Next-gen sequencing holds promise in gastric cancer

Targeted next-generation sequencing (NGS) is useful for identifying genomic alterations in patients with gastric cancer (GC) and, in turn, should aid patient stratification for treatment optimization, according to a Singapore study.

“GC has a high incidence and mortality rate, especially in East Asians, and about 90 percent [of the cases] are adenocarcinomas. Histological and aetiological heterogeneity and ethnic diversity make molecular subtyping of GC complicated, thus making it difficult to determine molecular division systems and standard treatment modalities,” the investigators said.

“[Meanwhile], the widely used hybrid capture–based NGS technology makes it possible to comprehensively understand the molecular features of each tumour and helps to lay out the foundation of patient stratification. More precise stratification strategies may provide more opportunities for precision therapy,” they added.

In the study, the investigators performed a targeted sequencing panel for 529 Chinese patients with gastric adenocarcinoma (median age at diagnosis, 60 years; 67.3 percent male). Twenty percent of these patients had a relatively early stage disease (stage I or II) on diagnosis, whereas over 60 percent were in late stage (stage III and IV).

NGS data revealed 449 clinically relevant gene mutations, with 47.1 percent of the patients harbouring at least one actionable mutation. The most frequently altered genes were TP53 (59.7 percent), ARID1A (21.9 percent), LRP1B (14.7 percent), PIK3CA (13.8 percent), ERBB2 (13.4 percent), CDH1 (13.0 percent), KRAS (11.7 percent), FAT4 (11.5 percent), CCNE1 (10.6 percent), KMT2D (10.4 percent), and RNF43 (10.4 percent). [Oncologist 2021;doi:10.1002/onco.13695]

Patients with high tumour mutational burden showed truncation mutations of ARID1A, KMT2D, RNF43, TGFBR2, and CIC. On the other hand, those with low tumour mutational burden had gene amplifications of ERBB2, CCNE1, CDK12, and CCND1.

Common gene alterations in the Wnt and PI3K/Akt signaling pathways emerged on pathway analysis. High microsatellite instability was significantly more common in Chinese patients with GC than in other cohorts, with high microsatellite instability and Epstein‐Barr virus (EBV)–positive features being mutually inclusive.

There were 45 germline mutations identified in 44 (8.3 percent) patients, and SPINK1 mutations (all SPINK1 c.194 + 2T > C) were present in seven of them (15.9 percent). Microorganisms found in the entire Chinese cohort included Helicobacter pylori, EBV, hepatitis B virus, and human papillomavirus types 16 and 18.

The present study might be the largest Chinese cohort on the genomic research of gastric adenocarcinoma to date, according to the investigators. “We found that many patients with GC may be able to benefit from either targeted therapy or immunotherapy.”

Furthermore, several genes such as ACVR2A, ARID1A, CIC, ERBB3, FAT4, and KMT2C have higher mutation rates in GC patients with both high tumour mutational burden and high microsatellite instability.

“Even though the mechanisms are not very clear, this phenomenon has been observed in certain genes in other types of cancer, such as ARID1A in ovarian cancer. Hence, recurrent mutation of these genes may add predictive value for immunotherapy response in GC,” the investigators pointed out. [Nat Med 2018;24:556-562]

“We hope these results will facilitate the development of clinical trials to explore new biomarkers and more precision therapy, ultimately deepening our understanding and improving patient survival of GC,” they said.