Skip to main content
Premium Trial:

Request an Annual Quote

Lung Cancer Subtypes Have Different Recurrent Mutations, Study Finds

NEW YORK (GenomeWeb) – Exome sequences for tumors from more than 1,000 individuals with lung adenocarcinoma or squamous cell carcinoma suggest the two common lung cancer subtypes contain somatic mutations and antigenic properties that may be vulnerable to targeted treatments or immunotherapy.

As they reported today in Nature Genetics, researchers from the US and Russia did exome sequencing, array-based copy number profiling, and/or immunogenicity predictions on matched tumor and normal samples from 660 individuals with lung adenocarcinoma, and 484 patients with squamous cell carcinoma.

In the process, the team detected dozens of significantly mutated genes, but only a handful were recurrently mutated in both lung cancer subtypes, suggesting that targeted treatments may differ for each subtype. On the neoantigen side, meanwhile, roughly half of tumors in each subtype expressed several different neoepitopes that might be susceptible to immunotherapy-boosted immune activity.

"We have identified several distinct recurrent mutations that are likely to be recognized by the immune system and therefore would be strong candidates for cancer vaccines," Joshua Campbell, a postdoctoral researcher affiliated with the Broad Institute and the Dana-Farber Cancer Institute, said in a statement.

Campbell and his colleagues used Agilent SureSelect exome kits to capture protein-coding regions of matched tumor and normal lung cancer samples collected for the Cancer Genome Atlas and other studies, then sequenced the exomes by Illumina paired-end sequencing. Using statistical methods, the team detected potential cancer driver mutations, and filtered out passenger mutations by comparing the data with matched normal samples and nearly 3,000 previously sequenced normal exomes.

Generally speaking, the results suggest the spectrum of significantly mutated genes differs between the two cancer subtypes, with each containing tumors with and without mutation signatures related to smoking.

"Future studies are needed to determine what allows a mutation in a gene to cause uncontrolled growth in one type of cell but not in another type," Campbell said. "This knowledge will give us a more complete understanding of the molecular pathways involved in tumor growth and help us design better drugs."

In particular, the team saw 38 genes mutated with significant frequency in lung adenocarcinoma tumors, including several genes not described in past studies of the disease such as PPP3CA, DOT1L, and FTSJD1. In lung squamous cell carcinoma, the analysis pointed to 20 significantly mutated genes, including RASA1, which has not been linked to this subtype before.

Six significantly mutated genes turned up in both lung cancer subtypes, as did 11 focal amplification peaks and 13 focal deletion peaks. But again, most gains and losses were specific to one tumor subtype or the other.

As described in the past, receptor tyrosine kinase mutations were common to lung adenocarcinomas. But in tumors from that subtype without targetable receptor tyrosine kinase alterations, the researchers found that mutations in genes such as SOS1, VAV1, RASA1, and ARHGAP35 were prevalent.

Overall, squamous cell carcinomas shared more molecular features with carcinomas described at other sites in the body, including bladder cancer, smoking-related epithelial cancer, and head and neck squamous cell carcinomas.

Finally, the team uncovered five or more neoepitopes in 47 percent of the lung adenocarcinoma tumors and 53 percent of the lung squamous cell carcinomas considered.

"Some highly recurrent mutations were predicted to result in neoepitopes," Campbell and his co-authors wrote. "Future studies may further unravel the relationship between these candidates and clinical responses to immune checkpoint inhibitors and customized vaccine therapies."