BRCA1 Founder Research Articles

DNA damage targeted therapy for advanced breast cancer.

Breast cancer (BC) is the most prevalent malignancy affecting women worldwide, including Portugal. While the majority of BC cases are sporadic, hereditary forms account for 5-10% of cases. The most common inherited mutations associated with BC are germline mutations in the BReast CAncer (BRCA) 1/2 gene (gBRCA1/2). They are found in approximately 5-6% of BC patients and are inherited in an autosomal dominant manner, primarily affecting younger women. Pathogenic variants within BRCA1/2 genes elevate the risk of both breast and ovarian cancers and give rise to distinct clinical phenotypes. BRCA proteins play a key role in maintaining genome integrity by facilitating the repair of double-strand breaks through the homologous recombination (HR) pathway. Therefore, any mutation that impairs the function of BRCA proteins can result in the accumulation of DNA damage, genomic instability, and potentially contribute to cancer development and progression. Testing for gBRCA1/2 status is relevant for treatment planning, as it can provide insights into the likely response to therapy involving platinum-based chemotherapy and poly[adenosine diphosphate (ADP)-ribose] polymerase inhibitors (PARPi). The aim of this review was to investigate the impact of HR deficiency in BC, focusing on BRCA mutations and their impact on the modulation of responses to platinum and PARPi therapy, and to share the experience of Unidade Local de Saúde Santa Maria in the management of metastatic BC patients with DNA damage targeted therapy, including those with the Portuguese c.156_157insAlu BRCA2 founder mutation.

Clinical features of breast cancer in Ashkenazi Jewish carriers of the two founder BRCA1 pathogenic variants.

e12557 Background: Germline pathogenic variants (PVs) in BRCA1 and BRCA2 are the most common cause of hereditary breast and ovarian cancer. Carriers have a significantly elevated risk of developing breast cancer (BC) and ovarian cancer (OC) compared to the general female population. Two prevalent PVs in Ashkenazi Jews (AJ) in the BRCA1 gene are 185delAG and 5382insC. This study aims to compare clinical features of disease between the PV carrier groups. Methods: Data was collected retrospectively on 282 BC patients who were carriers of 5382insC or 185delAG, treated in Hadassah and Shaare Zedek Medical Centers between the years 1978 and 2021. Data collected included features such as age at disease onset, staging at diagnosis, additional malignancies or recurrence of disease, pathological features such as hormone receptor status and HER2 status (tumor subtype), and treatments. Disease characteristics and outcomes were compared. Results: There were 207 carriers of the 185delAG PV, while 75 carried the 5382insC PV. Amongst carriers of 185delAG, vs. 5382InsC, 58.1% vs. 35.8% (p<0.01) had triple negative BC (TNBC), while 28.2% vs. 52.6% (p<0.01) had hormone positive BC, respectively (Table). There was no significant difference in disease-free or overall survival, even after adjusting for age, stage and other potential confounders. Although it appeared that 5382insC carriers suffered a higher rate of OC (14% vs. 9.6%), and that 185delAG had a higher rate of non-OC malignancies (8.2% vs. 4%), these differences did not reach statistical significance. Conclusions: Our study suggests that 5382insC and 185delAG differ in their patterns of disease. Despite the lower rates of TNBC, 5382insC carriers had similar survival to 185delAG carriers. This could suggest that the hormone receptor positive disease amongst 5382InsC carriers had a less favorable course of disease, with a similar outcome as in those with TNBC. Further studies are warranted to better understand this pattern of disease aggression. [Table: see text]

