Abstract 1685: Germline mutations in cancer predisposition genes are prevalent among survivors of childhood acute lymphoblastic leukemia in a Chinese population
Authors: Zhang Ru , Xue Yao , Zhu Liwen , Kang Meiyun , Xu Xiangye , Huang Jie , Rong Liucheng , Dai Juncheng , Hu Zhibin , Fang Yongjun , Wang Zhaoming 
Published: August 2019

Abstract
Landscape of pathogenic or likely pathogenic (P/LP) germline mutations in cancer predisposition genes have been well-studied among patients or survivors of childhood cancer in the US. However, little is known for cancer predisposing germline mutations in Chinese survivors of childhood cancer including acute lymphoblastic leukemia (ALL). To characterize the spectrum and prevalence of cancer predisposing germline mutations, and to assess the relationship between the mutation status and cancer family history, whole-exome sequencing (&gt;80-fold) was performed on blood DNA for 91 childhood ALL survivors who were ≥5 years from initial cancer diagnosis. All patients enrolled and consented for the study were previously diagnosed and treated either at Nanjing Children’s Hospital of Nanjing Medical University (n=28) or Guangzhou Women and Children’s Medical Center (n=63). Germline mutations in 156 cancer predisposition genes were analyzed and classified for their pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guideline. Clinical information was extracted from medical records and family history were collected based on questionnaire and phone interview. Of 91 survivors of childhood ALL (median age [range], 11 [6-22] years; 58 [63.7%] male), P/LP mutations were identified in 7 (6.4%) survivors. The mutations occurred in well-established ALL predisposition genes such as ATM, BLM, and SBDS, and other cancer-associated genes such as PALB2, for which two P/LP mutations were identified. Notably, PALB2 was also included in “Add-On” gene panel provided by Invitae, a genetic testing company, for leukemia predisposition testing. Most of these mutated genes (ATM, BLM, LIG4 and PALB2) are involved in DNA repair pathways. Using East Asian (EAS) population from Genome Aggregation Consortium (genomAD) database as controls, the cancer predisposing germline mutations were significantly enriched (Odds Ratio [95% CI], 6.3 [2.9-13.7]) among survivors of childhood ALL. Among survivors with cancer family information (n=82), the prevalence of mutation carriers is 18.8% (3/16) for survivors with positive cancer family history, compared to 4.5% (3/66) for survivors with negative family history, but the association between mutation status and cancer family history is not statistically significant (Fisher’s exact test P = 0.09). To our knowledge, we’re the
first to assess cancer predisposing mutations in Chinese survivors of childhood ALL. Our findings showed slightly higher level of prevalence of cancer predisposing mutation than US survivors, suggesting disparity across different populations. The results highlight the importance of genetic counselling and testing which could inform personalized screening strategy for second cancer for survivors and for cancer risk stratification and early prevention for other family members.
Note: This abstract was not presented at the meeting.
Citation Format: Ru Zhang, Yao Xue, Liwen Zhu, Meiyun Kang, Xiangye Xu, Jie Huang, Liucheng Rong, Juncheng Dai, Zhibin Hu, Yongjun Fang, Zhaoming Wang. Germline mutations in cancer predisposition genes are prevalent among survivors of childhood acute lymphoblastic leukemia in a Chinese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1685.