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Gastric Cancer Mutation Type Linked to Higher Mutational Load, But Better Prognosis

NEW YORK (GenomeWeb) – Gastric cancer patients with MUC16 gene mutations have higher tumor mutational loads than those who do not, according to a new study. These gene mutations could also identify patients who might benefit from immunotherapy.

More than 26,000 people are diagnosed with gastric cancer each year in the US, according to the National Cancer Institute, and slightly less than a third of patients survive five years.

MUC16 is commonly mutated in gastric cancer, and researchers from the US and China sought to examine its relationship to tumor mutational load and prognosis in cohorts from the Cancer Genome Atlas and from Asia. The Cancer Genome Atlas project investigators previously identified four molecular subtypes of gastric cancer that are associated with different prognoses, and the researchers noted that these subtypes are influenced by tumor mutational load.

As they reported today in JAMA Oncology, the researchers found MUC16 to be linked to a higher mutational load, but also a better prognosis in both cohorts. As they also found MUC16 mutations to affect immune response, the researchers suggested that it could be used to identify patients who might respond to immunotherapies.

"Immunotherapy treatment has shown remarkable benefit for some cancer patients whereas others experience toxicities," author Wei Zhang from Wake Forest Baptist Medical Center said in a statement. "More potential markers are urgently needed to help oncologists decide which patient would benefit from this promising new treatment strategy."

The researchers downloaded somatic mutation and gene expression data from 427 gastric cancer samples from the TCGA using the Genome Data Commons site and collected previously published somatic mutation and gene expression data on 256 Asian gastric cancer patients for analysis.

Within the TCGA cohort, MUC16 was the most commonly mutated gene, the researchers reported. Other frequent mutations affected BRCA1, BRCA2, POLE, and MLH3.

Samples with MUC16 mutations had a significantly higher mutation rate than those without, the researchers noted. They attributed tumor mutation load to tumor instability, which they said is prevalent in gastric cancer.

MUC16 mutations were also significantly associated with better survival outcome in the TCGA cohort: Patients with MUC16 mutations survived a median 46.9 months, as compared to 26.7 months for those without. The researchers noted that this effect held even when they controlled for confounding factors such as age, sex, BRCA1 or BRCA2 mutations, and defective DNA mismatch repair signature.

Zhang and his colleagues had similar results in the Asian cohort. Again, MUC16 was the most commonly mutated gene, and it was associated with a higher mutational count and better survival outcomes.

These MUC16 mutations appeared to influence the expression of other genes. In particular, the researchers reported that signaling pathways involved in the immune system, cell cycle checkpoints, antigen processing, and DNA replication and repair were altered in samples with MUC16 mutations, as compared to those without.

As MUC16 is also known to modulate immune response to cancer, the researchers suggested that patients with MUC16 mutations could benefit from therapies that boost the immune response.

However, the researchers noted that their study has a number of limitations, including that their Asian cohort was aggregated from four previous studies, but also that the mechanism behind the link between MUC16 mutations and tumor mutational load and survival is not clear.

In an accompanying commentary, the Royal Marsden Hospital's Elizabeth Smyth and the University of Cambridge's Rebecca Fitzgerald suggested that MUC16 mutations might not be directly linked to tumor mutational load. They noted that MUC16 is a large gene with low replication timing, which leads to an accumulation of mutations.

They also postulated that MUC16's association with increased survival could be due to its role in neoantigen presentation and that the culling of MUC16 neoantigen-presenting cancer cells would lead to a population of cells that don't express MUC16 and have reduced metastatic and immunosuppressive potential.

Still, they said that though these results are "preliminary and require further validation, they could provide a signpost for clinically relevant research in gastric cancer or, in view of the ubiquity of MUC16 mutations, in other tumor types."