Abstract PO5-08-11: Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort

Abstract Background: The Ashkenazi Jewish (AJ) population exhibits a distinctive mutation profile in BRCA1 and BRCA2 (BRCA1/2), characterized by 3 common founder mutations: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. These 3 mutations are associated with 10% of invasive breast cancer (BC) cases among AJ women. However, the frequency of non-founder pathogenic variants in BRCA1/2 and other BC-related genes in AJ women with BC remains unclear. Methods: This retrospective study included AJ patients diagnosed with stage I-II human epidermal receptor growth factor 2 negative BC between 2004-2022 at the Weill Cornell Breast Center. We collected clinicopathological characteristics and genetic information to determine the frequency of predisposing mutations in BC and non-BC related genes in AJ patients with early BC. We also analyzed the clinicopathological characteristics and outcomes of patients with and without germline mutations in these genes. Results: The study included 232 self-identified AJ patients, with 98% being females. The median age at BC diagnosis was 62 years (IQR: 50-70). Stage I and II cancers accounted for 68% and 32% of cases, respectively. Hormone receptor positivity (HR+) was observed in 71% of patients, while 29% had triple-negative tumors. Genetic testing was performed on 88% (n=203) of the patients, while 5% of patients declined to undergo genetic testing. Among the tested patients, 12% (n=25/203) had pathogenic variants in BRCA1 or BRCA2, with 44% and 16% of these corresponding to the BRCA1 and BRCA2 founder mutations, respectively. Testing beyond BRCA1/2 genes was conducted on 154 patients, and only 6% (n=9/154) were found to have pathogenic variants in CHEK2, while no mutations were detected in other prevalent BC-related genes, including PALB2 and ATM. Fourteen-percent of patients had pathogenic mutations in other genes including APC, CFTR, FH, DIS3L2, FANCC, MUTYH, NF1 and VHL. The frequency of pathogenic BRCA1/2 variants was inversely proportional to the age at BC diagnosis: 50% (n=8/16), 21% (n=8/39), 15% (n=6/40), and 3% (n=3/108) of patients diagnosed at age < 40, 40-49, 50-59, and >60 years, respectively, had a pathogenic variant in either BRCA1 or BRCA2. The frequency of founder mutations varied according to age at diagnosis: 63%, 75%, 17%, and 100% for patients aged < 40, 40-49, 50-59, and >60 years, respectively. Patients with BRCA1/2 mutations exhibited higher-risk clinicopathological features compared to those without mutations, including a higher proportion of high histological grade (88%), and triple-negative tumors (76%). Mastectomy was the primary surgical treatment for 56% and 23% of patients with and without BRCA1/2 mutations, respectively. No difference in disease-free survival was found between patients with and without BRCA1/2 mutations with a median follow up of 3 years (IQR: 1-4). Conclusions: In our cohort, 17% of AJ patients with early BC carried a pathogenic variant in a BC-related gene, with BRCA1/2 being the most commonly affected genes. The proportion of pathogenic variants in BRCA1/2 showed an inverse correlation with the age at BC diagnosis, reaching up to 50% in patients diagnosed under the age of 40. These findings contrast with the lower prevalence of pathogenic variants in BRCA1/2 (38%) reported in the existing literature for this age group. Additionally, 8% of patients had pathogenic variants in other tested cancer genes carrying a genetic predisposition to colorectal cancer (CRC). These findings contribute to our understanding of the genetic landscape of early BC in the AJ population and emphasize the importance of comprehensive genetic testing, particularly among young patients. These results also suggest the need for earlier and more frequent CRC screening in a population of BC patients that may not be adhering to recommended guidelines. Furthermore, our study provides insight into how this genetic landscape may vary when analyzing late-stage BC in women of AJ heritage. Citation Format: Laura Munoz Arcos, Eleonora Nicolò, Maira Pires, Letizia Pontolillo, Leticia Varella, Tessa Cigler, Eleni Andreopolu, Anne Moore, Ashley Schreier, Carlos Munoz-Zuluaga, Lisa Newman, Georgia Syrnioti, Massimo Cristofanilli. Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-11.

Abstract PO1-08-01: Identifying a founder BRCA1 variant in the Qatari population With unique genotype – phenotype correlations

Abstract PURPOSE: Hereditary breast and ovarian cancer syndrome (HBOC) is the most common cause of hereditary breast & ovarian cancers in Qatar and worldwide which is caused by pathogenic variants in the BRCA1& BRCA2 genes. The aim of this retrospective study is to describe a common recurrent founder pathogenic variant in the BRCA1 gene that was observed in the native Qatari population with unique genotype-phenotype correlations. METHODS: Medical records of Qatari patients (affected & unaffected) with personal and/or family history of breast & ovarian cancers who carry pathogenic/likely pathogenic mutations in the BRCA1 & BRCA2 genes were reviewed between 2013- 2020. Epidemiological information and clinical data were reviewed including age, gender, ethnic background, personal history of cancer, tumour characteristics and family history. We used frequencies and proportions to describe the data and used Kaplan-Meier curves and log-rank analysis to compare survival rates. For the analysis, we used Stata Corp. 2015. Stata Statistical Software: Release 14, College Station, TX: Stata Corp LP. Result: Our result confirms the presence of a common recurrent pathogenic variant in BRCA1 gene [(c.4787 C>A) (p. Ser 1596*)] among Qatari patients who belong to 8 consanguineous large families followed by BRCA1[ c.4065_4068delTCAA]. BRCA1 c.4787 variant is highly associated with early onset breast cancer specifically Invasive ductal carcinoma (IDC) triple negative breast cancer (stage I, grade III), rather than ovarian cancer. In addition, the c.4787 C>A was found to be highly penetrant in families for young onset breast cancer. Conclusion: We showed that BRCA1 c.4787 C>A pathogenic variant is a highly recurrent variant among Qatari consanguineous families and contributes to the early onset breast cancer in Qatar. Early identification of this variant can aide to improve patient’s survival & guide early personalized treatment and prevention. Citation Format: Salha Al-Bader, Hind Habish, Reem Al Sulaiman, Hajer Al-Mulla, Hafedh Ghazouani. Identifying a founder BRCA1 variant in the Qatari population With unique genotype – phenotype correlations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-01.

