Ovarian Cancer Cluster Region Research Articles

Breast cancer risk associated with missense variants in BRCA2.

10501 Background: Greater than 90% of missense variants in BRCA2 are classified as variants of uncertain significance (VUS). In addition, among the few known missense pathogenic variants (PVs) in BRCA2, breast cancer risk has been reported to be lower compared to pathogenic truncating variants (PTVs) (Li et al., 2022) . Herein, we aim to reclassify several missense variants in BRCA2 and investigate the associated breast cancer risk. Methods: A total of 450 BRCA2 missense variants in the C-terminal DNA binding domain (DBD) were evaluated for functional effect utilizing a previously validated homology-directed DNA double-strand repair (HDR) assay. The results of the functional evaluation along with clinical, structural, and in-silico data were applied to the rules-based ACMG/AMP criteria for variant classification to identify pathogenic/likely pathogenic (P/LP) variants and benign/likely benign (B/LB) variants. A pooled case-control analysis was performed comparing the frequency of reclassified P/LP missense variants among 82,372 women with breast cancer within the Ambry Genetics database as cases and 174,167 unaffected women within gnomAD, CARRIERS, and BRIDGES datasets as controls to evaluate associated breast cancer risk. Separate case-control analysis and comparisons with BRCA2 DBD PTVs, exon 11 PTVs, and known missense PV standards in ENIGMA were also performed. Results: From the 450 missense variants in the DBD, 137 (30.4%) were noted to be functionally deleterious and 313 (69.6%) were functionally neutral by the HDR assay. Incorporation of the functional and other data into an ACMG/AMP model led to the reclassification of 439 (97.6%) variants, with 131 as P/LP and 308 as B/LB variants. In a pooled case-control analysis, reclassified BRCA2 missense P/LP variants were associated with clinically significant increased risks of breast cancer (Odds Ratio (OR):5.6, 95%CI:3.9–8.0), whereas B/LB missense variants were not (OR:1.1, 95%CI:1.1–1.2). Similarly elevated risks of breast cancer were observed for BRCA2 PTVs in the DBD (OR:6.8, 95%CI:5.1–9.0) and missense PV standards in ENIGMA (OR:7.8, 95%CI:4.1–14.7). However, PTVs in exon 11 of BRCA2 were associated with a lower risk of breast cancer (OR:4.4, 95%CI:3.8–4.9) compared to PTVs in DBD, confirming the ovarian cancer cluster region effect in BRCA2. Conclusions: The study demonstrates that the HDR functional assay in conjunction with other clinical and genomic data can be a powerful tool that can aid in the reclassification of > 95% of missense variants in BRCA2. In addition, missense PVs in DBD were noted to have a similarly elevated risk of breast cancer as PTVs. The reclassification of the BRCA2 missense VUS and identification of associated breast cancer risk in this study will significantly influence breast cancer risk assessment and management strategies among carriers of these missense variants.

Abstract 1183: Mutation type and location in breast cancer susceptibility genes are associated with differential risk in the general population

