Abstract 1287: Mutations in the CBL gene among breast cancer patients in an Asian clinic-based population

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Abstract INTRODUCTION Although mutations in BRCA1 and BRCA2 are associated with familial hereditary breast and ovarian cancer, mutations are only found in 20 to 25% of these patients. This suggests that additional genes may be mutated. The Casitas B-lineage lymphoma (CBL) gene encodes a RING finger E3 ubiquitin ligase. Recent studies have shown that mutations in the CBL gene occurs in human acute myeloid leukemia and lung cancers. The relationship of the CBL gene with breast cancer, however, is not well characterized. The aim of this study was to identify mutations in the CBL gene in Asian patients with familial or early-onset breast cancer. METHODS All patients (n=75) were accrued at the risk assessment clinic at the National Cancer Centre Singapore, and presented with a family history of breast and/or ovarian cancer or early-onset breast cancer. Screening for mutations in the BRCA1 and BRCA2 genes was performed using Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). Next generation sequencing was done using the Agilent SureSelect target-enrichment technology on the Illumina MiSeq platform, followed by validation using Sanger sequencing. RESULTS Two mis-sense variants in the CBL gene were identified. They are CBL c. 560C>T (p. A187V) and c. 1858C>T (p.L620F) occurring in 2/75 (3%) and 8/75 (11%) of the patients, respectively. Both mis-sense mutations were predicted to be damaging using Polyphen-2 and SIFT. The p.A187V alteration was predicted to interrupt the N-terminal tyrosine kinase binding domain (TKB) that is important for ligand-induced ubiquitination of receptor tyrosine kinases (RTKs). The CBL c. 1858C>T variant has previously been reported in the NCBI database (rs2227988). Three individuals, who carried this mutation, had early-onset breast cancer. In addition, the p.L620F alteration within the proline-rich region, may disrupt the interactions of binding partners to the c-CBL protein, which are required to recruit c-CBL to RTKs. All patients, except one, with germline CBL mutations were negative for BRCA1 and BRCA2 mutations. CONCLUSION This preliminary study has identified damaging CBL mutations in an Asian population with breast cancer and warrants further investigations in other breast cancer populations. Citation Format: Edward Wong, Yoon Sim Yap, Ying Ying Cheng, Delia Chua, Lewis Zuocheng Hong, William F. Burkholder, Gay Hui Ho, Min Han Tan, Peter Ang, Ann S.G. Lee. Mutations in the CBL gene among breast cancer patients in an Asian clinic-based population. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1287. doi:10.1158/1538-7445.AM2014-1287