Using Portuguese BRCA pathogenic variation as a model to study the impact of human admixture on human health

BackgroundAdmixture occurs between different ethnic human populations. The global colonization in recent centuries by Europeans led to the most significant admixture in human history. While admixture may enhance genetic diversity for better fitness, it may also impact on human health by transmitting genetic variants for disease susceptibility in the admixture population. The admixture by Portuguese global exploration initiated in the 15th century has reached over 20 million of Portuguese-heritage population worldwide. It provides a valuable model to study the impact of admixture on human health. BRCA1 and BRCA2 (BRCA) are two of the important tumor suppressor genes. The pathogenic variation (PV) in BRCA is well determined to cause high risk of hereditary breast and ovarian cancer. Tracing the distribution of Portuguese BRCA PV in Portuguese-heritage population will help to understand the impact of admixture on cancer susceptibility in modern humans. In this study, we analyzed the distribution of the Portuguese-originated BRCA variation in Brazilian population, which has high degree Portuguese-heritage.MethodsBy comprehensive data mining, standardization and annotation, we generated a Portuguese-derived BRCA variation dataset and a Brazilian-derived BRCA variation dataset. We compared the two BRCA variation datasets to identify the BRCA variants shared between the two populations.ResultsThe Portuguese-derived BRCA variation dataset consists of 220 BRCA variants including 78 PVs from 11,482 Portuguese cancer patients, 93 (42.2%) in BRCA1 and 127 (57.7%) in BRCA2. Of the 556 Portuguese BRCA PV carriers carrying the 78 PVs, 331 (59.5%) carried the three Portuguese-BRCA founder PVs of BRCA1 c.2037delinsCC, BRCA1 c.3331_3334del and BRCA2 c.156_157insAlu. The Brazilian-derived BRCA variation dataset consists of 255 BRCA PVs from 7,711 cancer patients, 136 (53.3%) in BRCA1 and 119 (46.6%) in BRCA2. We developed an open database named dbBRCA-Portuguese (https://genemutation.fhs.um.edu.mo/dbbrca-portuguese/) and an open database named dbBRCA-Brazilian (https://genemutation.fhs.um.edu.mo/dbbrca-brazilian) to host the BRCA variation data from Portuguese and Brazilian populations. We compared the BRCA PV datasets between Portuguese and Brazilian populations, and identified 29 Portuguese-specific BRCA PVs shared between Portuguese and Brazilian populations, 14 in BRCA1 including the Portuguese founder BRCA1 c.3331_3334del and BRCA1 c.2037delinsCC, and 15 in BRCA2 including the Portuguese founder BRCA2 c.156_157insAlu. Searching the 78 Portuguese BRCA PVs in over 5,000 ancient human genomes identified evolution origin for only 8 PVs in Europeans dated between 37,470 and 3,818 years before present, confirming the Portuguese-specificity of Portuguese BRCA PVs; comparing the 78 Portuguese BRCA PVs Portuguese, 255 Brazilian BRCA PVs, and 134 African BRCA PVs showed little overlapping, ruling out the possibility that the BRCA PVs shared between Portuguese and Brazilian may also be contributed by African.ConclusionOur study provides evidence that the admixture in recent human history contributed to cancer susceptibility in modern humans.

Navigating the genetic landscape of breast cancer in South Africa amidst a developing healthcare system.

Breast cancer is a significant global health issue as it represents the leading cause of death in women worldwide. In 2021, the World Health Organization established the Global Breast Cancer Initiative framework with the aim to reduce the breast cancer mortality rate by the year 2040. In countries with developing healthcare systems, such as South Africa, the implementation of first-world technologies has been slow. We provide an overview of the strides taken to improve the cost-effectiveness of genetic service delivery for breast cancer patients in South Africa - from advances in the technology utilized for BRCA founder genotyping to variant screening in moderate-to high-penetrance genes. We furthermore reflect on research undertaken to improve accessibility by means of population-directed point-of-care genetic testing that is ideal for use in a primary healthcare setting. We also report on a pilot study utilizing exome sequencing at the intersection between research and service delivery. Finally, we discuss and conclude on the controversies, research gaps, and future prospects based on the most recent developments in first-world countries that are implementable in developing countries to improve early detection of breast cancer and overall disease management.