Abstract Two recent studies have defined population-based risk of breast cancer (BC) due to pathogenic variants (PVs) in well-established BC susceptibility genes. Prior studies in high-risk BC cohorts identified variable BC risks based on the position and type of mutation in BRCA1 and BRCA2, and based on the type of mutation in ATM, CHEK2, and PALB2. Whether this variability holds true in the general population has not been evaluated. To determine the BC risks associated with mutations of different types and in different locations in BC susceptibility genes in the general population, we carried out case-control analyses of 32247 cases and 32544 controls in the CARRIERS study, including 12 US population-based studies, and case-control analyses, subset to mutation carriers. We used age-adjusted logistic regression to estimate odds ratios (OR), relative OR (rOR), and 95% confidence intervals (CI) for PVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2. ORs were estimated using the full population of mutation carriers and noncarriers while rORs were estimated within subsets of individual gene mutation carriers. We identified 273 BRCA1, 421 BRCA2, 253 ATM, 351 CHEK2, and 148 PALB2 in women with BC and 35 BRCA1, 84 BRCA2, 139 ATM, 139 CHEK2, and 38 PALB2 variant carriers in those without BC. For BRCA1, we did not find differences in risk by mutation type or location. However, variants leading to nonsense mediated decay (NMD) predicted to have re-initiation at p.M128 had a non-statistical 3-fold higher risk for BC compared to those leading to NMD without re-initiation (rOR 3.1, 0.99-13.52, p = 0.0826). BRCA2 loss of function (LoF) mutations in exons 1-10 had a higher BC risk compared to LoF mutations in the exon 11 (rOR 2.7, 1.1-7.9, p=0.048) ovarian cancer cluster region (OCCR). We did not detect any differences in risk by mutation type or location in ATM, CHEK2, or PALB2. CHEK2 missense variants p.I157T (rOR 0.5, 0.4-0.7, p <0.001) and p.T476M (rOR 0.5, 0.3 - 0.8, p=0.005) were associated with lower BC risk relative to CHEK2 c.1100delC (OR 2.5, 2.0-3.3, p<0.001). The CHEK2 c.444+1G>A splicing variant was associated with highest BC risk among common CHEK2 variants (OR 4.2, 1.9-10.5, p<0.001), but was not statistically significantly different from c.1100delC (rOR 1.7, 0.8-4.3, p=0.230). In summary, we identified a higher BC risk for LoF variants in BRCA2, lower risk for CHEK2 missense mutations, and non-statistical higher risk for NMD/re-initiation BRCA1 variants and CHEK2 c.444+1G>A in this population-based study. Despite the large numbers included in the overall CARRIERS study, the number of PV carriers was relatively small, which may have limited the detection of associations. Nonetheless, we were able to detect genotype-risk associations that have implications for counseling women about their BC risk, and certainly for the development of individualized risks. Citation Format: Mwangala P. Akamandisa, Nicholas Boddicker, Chunling Hu, Siddhartha Yadav, Jeffrey N. Weitzel, Peter Kraft, Susan M. Domchek, Fergus J. Couch, Katherine L. Nathanson, for the CARRIERS Consortium . Mutation type and location in breast cancer susceptibility genes are associated with differential risk in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1183.

Correlation between the risk of ovarian cancer and BRCA recurrent pathogenic variants in Japan.

We previously reported that L63X and Q934X are BRCA1 common founder variants in Japan. So far, there have been no reports of a correlation between such BRCA common variants and the risk of BRCA-related cancers. In this analysis, we investigated the correlation between the risk of ovarian cancer (OC) and BRCA recurrent pathogenic variants. We examined the database of the Japanese organization of hereditary breast and ovarian cancer. The database contained 3517 probands who underwent BRCA genetic testing. Among them, 11.1% (392/3517) had germline BRCA1 pathogenic variant, and 8.3% (293/3517) had BRCA2 pathogenic variant. We calculated the OC prevalence, breast cancer (BC) prevalence, and the ratio of OC to BC within second-degree relatives. The ratio of OC to BC in Q934X family members was significantly higher than that in the overall BRCA1 family members (0.80 vs.0.52: p = 0.038), and the ratio in STOP799 was 0.42, which was relatively lower than the overall BRCA1 value. Both Q934X and STOP799 are located in the ovarian cancer cluster region (OCCR), however there seems to be a difference in the risk of OC. R2318X family members had a significant higher ratio of OC to BC at 0.32 than the overall BRCA2 value of 0.13 (p = 0.012). R2318X is known to be located in the OCCR. This is the first report to investigate the correlation between BRCA recurrent variants and the risk of OC in Japan. The family members of probands with Q934X or R2318X have a higher risk of OC than that with other BRCA variants.

Clinical outcomes of BRCA1/2 pathogenic variants in ovarian cancer cluster region in patients with primary peritoneal, epithelial ovarian, and fallopian tube cancer

ObjectiveAn “ovarian cancer cluster region” (OCCR) has been reported in both BRCA1 and BRCA2. However, the clinical significance of the OCCR of BRCA1/2 has not yet been investigated. MethodsThe medical records of 991 patients with epithelial ovarian, primary peritoneal, and fallopian tube cancer who underwent genetic testing for BRCA1 and/or BRCA2 from January 1, 2006, to August 31, 2019, were retrospectively reviewed. Sanger and next-generation sequencing analyses were used to test the BRCA1 and BRCA2 mutation status. Progression-free survival (PFS) and overall survival (OS) were compared according to the mutation location (OCCR vs. non-OCCR region). Survival outcomes were determined using Kaplan–Meier survival analysis. ResultsA total of 162 patients had BRCA1 pathogenic variants (PVs), and 76 had BRCA2 PVs. Patients with BRCA1 PV that in the OCCR region showed shorter PFS than those with BRCA1 PV outside the OCCR (22.6 months vs. 27.6 months, P = 0.038). In the platinum-sensitive subgroup of BRCA1, patients with BRCA1 PV in the OCCR region showed shorter PFS than those in the non-OCCR group (P = 0.0197). On the other hand, BRCA2 variants did not exhibit any particular trend (32.8 months vs. 27.9 months, P = 0.468). However, no significant differences were detected in OS between patients with BRCA1/2 PVs, regardless of the location of the variants. ConclusionsPatients with BRCA1 PV in the OCCR had shorter PFS than those outside the OCCR. This tendency was more pronounced in the platinum-sensitive subgroup. To our knowledge, this is the first study of BRCA1/2 mutations based on the OCCR.

