Abstract 2975: Comprehensive analysis of genetic alterations and DNA copy number in Borrmann type IV gastric cancer

The prognosis of patients with Borrmann type IV gastric cancer (Type IV) is extremely poor. Thus, there is an urgent need to elucidate the molecular mechanisms underlying the oncogenesis of Type IV and to identify new therapeutic targets. Although previous studies using whole-exome and whole-genome sequencing have elucidated genomic alternations in gastric cancer, no reports have focused on the comprehensive genetic analysis in Type IV. To find cancer relevant genes in Type IV, we performed whole exome sequencing and genome-wide copy number analysis on 14 patients of Type IV. The exome sequencing identified a total of 182 somatic mutations which cause amino-acid substitutions or splice-site alterations. Previously reported mutations in gastric cancer were detected, such as ARID1A, CDH1, TP53 and RHOA. Moreover, our study has found novel mutations that have not been reported in gastric cancer and other tumor types. Among the newly identified genetic alterations, a mutation in muscle RAS oncogene homolog (MRAS) was predicted to cause molecular dysfunction. MRAS belongs to the Ras subgroup of small G proteins, including the prototypic RAS oncogene, KRAS, HRAS, and NRAS. The MRAS mutation discovered by whole-exome sequencing was validated by mutation-specific PCR. To investigate the frequency of mutation in MRAS, we performed Sanger sequencing of additional 46 Type IV samples. A total of 9 non-synonymous mutations were discovered with a mutation frequency of 17%, showing that MRAS is recurrently mutated in Type IV. The genome-wide copy number analysis also showed that copy number was aberrant in 41 genes, including Insulin-like growth factor 1 receptor (IGF1R). The samples with IGF1R amplification showed remarkably higher expression levels of mRNA and protein compared with other samples. In conclusion, this is the first research to discover mutation in MRAS among human tumor samples, although introduction of artificially mutated MRAS is known to have oncogenic activity. In addition, these results suggested that MRAS mutation and IGF1R amplification could drive tumorigenesis of Type IV and could be a new therapeutic target for Type IV. Citation Format: Makiko Yasumoto, Sachiko Ogasawara, Jun Akiba, Hironori Kusano, Akiko Sumi, Taro Isobe, Junya Kizaki, Yoshito Akagi, Takuji Torimura, Etsuko Sakamoto, Hiraku Itadani, Tsutomu Kobayashi, Shinji Mizuarai, Shinji Oie, Hirohisa Yano. Comprehensive analysis of genetic alterations and DNA copy number in Borrmann type I