Estrogen receptor-positive breast cancer and adverse outcome in BRCA2 mutation carriers and young non-carrier patients

Estrogen receptor-positive (ER+) breast cancer generally confers a more favorable prognosis than ER-negative cancer, however, a different picture is emerging for BRCA2 mutation carriers and young patients. We used nationwide data from population-based registries to study prognostic effects in those two groups. Of all 2817 eligible women diagnosed with breast cancer in Iceland during 1980–2004, 85% had been tested for the Icelandic 999del5 BRCA2 (c.771_775delTCAAA) founder pathogenic variant. We compared breast cancer-specific survival, effects of ER status, other clinical parameters, and treatment, between three mutually exclusive groups: BRCA2-carriers, non-carriers diagnosed 40 years or younger, and older non-carriers. Prevalence of the BRCA2 mutation among tested patients <=40 years of age was 21.0%, but it was 5.4% among women diagnosed >40 years of age. For ER+ cancer, breast cancer-specific 15-year survival was 49.7%, 55.2%, and 74.7%, among BRCA2-carriers, young and older non-carriers, respectively, whereas for ER-negative cancer, survival was similar (64.0–69.3%) for all three groups. Neither BRCA2 carriers nor young non-carriers did tumor grade 3 predict worse survival than did tumor grade 1. The adverse outcome for the young cases cannot be explained by BRCA2 mutations, as carriers were excluded from the group. Those two clinically important patient groups need special attention with respect to treatment choices, in particular, if diagnosed with ER+ tumors. It is thus advisable to have knowledge of BRCA2 status when treatment decisions are made. Finally, it is important to understand the biological basis for the specific nature of ER+ tumors in young women and BRCA2 carriers.

Increased prevalence of the founder BRCA1 c.5309G>T and recurrent BRCA2 c.1310_1313delAAGA mutations in breast cancer families from Northerstern region of Morocco: evidence of geographical specificity and high relevance for genetic counseling

BackgroundInherited mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) confer high risks of breast and ovarian cancer. Because the contribution of BRCA1/2 germline mutations to BC in the Northeastern population of Morocco remains largely unknown, we conducted this first study to evaluate the prevalence and the phenotypic spectrum of two BRCA1/2 pathogenic mutations (the founder BRCA1 c.5309G>T and BRCA2 c.1310_1313delAAGA). This choice was also argued by the presence of an apparent specific geographical connection of these mutations and the Northeastern region of Morocco.MethodsScreening for the germline mutations c.5309G>T and BRCA2 c.1310_1313delAAGA was performed by sequencing on a total of 184 breast cancer (BC) patients originated from the Northeastern region of Morocco.The likelihood of identifying a BRCA mutation is calculated using the Eisinger scoring model. The clinical and pathologic features were compared between the BRCA-positive and BRCA-negative groups of patients. Difference in survival outcomes was compared between mutation carriers and non-carriers.ResultsBRCA1 c.5309G>T and BRCA2 c.1310_1313delAAGA are responsible for a significant proportion of all BC cases (12.5%) and at least 20% of familial BC. The screening of BRCA1/2 genes by NGS sequencing confirmed that there are no additional mutations detected among positive patients.The clinicopathological features in positive patients were in accordance with typical characteristics of BRCA pathogenic mutations. The mean features in the carriers were the early onset of the disease, familial history, triple negative status (for BRCA1 c.5309G>T) and worse prognosis in terms of overall surviving.Our study indicates that the Eisinger scoring model could be recommended to identify patients for referral to BRCA1/2 oncogenetic counseling.ConclusionOur findings suggest that BRCA1 c.5309G>T and BRCA2 c.1310_1313delAAGA mutations may have a strong founder and/or recurrent effect on breast cancer among the Northeastern Moroccan population. There contribution to breast cancer incidence is certainly substantial in this subgroup. Therefore, we believe that BRCA1 c.5309G>T and BRCA2 c.1310_1313delAAGA mutations have to be included in the array of tests aimed at revealing cancer syndrome carriers among subjects of Moroccan origin.

FAMILY MATTERS: CHEST PAIN AS THE INITIAL PRESENTATION OF EARLY-ONSET METASTATIC PROSTATE CANCER

FAMILY MATTERS: CHEST PAIN AS THE INITIAL PRESENTATION OF EARLY-ONSET METASTATIC PROSTATE CANCER

Abstract 2182: Ancestry inference and population-specific disparities in a real-world clinical sequencing cohort