The first study evaluating the distribution of gBRCA1/2 variants within the ovarian cancer cluster region in Japanese ovarian cancer patients

Objectives: Whether germline BRCA1 (gBRCA1) and BRCA2 (gBRCA2) variants are located within or outside a recently described ovarian cancer cluster region (OCCR) may influence risk variations for ovarian and breast cancers. However, the prevalence of gBRCA1 and gBRCA2 variants within the OCCR has never been evaluated in Japanese ovarian cancer patients. Using the CHARLOTTE study data, we described locations of gBRCA1 and gBRCA2 variants within the OCCR and characteristics of the relevant populations.

Association of gBRCA1/2 mutation locations with ovarian cancer risk in Japanese patients from the CHARLOTTE study.

Whether germline (g) breast cancer susceptibility gene (BRCA) mutations are located within or outside the ovarian cancer cluster region (OCCR) (1380‐4062 bp for gBRCA1, and between 3249‐5681 bp and 6645‐7471 bp for gBRCA2) may influence risk variations for ovarian cancers. This ad hoc analysis of the CHARLOTTE epidemiological study in Japan assessed the distribution of gBRCA1/2 mutations in patients with newly diagnosed ovarian cancer, and investigated an association between gBRCA1/2 mutation locations and ovarian cancer risk. Differences in patient background and clinical characteristics in subgroups stratified by gBRCA1/2 mutation locations were also evaluated. We analyzed the data of 93 patients (14.7%) from the CHARLOTTE study who were positive for gBRCA1/2 mutations. After excluding 16 cases with L63X founder mutation, 28 (65.1%) of gBRCA1 mutations were within the OCCR. Of 30 gBRCA2 mutations, 15 (50.0%) were within the OCCR. Of 27 patients (one patient excluded for unknown family history) with gBRCA1 mutations located in the OCCR, 11 (40.7%) had a family history of ovarian cancer; the proportion of patients with a family history of ovarian cancer and gBRCA1 mutations outside the OCCR was lower (13.3%). Sixty percent of patients with gBRCA1 mutations outside the OCCR had a family history of breast cancer; the proportion of patients with a family history of breast cancer and gBRCA1 mutations within the OCCR was relatively lower (33.3%). Understanding the mutation locations may contribute to more accurate risk assessments of susceptible individuals and early detection of ovarian cancer among gBRCA mutation carriers.

Precision prophylaxis: Identifying the optimal timing for risk-reducing salpingo-oophorectomy based on type of BRCA1 and BRCA2 cluster region mutations

ObjectivesCurrent risk-reducing salpingo-oophorectomy (RRSO) guidelines for individuals with BRCA1/2 mutations do not account for risk variability due to BRCA1/2 cluster region mutations that are associated with varying risks for the development of breast and ovarian cancer. We assessed whether current recommendations are appropriate for individual patients considering mutation-specific risks. MethodsUsing a hypothetical cohort of patients with BRCA1/2 mutations, we constructed Markov models allowing for the estimation of mean life expectancy based upon BRCA1/2 mutation, the presence of a cluster region mutation (Ovarian Cancer Cluster Region (OCCR), Breast Cancer Cluster Region (BCCR), or non-BCCR/OCCR), age at time of BRCA1/2 diagnosis (20–65), and age at time of RRSO (21–80). ResultsFor all BRCA1/2 mutation types, the optimal strategy was to undergo RRSO as early as possible. For BRCA1/2 carriers who delayed RRSO or who were identified with a mutation later in life, the OCCR mutation tended to be associated with lower life expectancy estimates than the BCCR and non-BCCR/OCCR mutations. Minimal delays in RRSO (i.e., neighboring 5-year intervals) were associated with minor losses in life expectancy. Variables associated with greatest impact on life expectancy included ovarian cancer risk after RRSO, breast cancer mortality rate, non-cancer mortality associated with RRSO, and breast cancer stage distribution. ConclusionsBRCA1/2 cluster regions may provide more precise estimates of life expectancy in counselling and shared decision-making. The most appropriate timing for RRSO is a complex decision and must be individualized for each patient.

