Abstract P2-10-13: Genetics and pathological correlation of BRCA status in patients of Asian origin diagnosed with breast or ovarian cancer; a UK Reference Genetics Laboratory Study
Authors: Longworth Aisling , Hoffman Jonathan , Sharma-Oates Archana , Ong Kai-Ren , Hart Rachel , Wallis Yvonne , Considine Anna , Dasani Pooja , Ganesan Raji , Tomlinson Ian , Sundar Sudha , Shaaban Abeer 
Published: March 2020

Abstract
Background/objective: Epidemiological and phenotypic differences exist in breast and ovarian cancers among patients of different ethnicity. Reasons for this are unclear and likely multifactorial. In Asian countries breast and ovarian cancers occur a decade earlier (1). In India, 15% of breast and ovarian cancer is diagnosed in patients over 65 years compared to approximately 50% in the UK, despite an increased UK incidence(1). Triple negative breast cancer is also more prevalent in India(1). A recent systematic review by our group examined the prevalence and spectra of BRCA1/2 mutations in the Indian population and concluded that there is a lack of high-quality genetic and histopathology data (2). This study examines BRCA mutation prevalence, spectra, and clinico-pathological features of breast and ovarian cancers in patients of Asian origin with familial risk.
Methods: 89 patients of Asian origin were identified out of a total of 3359 patients referred to the regional genetics service for BRCA1/2 testing between 2006-2016. Genetics data were correlated with recorded histopathological including the type of surgical excision, tumour type, size, grade and receptor status (breast cancers). Outcome data, where available, was also recorded. The BRCA1/2 genetic variants were searched in the ClinVar (3) and BIC (Breast cancer Information Core)databases (4) to confirm their pathogenicity.
Results: 51 patients were of Indian (57.30%), 21 of Pakistani (23.59%) and 3 of Bangladeshi (3.37%) origin with the remaining 14 of other unspecified or mixed Asian ethnicities (15.73%). 25 BRCA variants across 21 patients were identified. 16.85% (n=15) had a pathogenic variant (BRCA1 n= 11, BRCA2 n= 4) and 11.23% (n=10) had a variant of unknown significance (VUS) (BRCA1 n=1, BRCA2 n=9). One BRCA1 variant (c.3770_3771delAG, p.Glu1257GlyfsX9) occurred in 2 different patients, both of Indian origin. The Genome Aggregation Database (gnomAD) allele frequency of this variant in the South Asian population is reported as 3.27e-5. Pathology data for one or more parameters was available for 78 patients (87.64%). The majority were breast cancers, with a median age of 39 years. 90.90% of the BRCA1 and BRCA2 pathogenic variant breast cancers (PVBC) were of no special type (n =10, total 11). 87.50% of BRCA1 PVBCs (n=7, total 8) were HER2/oestrogen receptor (ER) negative and 85.71% were grade 3 (n=6, total 7). 100% (n=4, total 4) of BRCA2 PVBCs were grade 3 and ER positive. Two patients with a BRCA2 PVBC were male.
Conclusion: This study shows, for the first time, the real-time genetic and pathological correlation of BRCA status in breast and ovarian cancer patients of Asian origin with familial risk. The higher number of pathogenic BRCA1 alterations compared to BRCA2 as well as the higher number of BRCA2 VUS compared to BRCA1 VUS is consistent with our previous work of the Indian population(2). The BRCA1/2 histological and molecular features are consistent with profiles reported in the literature. The genetic makeup may explain, at least partly, the phenotypic and epidemiological breast and ovarian cancer differences observed within different ethnicities.
References:
1. Sundar S et al. Harnessing genomics to improve outcomes for women with cancer in India: key priorities for research. Lancet Oncol. 2018 Feb;19(2):e102-e112 2. Sharma-Oates A et al. Heterogeneity of germline variants in high risk breast and ovarian cancer susceptibility genes in India. Precis. Clin. Med. 2018 Sept; 1(2):75-87. 3. Landrum MJ et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067. 4. Breast Cancer Information Core. An Open Access On-Line Breast Cancer Mutation Database. https://research.nhgri.nih.gov/bic/
Citation Format: Aisling Longworth, Jonathan Hoffman, Archana Sharma-Oates, Kai-Ren Ong, Rachel Hart, Yvonne Wallis, Anna Considine, Pooja Dasani, Raji Ganesan, Ian Tomlinson, Sudha Sundar, Abeer Shaaban. Genetics and pathological correlation of BRCA status in patients of Asian origin diagnosed with breast or ovarian cancer; a UK Reference Genetics Laboratory Study [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 P2-10-13.