated with RT compared to those treated with radical prostatectomy (RP). METHODS We followed 1215 men diagnosed with early-stage PCa (clinical stage T1-T3/N0/M0) between 1993-2004 in the US Health Professionals Follow-up Study for progression to lethal PCa (distant metastases or PCa specific-mortality) and PCa recurrence (biochemical recurrence or lethal PCa). Six SNPs were genotyped to capture common variation (R2>0.8) across BRCA1. We used Cox proportional hazards models to estimate per-allele hazard ratios (HR) and 95% confidence intervals (CI) for the SNPs with progression to lethal PCa or recurrence, adjusted for age at diagnosis (primary model) and Gleason score and clinical stage (secondary models). To assess if the association of the SNPs and PCa progression differed by primary treatment we conducted stratified analyses by RT and RP. RESULTS Mean age at diagnosis was 69 years and median follow-up of 12 years, during which 90 men progressed to lethal disease and 300 had a recurrence event through 2012. 447 men received RT and 543 received RP as primary treatment. Overall, none of the SNPs were significantly associated with prostate cancer progression. However, 2 SNPs were associated with progression in men treated with RT, but not RP (See Table 1). Adjusting for Gleason score and clinical stage did not change the interpretation. CONCLUSIONS BRCA1 SNPs may play a role in modifying the response to radiation therapy in patients treated for localized PCa. Further studies are needed to evaluate these SNPs as potential tools to help determine the best treatment modality for patients. Table 1. SNPs associated with prostate cancer progression or lethal disease, stratified by treatment. HR = Hazard ratio, CI = 95% confidence intervals Lethal Recurrence RP RT RP RT SNP HR(CI) HR (CI) p-interaction HR(CI) HR(CI) p-interaction rs8176305 0.36(0.09-1.45) 3.55(2.04-6.17) 0.003 0.83(0.51-1.33) 1.80(1.25-2.59) 0.01 rs4474733 1.10(0.6-1.94) 0.66(0.34-1.22) 0.23 1.15(0.86-1.52) 0.66(0.48-0.91) 0.01 © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e832-e833 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Alejandro Sanchez More articles by this author Irene M. Shui More articles by this author Jonathan Schoenfeld More articles by this author Paul Nguyen More articles by this author Kathryn Penney More articles by this author Michelangelo Fiorentino More articles by this author Dipanjan Choudhury More articles by this author Meir Stampfer More articles by this author Edward Giovannucci More articles by this author Lorelei Mucci More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD31-06 DAIRY INTAKE AND PROSTATE CANCER RISK: RESULTS FROM THE CALIFORNIA COLLABORATIVE PROSTATE CANCER STUDY

familial prostate cancer (PCa) risk, few studies have assessed how common variation predicts PCa outcomes. We assessed whether common genetic variation in BRCA1 was associated with PCa progression. Moreover, we hypothesized that due to the relevance of the DNA repair pathway with radiosensitivity, the associations with BRCA1 SNPs and PCa outcomes would be stronger in patients treated with RT compared to those treated with radical prostatectomy (RP). METHODS: We followed 1215 men diagnosed with early-stage PCa (clinical stage T1-T3/N0/M0) between 1993-2004 in the US Health Professionals Follow-up Study for progression to lethal PCa (distant metastases or PCa specific-mortality) and PCa recurrence (biochemical recurrence or lethal PCa). Six SNPs were genotyped to capture common variation (R2>0.8) across BRCA1. We used Cox proportional hazards models to estimate per-allele hazard ratios (HR) and 95% confidence intervals (CI) for the SNPs with progression to lethal PCa or recurrence, adjusted for age at diagnosis (primary model) and Gleason score and clinical stage (secondary models). To assess if the association of the SNPs and PCa progression differed by primary treatment we conducted stratified analyses by RT and RP. RESULTS: Mean age at diagnosis was 69 years and median follow-up of 12 years, during which 90 men progressed to lethal disease and 300 had a recurrence event through 2012. 447 men received RT and 543 received RP as primary treatment. Overall, none of the SNPs were significantly associated with prostate cancer progression. However, 2 SNPs were associated with progression in men treated with RT, but not RP (See Table 1). Adjusting for Gleason score and clinical stage did not change the interpretation. CONCLUSIONS: BRCA1 SNPs may play a role in modifying the response to radiation therapy in patients treated for localized PCa. Further studies are needed to evaluate these SNPs as potential tools to help determine the best treatment modality for patients.