Abstract Accurate ancestry inference is crucial for identifying genetic determinants of cancer disparities among specific populations. While methods to infer genetic ancestry and admixture have historically relied upon genome-wide markers from broad-scale next-generation sequencing (NGS), the adaptation to targeted NGS panels presents an opportunity to prospectively incorporate ancestry inference as part of routine clinical diagnosis. Here we show that global ancestral contributions and admixture of African (AFR), European (EUR), East Asian (EAS), Native American (NAM) and South Asian (SAS) populations can be reliably inferred using markers from genomic regions covered by the FDA-authorized clinical NGS panel, MSK-IMPACT. We also show that individuals with Ashkenazi Jewish (ASJ) ancestry can be inferred with 97% accuracy using a set of ASJ ancestry-informative markers. We apply these methods to infer genetic ancestry for over 45,000 patients from the AACR GENIE v10.0-public cohort who were profiled using MSK-IMPACT. We observed 98% concordance between self-reported race and genetic ancestry for non-admixed individuals and were able to quantitatively infer ancestral contributions for individuals from recently admixed populations such as African American and Latin American. Of the discordant cases, manual review of clinical and family histories revealed the vast majority to represent clinical encoding errors where the inferred ancestry was confirmed correct. As self-reported race is not available for 17% of patients in the GENIE cohort, the ability to accurately infer genetic ancestry enables broader analysis of population-specific genomic and clinical features. We systematically evaluated the frequency of somatic and germline alterations in up to 468 genes for each cancer type and recapitulated known differences among ancestral populations. For example, we observed significantly higher frequency of EGFR somatic alterations in EAS (65%) and SAS (66%) compared to non-ASJ EUR (21%) with lung adenocarcinoma, a difference that remained significant even when limiting to never-smokers. Additionally, we found that the frequency of harboring at least one known BRCA founder mutation (BRCA1 68_69delAG, BRCA1 5266dupC, or BRCA2 5946delT) was 26x higher in genetically determined ASJ (5.1%) compared to non-ASJ (0.2%). Strikingly, while the overall rate of driver alterations in solid tumors was similar across different populations, we found that the proportion of patients with clinically actionable somatic alterations (OncoKB Level 1, 2, 3A, or 3B) was lowest in AFR (47%) patients compared to EUR, EAS and SAS (50% each). While this result is partially explained by different cancer type and subtype distributions in different populations in this real-world cohort, it highlights the urgency for greater equity in drug development programs to target alterations represented across all diverse populations. Citation Format: Kanika Arora, Thinh N. Tran, Yelena M. Kemel, Miika Mehine, Ying Liu, Shaleigh A. Smith, Subhiksha Nandakumar, Irina Ostrovnaya, Thomas C. Reynolds, Kenneth Offit, David Solit, Marc Ladanyi, Nikolaus Schultz, Ahmet Zehir, Carol L. Brown, Debyani Chakravarty, Zsofia K. Stadler, Chaitanya Bandlamudi, Michael F. Berger. Ancestry inference and population-specific disparities in a real-world clinical sequencing cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2182.

Germline BRCA1 and BRCA2 mutations and the risk of bladder or kidney cancer in Poland

IntroductionThe role of the BRCA1 and BRCA2 genes in bladder and renal tumorigenesis is unclear. Our goal was to determine the prevalence of specific founder mutations genes BRCA1 (5328 insC, C61G and 4153 delA) and BRCA2 (C5972T) mutations in bladder and kidney cancer patients from Poland.Materials and methodsWe genotyped 1028 patients with bladder cancer and 688 cases with kidney cancer and two control groups.ResultsA BRCA1 mutation (all variants combined) was detected in peripheral blood leukocytes in 5 out of 1028 (0.5%) bladder cases and in 17 of 4000 controls (0.4%) (odds ratio [OR], (OR = 1.1; 95% CI 0.42–3.11; p = 1.0). Among 688 unselected kidney cancer cases a BRCA1 mutations was reported in three patients (0.4%) (OR = 1.0; 95% CI 0.29–3.51; p = 1.0). The mutation C5972T in BRCA2 was observed in 54 bladder cancer patients (5.2%) and in 159 of 2791 healthy controls (5.7%) (OR = 0.9; 95% CI 0.66–1.26; p = 0.6). Fifty kidney cancer cases carried a BRCA2 mutation (7.3%) (OR = 1.3; 95% CI 0.93–1.80; p = 0.1).ConclusionIn conclusion, we found no difference in the prevalence of BRCA1 and BRCA2 founder mutations between cases and healthy controls. The mutations BRCA1 and BRCA2 seem not to play a role in bladder and kidney cancer development in Polish patients.

Common founder BRCA2 pathogenic variants and breast cancer characteristics in Ethiopian Jews

BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin. We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls. We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%]). EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted.

