Distribution of BRCA1/2 germline and somatic alterations across cancer type.
Authors: Jingde Chen, Ming Quan, Zhengqing Yan, Shiqing Chen, Mei Huang, Jiujie Cui, Zhiqin Chen, Yong Gao
Journal: Journal of Clinical Oncology (2021)

10590 Background: PARP inhibitors (e.g. Olaparib or niraparib) have been approved by FDA as a targeted therapy for many tumors harboring germline or somatic BRCA1/2 (g or sBRCA1/2), including ovarian cancer, prostate cancer, breast cancer and pancreases cancer. It is imperative to study the distribution of BRCA1/2 across cancer type. In this study, we aim to assess the landscape of BRCA1/2 alterations in solid tumors and evaluate the feasibility of circulating tumor DNA (ctDNA) tested by next-generation sequence (NGS) as a tool to detect BRCA1/2 alterations. Methods: For tissue specimen, genomic DNA from formalin fixed paraffin-embedded (FFPE) tumor specimens or fresh tumor tissues was used for sequence analysis. Genomic DNA (gDNA) from white blood cells was extracted using the QIAamp DNA Mini Kit (Qiagen). For ctDNA, cell-free DNA libraries were prepared using the KAPA Hyper Prep Kit following the manufacturer’s protocol. The captured libraries were loaded onto a NovaSeq 6000 platform (Illumina) for 100bp paired-end sequencing. The testing was performed in the College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) -certified 3D Medicines Library. Results: A total of 27, 835 patients were tested using tumor tissue during Jan. 1th 2017 to June 1th 2020, including 43% (N = 12089) of non-small cell lung cancer, 19% (N = 5357) of colorectal cancer, 8% (N = 2181) of liver cancer, 6% (N = 1621) of gastric cancer, 5% (N = 1479) of biliary tract cancer, 4% (N = 1084) of kidney cancer, 4% (N = 1045) of pancreas cancer, 3% (N = 689) of breast cancer and 2% (N = 599) of ovarian cancer. Across all tumor types, the known or likely deleterious BRCA1/2 alterations were identified in 2147 (7.7%) patients. Ovarian cancer had the highest frequency of BRCA1/2 alteration (23.4%), followed by endometrial cancer (12.7%) and breast cancer (10.6%). BRCA1/2 alteration was found in 8.8% prostate cancer and 4.2% pancreas cancer respectively. Across all tumor types, the known or likely deleterious gBRCA1/2 alterations were identified in 369 (1.3%) patients. Notably, ovarian cancer had the highest frequency of gBRCA1/2 alteration (13.9%), followed by breast cancer (7%), prostate cancer (4.4%) and endometrial cancer (4.1%). No clear hotspot mutations and mutated codons were spread throughout g or sBRCA1/2 mutations. Additionally, among 15699 patients who suffered ctDNA sequencing, any known or likely deleterious sBRCA1/2 alterations were identified in 358 (2%) patients. Similar to the results of tissue sequencing, ovarian cancer had the highest frequency of sBRCA1/2 alteration (16.67%), followed by endometrial cancer (9.68%), prostate cancer (7.18%) and breast cancer (5.58%) in the blood cohort. Conclusions: BRCA1/2 alterations existed across tumor types and the landscape of g or sBRCA1/2 alterations varied according to cancer type. Furthermore, ctDNA can be used as a potential tool to detect BRCA1/2 alterations.