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Muscle RAS oncogene homolog (MRAS) recurrent mutation in Borrmann type IV gastric cancer

Makiko Yasumoto^1,2, Etsuko Sakamoto³, Sachiko Ogasawara¹

¹Department of Pathology, Kurume University School of Medicine, Kurume, Japan.

Cancer Medicine

|November 29, 2016

Abstract:

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 alterations in gastric cancer, none has focused on comprehensive genetic analysis of Type IV. To discover cancer-relevant genes in Type IV, we performed whole-exome sequencing and genome-wide copy number analysis on 13 patients with Type IV. Exome sequencing identified 178 somatic mutations in protein-coding sequences or at splice sites. Among the mutations, we found a mutation in muscle RAS oncogene homolog (MRAS), which is predicted to cause molecular dysfunction. MRAS belongs to the Ras subgroup of small G proteins, which includes the prototypic RAS oncogenes. We analyzed an additional 46 Type IV samples to investigate the frequency of MRAS mutation. There were eight nonsynonymous mutations (mutation frequency, 17%), showing that MRAS is recurrently mutated in Type IV. Copy number analysis identified six focal amplifications and one homozygous deletion, including insulin-like growth factor 1 receptor (IGF1R) amplification. The samples with IGF1R amplification had remarkably higher IGF1R mRNA and protein expression levels compared with the other samples. This is the first report of MRAS recurrent mutation in human tumor samples. Our results suggest that MRAS mutation and IGF1R amplification could drive tumorigenesis of Type IV and could be new therapeutic targets.

Insights

This study reveals recurrent mutations in muscle RAS oncogene homolog (MRAS) and insulin-like growth factor 1 receptor (IGF1R) amplifications in Borrmann type IV gastric cancer. These genetic alterations may drive tumor development and represent potential therapeutic targets.

Area of Science:

Oncology
Genetics
Molecular Biology

Background:

Borrmann type IV gastric cancer has a poor prognosis, necessitating research into its molecular drivers and therapeutic targets.
Previous genomic studies on gastric cancer have not specifically analyzed type IV, highlighting a gap in understanding its unique genetic landscape.
Identifying novel oncogenic mutations and amplification events is crucial for developing targeted therapies for this aggressive cancer subtype.

Purpose of the Study:

To conduct a comprehensive genetic analysis of Borrmann type IV gastric cancer.
To identify key genes and molecular mechanisms involved in the oncogenesis of type IV gastric cancer.
To discover potential new therapeutic targets for type IV gastric cancer.

Main Methods:

Whole-exome sequencing and genome-wide copy number analysis were performed on 13 Borrmann type IV gastric cancer samples.
Somatic mutations and copy number alterations were identified and analyzed.
The frequency of muscle RAS oncogene homolog (MRAS) mutations was assessed in an additional 46 type IV samples.

Main Results:

Whole-exome sequencing identified 178 somatic mutations, including recurrent mutations in muscle RAS oncogene homolog (MRAS) in 17% of type IV samples.
Genome-wide copy number analysis revealed focal amplifications and homozygous deletions, notably insulin-like growth factor 1 receptor (IGF1R) amplification.
Samples with IGF1R amplification exhibited significantly higher IGF1R mRNA and protein expression.

Conclusions:

Recurrent MRAS mutations and IGF1R amplification are identified as potential drivers of Borrmann type IV gastric cancer tumorigenesis.
This study provides the first report of recurrent MRAS mutations in human tumor samples.
MRAS mutations and IGF1R amplification represent promising novel therapeutic targets for Borrmann type IV gastric cancer.

Read full analysis

Keywords:

MRAS IGF1R Borrmann type IV gastric cancer mutation

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