Clinical Evaluation of BRCA1/2 Mutation in Mexican Ovarian Cancer Patients

Ovarian cancer (OC) is an important cause of gynecologic cancer-related deaths. In Mexico, around 4700 new cases of OC are diagnosed per year and it represents the second cause of gynecological cancer mortality with more than 2700 deaths. Germline mutations in BRCA1/2 genes are present in 13–18% of OC cases. Few studies have evaluated the presence of mutations in BRCA genes in a population of OC Mexican patients and their relationship with clinical response and survival rates.A total of 179 OC patients were studied by molecular testing for BRCA1/2 through next-generation sequencing and multiplex ligation-dependent probe amplification. Recurrence-free survival (RFS) was estimated by the Kaplan–Meier method. BRCA mutation was detected in 33% of patients. A percentage of 66.1% were BRCA1 mutated and 33.9% were BRCA2 mutated. BRCA1 mutation carriers had a worst RFS compared with BRCA2 mutation carriers (37.6 [29–46.2] vs 72.7 [38.4–107.2]; P = 0.030). The most common mutation for BRCA1 was ex9-12del (28.2%) (Mexican founder mutation). The Mexican founder mutation had a better RFS than other BRCA1 mutations (86.1 [37.2–135.1] vs 34.5 [20.7–48.2]; P = 0.033). The presence of BRCA2 mutations in the ovarian cancer cluster region (OCCR) had a significantly better RFS than mutations in breast cancer cluster regions (BCCR) and not-related risk region (NRR) (NR vs 72.8 [39–106.6] vs 25.8 [8.3–43.2]; P = 0.013). These results demonstrate that the prevalence of BRCA1/2 positive patients in OC Mexican patients are the highest reported. Patients with mutations in BRCA2 have a better prognosis than those mutated in BRCA1. The Mexican founder mutation has an important role in clinical outcomes. These results highlight the importance to test all the HGSP (high-grade serous papillary) OC patients with or without cancer family history (CFH) in Mexican population.

BRCA1 and BRCA2 mutations and clinical interpretation in 398 ovarian cancer patients: comparison with breast cancer variants in a similar population

BackgroundOvarian cancer is the leading cause of death worldwide among gynecologic malignancies. The recent approval of inhibitors of poly (ADP-ribose) polymerase (iPARP) in the treatment of ovarian cancer in the presence of a BRCA1/2 mutation has sparked the analysis of women with such diagnosis, which can further benefit from the detection of carriers in the family. Germline sequence and large rearrangements for BRCA1/2 were tested in 398 consecutive epithelial ovarian cancer (EOC) patients.The aim of this study was to identify the frequency and spectrum of germline BRCA1/2 pathogenic alterations in a cohort of patients with ovarian serous carcinoma, with a view to adequately selecting patients for prevention through family counseling and correlating this frequency with platinum sensitivity as a guidance to identify patients eligible for iPARP in our population.ResultsA total of 96 patients carried a pathogenic germline mutation, accounting for an overall 24.1% mutation incidence. Among mutation carriers, BRCA1 showed 62.5% incidence, BRCA2 rendered 36.5%, and one patient exhibited a mutation in both genes. Three pathogenic mutations were recurrent mutations detected five, three, and four times and represented 12.5% of the mutated samples. Worth highlighting, a 50% mutation incidence was detected when breast and ovarian cancer coexisted in the same patient. Novel mutations amounted to 9.4% of the total mutations, as compared to 4.7% in breast cancer. Forty out of 60 BRCA1 mutations were beyond the ovarian cancer cluster region (OCCR), in stark contrast with 22 out of 36 BRCA2 mutations being inside the OCCR. Taken together, germline BRCA1/2 mutations in EOC patients showed a distinct mutational spectrum compared to our previously published data on breast cancer patients.ConclusionsIn sum, our study provides novel data on ovarian BRCA1/2 mutation prevalence worldwide, enhances adequate patient selection for family counseling and prevention, and sheds light on the benefits of iPARP treatment.