ENIGMA-Evidence-based network for the interpretation of germline mutant alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes

As genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant fraction of tests results in the detection of a genetic variant for which disease association is not known. The finding of an "unclassified" variant (UV)/variant of uncertain significance (VUS) complicates genetic test reporting and counseling. As these variants are individually rare, a large collaboration of researchers and clinicians will facilitate studies to assess their association with cancer predisposition. It was with this in mind that the ENIGMA consortium (www.enigmaconsortium.org) was initiated in 2009. The membership is both international and interdisciplinary, and currently includes more than 100 research scientists and clinicians from 19 countries. Within ENIGMA, there are presently six working groups focused on the following topics: analysis, clinical, database, functional, tumor histopathology, and mRNA splicing. ENIGMA provides a mechanism to pool resources, exchange methods and data, and coordinately develop and apply algorithms for classification of variants in BRCA1 and BRCA2. It is envisaged that the research and clinical application of models developed by ENIGMA will be relevant to the interpretation of sequence variants in other disease genes.

BRCA1 mutations and colorectal cancer in Poland

Evidence to date that germline mutations in the tumor suppressor gene BRCA1 increase the incidence of colorectal cancer is mixed, and both positive and negative results have been reported. To establish whether or not inherited variation in BRCA1 influences the risk of colorectal cancer, we genotyped 2,398 unselected patients with colorectal cancer and 4,570 controls from Poland for three BRCA1 founder mutations (C61G, 4153delA and 5382insC). A BRCA1 mutation was present in 0.42% of unselected cases of colorectal cancer and in 0.48% of controls (OR = 0.8; P = 0.8). The mutation frequency was slightly higher (0.93%) in 321 cases who reported a family history of colon cancer in a first- or second-degree relative (OR = 1.9; P = 0.5). A BRCA1 mutation was also seen in excess (0.82%) in 851 cases who were diagnosed with colorectal cancer at age 60 or earlier (OR = 1.7; P = 0.3). The mean age at onset in carriers was 7 years younger than in non-carriers (57.0 years vs. 64.0) and the difference was significant (P = 0.05). This study suggests that BRCA1 mutations may be associated with early-onset of colorectal cancer.

BRCA1 mutations and prostate cancer in Poland

Evidence to date that BRCA1 mutation carriers are at an increased risk of prostate cancer is mixed - both positive and negative studies have been published. To establish whether or not inherited variation in BRCA1 influences prostate cancer risk we genotyped 1793 men with prostate cancer in Poland and 4570 controls for three founder mutations (C61G, 4153delA and 5382insC). A BRCA1 mutation was present in 0.45% of the cases and 0.48% of the controls (odds ratio=0.9; P=1.0). The odds ratios varied substantially by mutation. The 5382insC mutation is the most common of the three founder mutations. It was detected only in one case (0.06%), whereas it was seen in 0.37% of controls (P=0.06). In contrast, the 4153delA was more common in prostate cancer cases (0.22%) than in controls (0.04%) (odds ratio=5.1; 95% confidence interval: 0.9-27.9; P=0.1). The C61G mutation was also found in excess in cases (0.17%) compared with controls (0.07%) (odds ratio=2.6; 95% confidence interval: 0.5-12.7; P=0.5). Eight men with prostate cancer carried a mutation. Only one of these carried the 5382insC mutation, compared with 17 of 22 individuals with mutations in the control population (P=0.003). These data suggest that the 5382insC mutation is unlikely to be pathogenic for prostate cancer in the Polish population. The presence of one of the other alleles was associated with an increased risk for prostate cancer (odds ratio=3.6; 95% confidence interval: 1.1-11.3; P=0.045); in particular for familial prostate cancer (odds ratio=12; 95% confidence interval: 2.9-51; P=0.0004). We consider that the risk of prostate cancer in BRCA1 carriers varies with the position of the mutation.

A Haplotype-Based Case-Control Study of BRCA1 and Sporadic Breast Cancer Risk

Rare, highly penetrant germ line mutations in BRCA1 strongly predispose women to a familial form of breast and ovarian cancer. Whether common variants (either coding or noncoding) at this locus contribute to the more common form of the disease is not yet known. We tested common variation across the BRCA1 locus in African American, Native Hawaiian, Japanese, Latino, and White women in the Multiethnic Cohort Study. Specifically, 28 single nucleotide polymorphisms (SNPs) spanning the BRCA1 gene were used to define patterns of common variation in these populations. The majority of SNPs were in strong linkage disequilibrium with one another, indicating that our survey captured most of the common inherited variation across this gene. Nine tagging SNPs, including five missense SNPs, were selected to predict the common BRCA1 variants and haplotypes among the non-African American groups (five additional SNPs were required for African Americans) and genotyped in a breast cancer case-control study nested in the Multiethnic Cohort Study (cases, n = 1,715; controls, n = 2,502). We found no evidence for significant associations between common variation in BRCA1 and risk of breast cancer. Given the large size of our study population and detailed analysis of the locus, this result indicates either that common variants in BRCA1 do not substantially influence sporadic breast cancer risk, or that unmeasured heterogeneity in the breast cancer phenotype or unmeasured interactions with genetic or environmental exposures obscure our ability to detect any influence that may be present.

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

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