Prevalence of specific and recurrent/founder pathogenic variants in BRCA genes in breast and ovarian cancer in North Africa

BackgroundElucidation of specific and recurrent/founder pathogenic variants (PVs) in BRCA (BRCA1 and BRCA2) genes can make the genetic testing, for breast cancer (BC) and/or ovarian cancer (OC), affordable for developing nations.MethodsTo establish the knowledge about BRCA PVs and to determine the prevalence of the specific and recurrent/founder variants in BRCA genes in BC and/or OC women in North Africa, a systematic review was conducted in Morocco, Algeria, and Tunisia.ResultsSearch of the databases yielded 25 relevant references, including eleven studies in Morocco, five in Algeria, and nine in Tunisia. Overall, 15 studies investigated both BRCA1 and BRCA2 genes, four studies examined the entire coding region of the BRCA1 gene, and six studies in which the analysis was limited to a few BRCA1 and/or BRCA2 exons. Overall, 76 PVs (44 in BRCA1 and32 in BRCA2) were identified in 196 BC and/or OC patients (129 BRCA1 and 67 BRCA2 carriers). Eighteen of the 76 (23.7%) PVs [10/44 (22.7%) in BRCA1 and 8/32 (25%) in BRCA2] were reported for the first time and considered to be novel PVs. Among those identified as unlikely to be of North African origin, the BRCA1 c.68_69del and BRCA1 c.5266dupC Jewish founder alleles and PVs that have been reported as recurrent/founder variants in European populations (ex: BRCA1 c.181T>G, BRCA1 c1016dupA). The most well characterized PVs are four in BRCA1 gene [c.211dupA (14.7%), c.798_799detTT (14%), c.5266dup (8.5%), c.5309G>T (7.8%), c.3279delC (4.7%)] and one in BRCA2 [c.1310_1313detAAGA (38.9%)]. The c.211dupA and c.5309G>T PVs were identified as specific founder variants in Tunisia and Morocco, accounting for 35.2% (19/54) and 20.4% (10/49) of total established BRCA1 PVs, respectively. c.798_799delTT variant was identified in 14% (18/129) of all BRCA1 North African carriers, suggesting a founder allele. A broad spectrum of recurrent variants including BRCA1 3279delC, BRCA1 c.5266dup and BRCA2 c.1310_1313detAAGA was detected in 42 patients. BRCA1 founder variants explain around 36.4% (47/129) of BC and outnumber BRCA2 founder variants by a ratio of ≈3:1.ConclusionsTesting BC and/or OC patients for the panel of specific and recurrent/founder PVs might be the most cost-effective molecular diagnosis strategy.

Abstract P3-07-04: Geographical patterns of pathogenic genetic variants associated with hereditary breast, ovarian and prostate cancer (HBOPC) in Portugal

Abstract Introduction:HBOPC syndrome is mostly associated with germline pathogenic and likely pathogenic variants (PV) in BRCA1 and BRCA2 genes. Other high and moderate penetrance genes are increasingly diagnosed in these families, especially after implementation of NGS methodologies in clinical practice. In this study we analyze the global and regional mutational patterns of Portuguese HBOPC families, looking for associated phenotypes and possible clusters of specific PV. Methods:Observational study including all index patients (pts) with identified PV in genes associated with breast, ovarian and prostate cancers in our Centre, between 2000 and 2020. Geographical mapping of variants was done regarding residency and birth origin. Main cancer diagnoses of pts were also registered. Results:Between January 2000 and December 2020, 5233 index pts consented in genetic testing and 658 (12.6%) tested positive for a PV associated with HBOPC syndrome (84 were non-Portuguese residents). Regarding these 658 positive pts, 537 (81.6%) had breast (BC), 113 (17.2%) had ovarian and 9 (1.4%) had prostate cancer. BRCA2 was the most mutated gene (302 pts, 45.9%), followed by BRCA1 (179 pts, 27.2%), while PV in other genes were diagnosed in 177 (26.9%) pts (CHEK2, ATM, PALB2, RAD51C, TP53, RAD51D, MUTYH, BRIP1, RAD50, BLM and PTEN PV were identified in 54 (8.2%), 27 (4.1%), 21 (3.2%), 17 (2.6%), 16 (2.4%), 14 (2.1%), 11 (1.7%), 7 (1.1%), 4 (0.6%), 4 (0.6%) and 2 (0.3%) pts, respectively). PV in MSH2, MLH1, FAM175A and MRE11A were each described in 1 (0.15%) pt, all diagnosed with BC. Double heterozygosity was identified in 7 (1.1%) pts: BRCA1/BRCA2, BRCA1/CHEK2, BRCA2/PALB2, BRCA2/CHEK2, ATM/PALB2, ATM/RAD51C and MUTYH/MSH2. BRCA2 PV were more frequent than BRCA1 in all Portuguese regions except Algarve, where BRCA2 frequency was lower (BRCA1:BRCA2 &amp;gt; 1). The known BRCA2 founder c.156_157insAlu was the most recurrently diagnosed PV: 36.4% of all BRCA2 families including 8 non-Portuguese families (6 from Angola, 1 from France and 1 from Brazil). Further analysis revealed 3 possible regional clusters: 1- Duplication of exon 12 (previously described as ins6KbEx13) was the only BRCA1 identified in Algarve, with 90.9% of all families with this PV originating in this region; 2- 75% of all BRCA2 c.6405_6409del; p.(Asn2135LysfsTer3) families have origin in Alentejo, being the third most diagnosed BRCA event in the region, after c.156_157insAlu and c.5266dup; p.(Gln1756ProfsTer74); 3- c.3331_3334del; (p.Gln1111AsnfsTer5) was the only BRCA1 PV identified in Madeira (6 families). When comparing Portuguese and foreign pts, similar rates of breast, ovarian and prostate cancers were found (81.5%, 17.2% and 1.2% versus 82.1%, 16.7% and 2.4%, respectively). Most foreign residents lived in Lisboa and Vale do Tejo (82,1%) and their BRCA1:BRCA2 ratio was 0,87 (versus 0,46 in Portuguese pts), while in Algarve (13,5%) their BRCA1:BRCA2 was even higher (1.5 versus 0,69 in Portuguese pts). Discussion and conclusion:Our study confirms that BRCA2 PV are more frequent than BRCA1 PV in Portugal, with the exception of the Algarve region. Our data suggests that foreign pts accessing genetic testing in this region may have imbalanced the BRCA1:BRCA2 ratio, while for the whole population the imbalance towards BRCA2 is associated with the known founder BRCA2 c.156_157insAlu. Our data identified 2 BRCA1 (Algarve and Madeira) and 1 BRCA2 (Alentejo) geographical clusters. Citation Format: Inês Calvinho de Oliveira, Sofia Fragoso, Sidónia Santos, Teresa Duarte, Catarina Bexiga, Beatriz Mira, Isália Miguel, Ana Luís, Fátima Vaz. Geographical patterns of pathogenic genetic variants associated with hereditary breast, ovarian and prostate cancer (HBOPC) in Portugal [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-04.