Abstract A23: Germline BRCA1 and BRCA2 mutations in Brazilian ovarian and breast cancer patients

Abstract Background: Approximately 5-10% of epithelial ovarian and breast cancer cases are hereditary and germline mutations in BRCA1 and BRCA2 genes are the most common in these patients. Prevalence of clinically relevant mutations in BRCA1/2 differs among different populations, and specifically in Brazil, a country with great ethnic diversity and miscegenation, and only limited data are available to the present moment. In our country, the public health system (SUS) is responsible for the health care of almost 75% of the population; however, genetic tests are not yet covered. Our aim was to evaluate the complete coding sequence of BRCA1/2 genes and large rearrangements in patients diagnosed with epithelial ovarian and breast cancer in the largest cancer hospital from the Brazilian public health system. Methodology: The complete coding sequence of BRCA1/2 genes were evaluated through next-generation or capillary sequencing, and large deletions were investigated through multiplex ligation-dependent probe amplification (MLPA) in four cohorts of patients: 102 unrelated patients diagnosed with epithelial ovarian cancer unselected for family history of breast and/or ovarian cancer; 89 unrelated early-onset breast cancer patients (<35 years); 42 unrelated postmenopausal breast cancer patients (> 55 years) reporting positive breast and ovarian family history; and 49 unrelated breast cancer patients selected through Frank, BRCApro, and Evans algorithms (risk > 10%). Results: Pathogenic mutation in BRCA1/2 genes was detected in 44 patients (44/282: 15.6%; BRCA1, n=27; BRCA2, n=17) featuring 33 different mutations (16 in BRCA1 and 17 in BRCA2), including two large deletions in BRCA1 (exon 1-2 deleted and exon 5-7 deleted). Five mutations were detected more than once in BRCA1 gene (c.211A>G, c.3331_3334delCAAG, c.4484G>T, c.5074+2T>C, and c.5266dupC); however, all mutations in BRCA2 gene were detected only once. Only three ovarian cancer patients had a mutation localized in an ovarian cancer cluster region (OCCR) of BRCA1 and two breast cancer patients in BRCA1 breast cancer cluster regions (BCCR). Ovarian cancer patents most commonly presented BRCA1 mutations and young breast cancer mainly presented BRCA2 mutation. In this series of patients, 24 missense variants of uncertain significance were detected (BRCA1: n=6 and BRCA2: n=18). Considering distribution of pathogenic mutation among the patient groups, a high frequency was observed in two groups: patients diagnosed with epithelial ovarian cancer (18.36%) and breast cancer patients selected by Frank, BRCApro, and Evans algorithms (18.6%). Conclusion: The chance of carrying a BRCA1/2 germline mutation in Brazilian high-risk ovarian and breast cancer patients is 15.6%. The entire gene should be analyzed as mutations are detected in various regions. Financial support: FAPESP, CNPq. Citation Format: Simone Maistro, Giselly Encinas, Tauana Nagy, Natalia Teixeira, Maria Lucia H. Katayama, Ana Carolina R. C. Gouvêa, Maria del Pilar E. Diz, Roger Chammas, Geertruida H. de Boch, Maria Aparecida A. K. Folgueira. Germline BRCA1 and BRCA2 mutations in Brazilian ovarian and breast cancer patients [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A23.

Ovarian cancer in BRCA1/2 mutation carriers: The impact of mutation position and family history on the cancer risk

ObjectivesAssessing the combined impact of mutation position, regarding the ovarian cancer cluster region (OCCR), and type of cancer family history (FH) on age-related penetrance of ovarian cancer (OC) in women from BRCA1/2 families from the northern Netherlands. Study designA consecutive series of 1763 mutation carriers and their first-degree relatives from 355 proven BRCA1/2 families with a history of breast and/or ovarian cancer with in total 248 OC cases was included. Mutations were stratified for gene (BRCA1 or BRCA2) and location (within or outside the OCCR). FH was stratified for type of cancer occurring in first and second-degree relatives (OC only, breast cancer (BC) only or both OC and BC). Main outcome measuresCox-proportional hazard models were applied to estimate the OCCR effect, including and excluding a FH of cancer. ResultsAmong BRCA1 families, OC risks were higher in women with OCCR mutations versus those with non-OCCR mutations (HR=1.59, 95%CI=1.19–2.12). This effect remained significant after adjustment for the type of FH (HR=1.50, 95%CI=1.11–2.01). In BRCA2 families, mutation position did not significantly affect the OC risk (HR=1.50, 95%CI=0.74–3.04). However, in the BRCA2 group, a FH including only OC presented by itself a strong impact on OC risk (HR=4.63, 95%CI=2.38–9.02), which remained stable after adjustment for mutation position (HR=4.48, 95%CI=2.28–8.81). ConclusionOCCR mutations significantly increased the OC risk in BRCA1 families regardless of the type of FH, but in BRCA2 families, type of FH seems to have a higher impact than mutation position on OC risk.

