Abstract 4288: Inherited mutations in BRCA1 and BRCA2 in an unselected multi-ethnic cohort of Asian breast cancer patients and healthy controls from Malaysia
Authors: Wen Wei Xiong , Lai Kah Nyin , Allen Jamie , Luccarini Craig , Mariapun Shivaani , Yip Cheng Har , Taib Nur Aishah Mohd , Dunning Alison , Easton Douglas , Teo Soo Hwang 
Published: July 2017

Abstract
Background: BRCA1 and BRCA2 are significant cancer predisposition genes which have hitherto primarily been tested in breast cancer patients selected on the basis of age of onset of breast cancer and family history of breast and ovarian cancer. Given that only 40% of breast cancer occur in post-menopausal women in many Asian countries including Malaysia, compared to close to 80% in many Caucasian countries, the proportion of risk attributable to genetic factors is likely to be correspondingly higher in Asians. We sought to determine the prevalence of germline mutations in BRCA1 and BRCA2 in an unselected cohort of Asian breast cancer patients and healthy controls.
Methods: Women diagnosed with invasive breast cancer recruited from University Malaya Medical Centre between October 2002 and April 2015, and Sime Darby Medical Centre between September 2012 and April 2015 [n=2,592]. Eligible control subjects were recruited from women attending an opportunistic mammography screening programme at University Malaya Medical Centre between January 2014 and April 2015, and Sime Darby Medical Centre between October 2011 and April 2015 [n=2,851]. Amplicon-based targeted sequencing of exonic and proximal splice site junction regions of 31 known and probable breast cancer susceptibility genes were performed on Fluidigm Access Array system, with sequencing conducted on the Illumina HiSeq2500 platform. Variant calling was performed as per GATK recommended best practices with UnifiedGenotyper using the default parameters except -minIndelFrac 0.05. Variants were annotated with ANNOVAR and variants with MAF &gt;1% as reported in population databases were filtered out. Nonsense, frameshift indels, and splice site variants were presumed to be deleterious.
Results: Overall, 111 distinct mutations (50 BRCA1 and 61 BRCA2) were identified in 143 carriers (70 BRCA1 and 73 BRCA2) among breast cancer patients, and 11 carriers (5 BRCA1 and 6 BRCA2) were identified among healthy controls. Germline carriers were more likely to be younger, have family history of breast and/or ovarian cancer, have higher grade tumours and for BRCA1 carriers, they were more likely to have breast cancers which are negative for estrogen receptor and ERBB2 receptor. Notably, 45% of breast cancer patients fulfilled the NCCN guidelines for recommendation for genetic counseling and genetic testing, and of these, 80% of carriers fulfill the NCCN guidelines. Taken together, our results show that ~5% of Asian breast cancer patients have pathogenic mutations in BRCA1 or BRCA2, and that germline testing can be cost-effectively delivered to Asian women by focusing primarily on women with early onset breast cancer in the presence of family history of breast and ovarian cancers.
Citation Format: Wei Xiong Wen, Kah Nyin Lai, Jamie Allen, Craig Luccarini, Shivaani Mariapun, Cheng Har Yip, Nur Aishah Mohd Taib, Alison Dunning, Douglas Easton, Soo Hwang Teo. Inherited mutations in BRCA1 and BRCA2 in an unselected multi-ethnic cohort of Asian breast cancer patients and healthy controls from Malaysia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4288. doi:10.1158/1538-7445.AM2017-4288