A case\u2013control study of BRCA1 founder mutations 185delAG and 5382insC in a cohort of Egyptian ovarian cancer patients using pyrosequencing technique

BackgroundOvarian cancer (OC) is considered a leading cause of death among women with gynecological malignancies. OC, like breast cancer, shows a familial predisposition to germline mutations in genes BRCA1 or BRCA2, which have proved to play important roles in the incidence and progression of cancers. In Arab countries there are limited data concerning BRCA1 or BRCA2 founder mutations associated with familial ovarian cancer (FOC). Therefore, the aim of this pilot study was to assess two common founder mutations of BRCA1 (185delAG and 5382insC) in a cohort of Egyptian patients with FOC. The study included fifty female patients with FOC and twenty healthy controls. Clinical, laboratory, and pathological findings were assessed as well as response to therapy. Genetic testing for BRCA1 (185delAG and 5382insC) mutations was performed on peripheral blood samples using a short-fragment sequencer (pyrosequencer).ResultsThe BRCA1 185delAG mutation was not observed in either the FOC patients or the controls. However, the carrier frequency of heterozygous BRCA1 5382insC mutation was 8%. All the FOC patients with a BRCA1 5382insC mutation had a positive family history of cancer (p = 0.009). All carriers of the BRCA1 5382insC mutation showed a preliminary good response to chemotherapy. The majority of carrier patients were diagnosed at an advanced stage of the disease with high-grade tumors and distant metastasis (75% of cases).ConclusionThe frequency of the BRCA1 5382insC mutation in FOC patients was 8%. The strong association between the mutation and the positive family history suggests that a wider screening for BRCA1 founder mutations would be valuable in predicting high-risk individuals.

Evaluating the Effectiveness of a Telehealth Cancer Genetics Program: A BRCA Pilot Study

Introduction: Ashkenazi Jewish (AJ) individuals face a 1 in 40 (2.5%) risk of having a BRCA mutation, which is 10 times the general population risk. JScreen launched the PEACH BRCA Study, a telehealth-based platform for BRCA education and testing, with the goal of creating an effective model for BRCA testing in low-risk AJ individuals who do not meet national testing criteria. Other goals were to determine the rate of BRCA mutations in this group, to assess the adequacy of screening for the 3 common AJ founder mutations only, and to assess satisfaction with the telehealth model to help inform a national launch of a broader cancer genetic testing program. Methods: Criteria for participation included those who were AJ, resided in the metro-Atlanta area, were aged 25 and older, and had no personal or close family history of BRCA-related cancers. Pre-test education was provided through a video and written summary, followed by complimentary BRCA1/2 sequencing and post-test genetic counseling. Participants responded to pre- and post-test surveys, which assessed knowledge and satisfaction. Those who were not eligible to participate were sent genetic counseling resources and later surveyed. Results: Five hundred one participants were tested and the results included 4 positives (0.8% positivity rate), 494 negatives, and 3 variants of uncertain significance. Overall satisfaction with the study process was high (96.9/100), knowledge about BRCA was high (97.5% of participants passed a pre-test knowledge quiz), and satisfaction with pre- and post-test education was high (97.9% of participants were satisfied with the pre-test video and written summary, and 99.5% felt that their post-test genetic counseling session was valuable). Many participants expressed interest in receiving broader cancer testing. Conclusions: The BRCA founder mutation rate in a low-risk AJ population was significantly lower than the previously established AJ rate of 1 in 40. It was also determined that a telehealth model for a cancer genetics program is effective and acceptable to the population tested. This study established interest in broader cancer genetic testing through a telehealth platform and suggested that testing may be successful in the Jewish community at a national level and potentially in other populations, provided that patient education and genetic counseling are adequately incorporated.