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14

Hereditary breast and ovarian cancer are mainly linked to mutations in BRCA1 and BRCA2 genes which confer a similar cumulative risk of developing breast cancer. Importantly, while BRCA2 mutation carriers generally have a lower cumulative risk for ovarian cancer, mutations clustered in the central portion of BRCA2 are associated with a higher proportion of ovarian compared with breast cancer cases. The boundaries of this ovarian cancer cluster region (OCCR) have been tentatively defined within a 3.3kb region of BRCA2 exon 11, and herein, we reassessed these boundaries using our series of Italian breast/ovarian cancer families. We used direct sequencing to investigate BRCA mutations in 367 breast/ovarian cancer families. We also studied the association between the location of the mutations and the ovarian cancer phenotype in our cohort of BRCA2-mutated families. We observed the novel c.7309_7309delA frameshift mutation and the c.7007G>A deleterious mutation in BRCA2 exons 14 and 13, respectively, in five independent Italian families characterized by a high proportion of ovarian cancer cases. Of note, a significantly higher proportion of ovarian versus breast cancer cases was associated not only with mutations in the previously defined OCCR (OR=5.91; p=0.004), but also with the exon 13-14 region (OR=7.37; p=0.001) in our BRCA2-mutated families. Our data provide initial evidence for a novel putative OCCR in BRCA2 exons 13-14.

Genotype inBRCA-associated Breast Cancers

Women with BRCA1 or 2 mutations are at high risk for breast cancer. For BRCA1, a trend of increasing risk has been associated with increasing downstream (3') location for mutations compared to the upstream (5') mutations in the gene. For BRCA2, an increased risk of breast cancer has been associated with mutations outside of the ovarian cancer cluster region (OCCR). We sought to determine the mutation position in BRCA-associated breast cancers and whether or not there was a genotype-phenotype correlation. Breast cancer patients with BRCA1/2 mutations were identified by a search of a prospectively maintained data base. Mutation site, patient, and tumor characteristics were determined through retrospective review. One hundred and sixty-four patients with BRCA1-associated breast cancer and 109 patients with BRCA2-associated breast cancer were identified. Among patients with BRCA1-associated cancers, 86 (52%) had mutations in the 5' half of the gene. Among patients with BRCA2-associated breast cancers, 40 (37%) had OCCR mutations. Although BRCA1-associated tumors were more likely to be ER/PR- than BRCA2-associated cancers (p < 0.0001), there was no difference in the tumor characteristics among BRCA1 or BRCA2-associated cancers based on mutation location. In this single-institution study, over half of BRCA1-associated and over a third of BRCA2-associated breast cancers were associated with putative lower risk mutations. Although we cannot exclude the possibility that mutations in these regions confer a lower relative risk for breast cancer, vigilance in cancer screening and prevention remains necessary. Further studies in genotype/phenotype correlation are needed to individualize prevention strategies.

Mutation position in BRCA-associated breast cancers.

1542 Background: Individuals with germline BRCA1 or 2 mutations are at high risk for breast cancer; studies are ongoing to determine subgroups that may be at lower risk. For BRCA1, a trend of increasing risk has been associated with increasing downstream (3′) location of mutations compared to the upstream (i.e., 5’) mutations. For BRCA2, compared with no mutation, an increased risk of breast cancer has been associated with mutations outside of the “ovarian cancer cluster region” (OCCR). We sought to determine the mutation position in BRCA- associated breast cancers and whether there was a genotype-phenotype correlation. Methods: Patients with breast cancer with BRCA1 or 2 mutations were identified by a search of a prospectively maintained database at a major cancer center. BRCA mutation site, patient and tumor characteristics were determined through retrospective review. Results: One hundred and sixty patients with BRCA1-associated breast cancers and 102 patients with BRCA2-associated breast cancer were identified. Of 160 patients with BRCA1-associated cancers, 85 (53%) had mutations in the 5’ half of the gene. There was no difference in median age, tumor size, ER/PR status and nodal status between patients with 5’ vs. 3’ mutations. Of the 102 patients with BRCA2-associated breast cancers, 37 (36%) had OCCR mutations. There was no difference in median age, tumor size, ER/PR status and nodal status between patients with OCCR vs non-OCCR mutations. Conclusions: In this single institution study, over half of BRCA1-associated breast cancers and over a third of BRCA2-associated breast cancers were associated with putative lower risk mutation positions. Although we cannot exclude that patients with mutations in these regions have a lower relative risk for breast cancer, vigilance in cancer screening and prevention remains necessary. Further studies in genotype/phenotype correlation are needed to individualize cancer prevention strategies. No significant financial relationships to disclose.

