Abstract 1294: Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia
Authors: Yang Xiaohong (Rose) , Devi Beena , Sung Hyuna , Guida Jennifer , Xiao Yanzi , Garland Lisa , Hu Nan , Rodriguez-Herrera Maria , Wang Chaoyu , Jones Kristine , Luo Wen , Hicks Belynda , Tang Tieng Swee , Moitra Karobi , Dean Mike 
Published: July 2017

Abstract
Germline mutations in the BRCA1 and BRCA2 genes result in predisposition to breast and ovarian cancer. Detection of BRCA mutation carriers can lead to improved prevention and therapeutic interventions such as the targeted therapy using poly ADP ribose polymerase (PARP) inhibitors, which are particularly effective in BRCA mutation carriers. The spectrum of BRCA mutations varies depending on geographic origin, population, and ethnic group; however, the prevalence of BRCA mutations in non-Caucasian populations has been poorly characterized, particularly in a population-based setting. The goal of this study was to characterize the spectrum of germline mutations in BRCA1/2 and PALB2 in unselected breast cancer cases who were seen in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated. We performed targeted sequencing using a validated AmpliSeq panel on 467 cases with available risk factor questionnaire and clinical follow-up data. Breast cancer subtypes were defined by the joint expression of ER, PR, and HER2. Common variants with frequency &gt;1% in any public database (1000 Genome, Exome Sequencing Project, The Exome Aggregation Consortium) were excluded. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants (frameshift and stop-gain), and variants that alter the first or second base of the splice site. Variants of unknown significance (VUS) were also defined using the ClinVar classification. We found 10 BRCA1 pathogenic variants in 12 patients, 10 BRCA2 pathogenic variants in 15 patients, and 4 PALB2 pathogenic variants in 4 patients, which gave a BRCA mutation prevalence of 5.78% among the unselected breast cancer cases in this population. All these variants were extremely rare in the general population (&lt;0.05%). Only 4 of them were recurrent variants (2 in BRCA1 and 2 in BRCA2) and all four are known variants that were reported previously in other populations. In addition, we identified a novel deleterious mutation (stop-gain) that has never been reported and a number of VUS variants in this population. Patients with pathogenic BRCA and PALB2 variants were associated with an earlier age at onset (7 years younger, p=0.0005), a positive family history (20% higher, p=0.01), and the triple-negative (TN) subtype (56% vs. 18%, p&lt;0.0001), compared to patients without mutations. Mutation carrier cases had worse survival compared to non-carriers, however, the association was mostly driven by the higher frequency of TN in mutation carriers. Our study for the first time reported the prevalence of germline mutations in BRCA and PALB2 in a quasi-population-based case series unselected for age and family history in an under-studied Asian population. Our results may have important clinical implications for performing genetic testing on selected patients in a low-resource setting.
Citation Format: Xiaohong (Rose) Yang, Beena Devi, Hyuna Sung, Jennifer Guida, Yanzi Xiao, Lisa Garland, Nan Hu, Maria Rodriguez-Herrera, Chaoyu Wang, Kristine Jones, Wen Luo, Belynda Hicks, Tieng Swee Tang, Karobi Moitra, Mike Dean. Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, 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 1294. doi:10.1158/1538-7445.AM2017-1294