Pioneering BRCA1/2 Point-Of-Care Testing for Integration of Germline and Tumor Genetics in Breast Cancer Risk Management: A Vision for the Future of Translational Pharmacogenomics.

Research performed in South African (SA) breast, ovarian and prostate cancer patients resulted in the development of a rapid BRCA point-of-care (POC) assay designed as a time- and cost-effective alternative to laboratory-based technologies currently used for first-tier germline DNA testing. In this study the performance of the new assay was evaluated for use on a portable screening device (ParaDNA), with the long-term goal to enable rollout at POC as an inventive step to meet the World Health Organization’s sustainable development goals for Africa. DNA samples for germline testing were obtained retrospectively from 50 patients with early-stage hormone receptor-positive breast cancer referred for genomic tumor profiling (MammaPrint). Currently, SA patients with the luminal-type breast cancer are not routinely selected for BRCA1/2 testing as is the case for triple-negative disease. An initial evaluation involved the use of multiple control samples representing each of the pathogenic founder/recurrent variants included in the BRCA 1.0 POC Research Assay. Comparison with a validated laboratory-based first-tier real-time polymerase chain reaction (PCR) assay demonstrated 100% concordance. Clinical utility was evident in five patients with the founder BRCA2 c.7934delG variant, identified at the 10% (5/50) threshold considered cost-effective for BRCA1/2 testing. BRCA2 c.7934delG carrier status was associated with a significantly younger age (p=0.03) at diagnosis of breast cancer compared to non-carriers. In three of the BRCA2 c.7934delG carriers a high-risk MammaPrint 70-gene profile was noted, indicating a significantly increased risk for both secondary cancers and breast cancer recurrence. Initiating germline DNA testing at the POC for clinical interpretation early in the treatment planning process, will increase access to the most common pathogenic BRCA1/2 variants identified in SA and reduce loss to follow-up for timely gene-targeted risk reduction intervention. The ease of using cheek swabs/saliva in future for result generation within approximately one hour assay time, coupled with low cost and a high BRCA1/2 founder variant detection rate, will improve access to genomic medicine in Africa. Application of translational pharmacogenomics across ethnic groups, irrespective of age, family history, tumor subtype or recurrence risk profile, is imperative to sustainably implement preventative healthcare and improve clinical outcome in resource-constrained clinical settings.

766P Mapping BRCA1/2 variants in ovarian cancer patients: Contribution of a BRCA2 founder effect

Despite the increasing number of genes associated with hereditary breast/ovarian cancer (HBOC), BRCA1/2 explain most cases of this entity. Both BRCA1 and BRCA2 contribute to ovarian cancer (OC), cumulative risk of 25-40% and 11-18%, respectively. In contrast to other populations, HBOC Portuguese patients (pts) have a higher prevalence of BRCA2 variants, partially due to the effect of the founder BRCA2 variant: c.156_157insAlu. The aim of this study was to map and analyze BRCA1/2 variants from OC pts in our HBOC program.

765P Prognosis of BRCA1 and BRCA2 ovarian cancer: Prospective follow-up data from a multidisciplinary program

BRCA1 and BRCA2 are tumour suppressor genes associated with the hereditary breast and ovarian cancer syndrome (HBOC). Previous data regarding BRCA1/2 penetrance estimated a median cumulative risk of ovarian cancer (OC) by 70 years of 25-40% and 11-18% for BRCA1 and BRCA2 carriers, respectively. In contrast to other populations, HBOC Portuguese patients (pts) have a higher prevalence of BRCA2 mutations, partially due to the effect of the founder BRCA2: c.156_157insAlu. In this study, we analyse the effect on prognosis of BRCA1 and BRCA2 variants in a Portuguese OC cohort.

Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications.

Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes. Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed. Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1-2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36-76years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines. This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies.