Abstract 4492: Investigation of the germline mutational landscape of GBA in general cancer patients and its role in the tumorigenesis
Authors: Junghoon Shin, Daeyoon Kim, Youngil Koh, Sungsoo Yoon
Journal: Cancer Research (2016)

Abstract Introduction Gaucher disease (GD) is an autosomal recessive disease resulting from defective enzymatic activity of acid β-glucosidase (β-glucocerebrosidase). Approximately 400 point mutations in GBA, located in 1q21, have been described and genotype-phenotype correlation was revealed. Previous studies have shown the association of type 1 GD and development of various types of cancers. However, the mutational landscape of GBA and its clinical implication in general cancer patients have not been systematically explored. Methods We used publicly available data obtained from ICGC and TCGA data portal (sftp://dccsftp.nci.nih.gov) for the analysis of single nucleotide variants (SNVs) in GBA in general cancer patients. GenBank reference sequence NM_001005741 was used for SNP identification. Results A total of 2124 cancer patients comprising 29 cancer types were included. Mutations with allele frequency lower than 0.3 or coverage depth lower than 15 were filtered out from analysis. Overall, 7% (151 out of 2124) were GBA mutation carriers, including 1 nonsense (involving exon 1) and 153 missense mutations, including 5 homozygous alternate. The most frequently detected SNVs included rs2230288 (c.1093G&amp;gt;A:p.E365K, 3 homozygous alternate), rs75548401 (c.1223C&amp;gt;T:p.T408M), rs143187997 (c.58A&amp;gt;G:p.I20V, 1 homozygous alternate), rs150466109 (c.38A&amp;gt;G:p.K13R, 1 homozygous alternate), rs76763715 (c.A1226G:p.N409S), and rs421016 (c.1448T&amp;gt;C, p.L483P), accounting for 1.88%, 1.55%, 1.27%, 1.04%, 0.85%, and 0.28% of the entire cancer population, respectively. We compared our data with 1000 Genomes data of 2504 normal subjects (ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502), which revealed that the prevalence of rs2230288, rs75548401, and rs76763715 carriers was significantly higher in the cancer group than 1000 Genomes population (p = 0.01, &amp;lt;0.001, and &amp;lt;0.001 by chi-square test, respectively). Regarding somatic mutational profile of tumor samples of 151 germline GBA mutation carriers, the most frequently mutated genes included TP53, PIK3CA, and KRAS, accounting for 28.5%, 7.9%, and 7.9%, respectively. Conclusion Although overall prevalence of germline GBA mutation carriers was not significantly different between cancer patients and general population collected from 1000 Genomes data, SNVs in some specific positions showed statistically significant difference in prevalence between 2 groups, implying association between specific mutational loci of GBA and cancer-developing mechanism, even in heterozygous carriers. Citation Format: Junghoon Shin, Daeyoon Kim, Youngil Koh, Sungsoo Yoon. Investigation of the germline mutational landscape of GBA in general cancer patients and its role in the tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4492.