Xianyu Zhang¹, Xiaohong Wang², Bingshu Xia¹, Xiaofei Ye², Jingjing Xie¹, Yanqing Zhou², Shida Zhu², Jun Wang², Da Pang³

¹Department of BreastSurgery, Harbin Medical University Cancer Hospital, ²BGI-Research,BGI-Shenzhen, ³Translational MedicineResearch and Cooperation Center of Northern China, Heilongjiang Academy ofMedical Sciences

Objective:Currently, dozens of susceptibility geneshave been defined for hereditary breast cancer. Though several researches haveproved the clinical utility of multiple-gene sequencing in assessment of peoplewith high hereditary cancer risk, little clinical approach is available.Especially, there is limited such research in China, which country counts forapproximately one fifth of world population. Here, we use a multiple-genesequencing assessment to identify the variant spectrum, analyze the differencesof variant spectrum between Chinese and other cohort and evaluate the clinicalutility of this assessment in Chinese with high risk of breast cancer. Method:Breast cancer patients, who meet the enrollment criteria of NCCN guidelinesof breast and/or ovarian cancer genetic assessment were informed and involvedin this research. DNA was extracted from peripheral blood. The coding regionsof 115 genes, which are reported associated with the susceptibility orpotential risk of 38 types of cancers were captured and sequenced using nextgeneration sequencing platform. Single Nucleotide Polymorphism and smallInsertion/deletion variants were defined and analyzed. Pathogenic variants andpotentially actionable results were informed to participants according to theirwillingness. Result: Totally, 400 high-risk breast cancer patientsparticipated in the research. From which, 88(22%) patients carried pathogenicvariants, including 58(14.5%) with BRCA1/BRCA2/PALB2 pathogenic variants,28(7%) with other genes pathogenic variants and 2(0.5%) with BRCA1/BRCA2/PALB2and other gene pathogenic variants at the same time. 203 variants of uncertainsignificance (VUS) spots from 27 breast cancer susceptibility genes wereidentified in 400 patients, and this cohort's VUS number was about 1.8 times ofa American research cohort in their overlap genes. Additionally, other genepathogenic variant carriers with guideline or sufficiently studied in 23families were invited to particular cancer disease screening for clinical preventionand monitoring. Overall, there were 11 families accepted clinical screeningsuch as breast ultrasound, gastroscopy, fibercolonoscopy and serum tumor markerdetection. Positive gastroenteric precancerous lesions have been observed in 3families with ATM, PMS2, ATM and PALB2 pathogenic variants respectively. Inthis research, pathogenic variants were identified in 25(21.7%) genes of the115 gene panel, considering cost-effectiveness, the panel components need to beoptimized in future. Conclusion: Overall, based on this research, wehave revealed a comprehensive susceptibility variations spectrum and firstlyevaluated clinical utility of a multiple-gene sequencing assessment in Chinesewith high risk of breast cancer.

Key Words: hereditary breast cancermultiple-gene sequencing BRCA1 BRCA2