2154 BRCA2 MUTATION WITH A DIAGNOSIS OF PROSTATE CANCER FROM HIGH RISK BREAST CANCER FAMILIES CONFERS A SUBSTANTIALLY INCREASED RISK OF CANCER RELATED MORTALITY

You have accessJournal of UrologyProstate Cancer: Detection and Screening V1 Apr 20102154 BRCA2 MUTATION WITH A DIAGNOSIS OF PROSTATE CANCER FROM HIGH RISK BREAST CANCER FAMILIES CONFERS A SUBSTANTIALLY INCREASED RISK OF CANCER RELATED MORTALITY Ivan Ho, Heather Thorne, Amber Willems, David Clouston, Stephen Fox, Jason Li, and Damien Bolton Ivan HoIvan Ho Heidelberg, Melbourne, Australia More articles by this author , Heather ThorneHeather Thorne Melbourne, Australia More articles by this author , Amber WillemsAmber Willems Melbourne, Australia More articles by this author , David CloustonDavid Clouston Melbourne, Australia More articles by this author , Stephen FoxStephen Fox Melbourne, Australia More articles by this author , Jason LiJason Li Melbourne, Australia More articles by this author , and Damien BoltonDamien Bolton Melbourne, Australia More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2256AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To ascertain the impact upon clinical and pathologic features of men with a verified diagnosis of prostate cancer who are confirmed carriers and non carriers of a family specific pathogenic BRCA1 or BRCA2 mutation. METHODS From a database of familial breast cancer 167 cases of prostate cancer were identified. Genotyping was undertaken to ascertain BRCA mutation status of the patients concerned, identifying 35 males positive for BRCA2 mutation. The clinical and pathologic outcomes of prostate cancer were assessed in detail for this group, with review of medical records and reassessment of all prostate cancer tissue by a specialist uropathologist. RESULTS 77% of BRCA2 mutation positive prostate cancers were in the high risk category for progression to advanced disease, with a preponderence of Gleason score 8 or higher cancers noted. 20 of the 35 patients had died, 19 from their prostate cancers. Mean time from diagnosis to death in this group was 4.7 years. Twenty additional solid organ cancers had been detected in this group, including melanoma and male breast cancer, indicating the general tumor suppressor function of the BRCA gene. Position of the BRCA2 mutation within the central region of the locus (the area termed the ovarian cancer cluster region in females) did not appear to affect disease outcome. Overall survival does appear to be longer in these patients where there has been early diagnosis of the prostate cancer at a stage sufficient to justify attempted radical local therapy. CONCLUSIONS A diagnosis of prostate cancer in males with proven BRCA2 mutation confers a much higher risk of disease progression than is seen with prostate cancer in the community. Early awareness of this trend to more rapid disease progression is essential in males from high risk families and consideration should be given to screening of this high risk cohort with PSA testing and prostate biopsy. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e837 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ivan Ho Heidelberg, Melbourne, Australia More articles by this author Heather Thorne Melbourne, Australia More articles by this author Amber Willems Melbourne, Australia More articles by this author David Clouston Melbourne, Australia More articles by this author Stephen Fox Melbourne, Australia More articles by this author Jason Li Melbourne, Australia More articles by this author Damien Bolton Melbourne, Australia More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Identification of a Novel Pathogenic Mutation in BRCA2 in a Spanish Breast-Ovarian Cancer Family

Germline mutations in the BRCA1/2 genes contribute to most of inherited breast and ovarian cancers. We analyzed a family fulfilling classical criteria of hereditary breast/ovarian cancer. After complete sequencing of coding regions and splice junctions of both genes, a nonpreviously reported mutation in BRCA2 was detected in the index case. Direct mutation detection was performed with their relatives, and three of them were also mutation carriers, two healthy males and a patient afflicted with borderline ovarian cancer. The c.2999delCT, consists of a deletion of two bases in exon 11, in the limits of the ovarian cancer cluster region. This is a frameshift mutation that causes a disruption of the translational reading frame resulting in a stop codon 10 amino acids downstream in the 934 position of the BRCA2 protein, causing a truncation protein. This often causes a loss of function in the protein as critical parts of the amino acid chain are no longer created. Because of it, this mutation must be classified as pathogenic and can be regarded as the cause of the cancers in this family.

BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases

It is believed that BRCA1 and BRCA2 germline mutations account for the majority of hereditary ovarian carcinomas; however, to the authors' knowledge, there are scant data on the prevalence and spectrum of mutations, genotype/phenotype correlations, tumor histology, and family history characteristics. To address this gap, the authors conducted a population-based study of 232 incident epithelial ovarian carcinomas in the Tampa Bay area. Genetic testing for the BRCA1 and BRCA2 genes was performed through full sequencing and BRCA1 rearrangement testing. Of 209 women with invasive ovarian carcinoma, 32 women (15.3%) had mutations in BRCA1 or BRCA2, including 20 BRCA1 mutations and 12 BRCA2 mutations. Of the BRCA2 mutations, 58% were outside the "ovarian cancer cluster region" (OCCR). Variants of uncertain significance were detected in 8.2% of women with invasive ovarian carcinoma. No mutations were identified in women with borderline or invasive mucinous tumors. Among the BRCA mutation-positive women, 63% had serous tumors. A family history of breast and/or ovarian carcinoma was reported in 65%, 75%, and 43.5% of relatives of BRCA1 carriers, BRCA2 carriers, and non-BRCA1/BRCA2 carriers, respectively. The data from this study suggested that 1) previous studies may have underestimated the frequency of BRCA1 and BRCA2 mutations in ovarian carcinomas, especially outside the OCCR; 2) it may be reasonable to offer genetic counseling to any woman with an invasive, nonmucinous epithelial ovarian tumor; and 3) among patients with invasive ovarian carcinoma, family history is not sufficiently accurate to predict mutation status.

Does nonsense-mediated mRNA decay explain the ovarian cancer cluster region of the BRCA2 gene?

BRCA2 (BReast CAncer susceptibility gene 2) germline mutation carriers are at increased risk for breast and ovarian cancers. Mutations occurring in the ovarian cancer cluster region (OCCR) are linked to higher ovarian cancer and/or lower breast cancer risk(s) than mutations occurring elsewhere in BRCA2. Most BRCA2 germline mutations introduce premature termination codons (PTCs), making their mRNAs likely targets of nonsense-mediated mRNA decay (NMD), a mechanism that eliminates PTC-bearing transcripts to prevent expression of truncated proteins. Contradictory evidence exists regarding whether NMD can be triggered by PTCs located far upstream of the nearest exon-exon junction (EEJ). Since the OCCR comprises a major portion of the 4.9 kb exon 11 of BRCA2, we investigated if transcripts bearing PTCs in this large exon are unable to trigger NMD, and if this might contribute to the phenotypic difference associated with the OCCR. We examined cDNA from 18 carriers of PTC-introducing germline mutations located throughout BRCA2, and found that PTC-bearing transcripts were 1.4-3.3-fold less prevalent than their nonmutated counterparts irregardless of PTC position. We conclude that NMD can recognize PTCs up to 4.5 kb upstream of the nearest EEJ, demonstrating that a general inability of NMD to recognize PTCs in exon 11 is unlikely to explain the genotype-phenotype correlation associated with the OCCR.

Determining joint carrier probabilities of cancer-causing genes using Markov chain Monte Carlo methods

In genetic counseling for cancer risk, the probability of carrying a mutation of a cancer-causing gene plays an important role. Family history of various cancers is important in calculating this probability. BRCAPRO is a widely used software for calculating the probability of carrying mutations in BRCA1 and BRCA2 genes given the family history of breast and ovarian cancer in first- and second-degree relatives. BRCAPRO uses an analytical (exact) calculational procedure. Using Markov chain Monte Carlo (MCMC) methods, we extend BRCAPRO to handle, in principle, any type of cancer, family history, any number of genes and alleles that each gene may have. When the information used in this MCMC approach is the same as for BRCAPRO (two genes: BRCA1 and BRCA2; two cancers: breast and ovarian; first- and second-degree relatives only), the two approaches give essentially the same answer. Extending the model to include (1) prostate cancer, (2) two mutated alleles of BRCA2, namely, mutations in Ovarian Cancer Cluster Region (OCCR) and non-OCCR region, and (3) relatives of degree greater than second-degree, leads to different carrier probabilities. The MCMC approach is a useful tool in building a comprehensive model to give accurate estimates of carrier probabilities. Such an approach will be even more important as additional information about the genetics of various cancers becomes available.