MUC16 mutations tied to better survival for gastric cancer patients

Last Updated: 2018-08-17

By Marilynn Larkin

NEW YORK (Reuters Health) - MUC16 mutations seem to be associated with higher tumor mutation load (TML) and better survival outcomes in patients with gastric cancer and may be used to guide immunotherapy treatment, researchers say.

"Despite progress in Helicobacter pylori eradication and early cancer diagnosis, the five-year survival rate of gastric cancer remains less than 30%," Dr. Wei Zhang of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, told Reuters Health. "Gastric cancer is one of the most common cancer types in Asia, but the incidence has seen a steady increase in the United States in recent years."

"There is accumulating evidence that high TML (high numbers of gene mutations in the tumor) can provide a signal to activate immune response systems, thus rendering tumors more sensitive to immunotherapy," he said by email.

To investigate further, Dr. Zhang and colleagues analyzed 437 samples from U.S. gastric cancer patients from The Cancer Genome Atlas (TCGA) and 256 gastric cancer samples from an Asian cohort. Samples from the TCGA cohort comprised the discovery set (median age, 67.6; 64.1% male); the Asian cohort was a validation set (median age, 63; 55.1% male).

As reported online August 9 in JAMA Oncology, MUC16 was mutated in 38.4% of samples from the TCGA cohort and 22.3% from the Asian cohort. In both cohorts, samples with MUC16 mutations had significantly greater TML: median mutation counts for the TCGA cohort were 264 with MUC16 mutations versus 115 without, and for the Asian cohort, 134 with versus 74.

This association was independent of mutations in POLE and BRCA1/2 and mutational signatures in both cohorts: odds ratio, 1.87 for the TCGA and 1.69 for the Asian cohort.

MUC16 mutations (versus wild type) were significantly associated with better prognosis in both cohorts. Median overall survival was 46.9 vs. 26.7 months in the TCGA cohort. Median overall survival of those with MUC16 mutations could not be calculated in the Asian cohort because more than half of patients were alive; those with the wild type gene survived a median of 36.8 months.

The association remained statistically significant after controlling for age, sex, TNM stage, mutations in POLE and BRCA1/2, and mutational signatures (hazard ratio, 0.61).

Further, in samples with MUC16 mutations, immune response and cell cycle regulation circuits were among the top altered signaling pathways.

The prognostic significance of MUC16 mutations in the TCGA cohort was validated in the Asian cohort, the authors say.

"These findings indicate that MUC16 mutations may be associated with higher TML, better survival outcomes, and immune response and cell cycle pathways," they state. "These findings may be immediately applicable for guiding immunotherapy treatment for patients with gastric cancer."

Dr. Zhang noted, "Interestingly, the MUC16 gene also encodes a protein known as CA125, which is a key blood marker for ovarian cancer. We do not know whether MUC16 mutations may translate into elevated or decreased CA125 levels in the blood in gastric cancer. Future studies may decide whether CA125 can also be a useful blood marker for gastric cancer."

"The mucin gene family has emerged as a clinically important group of genes," he said. "In another recent study, we reported that mutations of several other MUC genes may contribute to better response to a metabolic targeting drug called CPI-613 in pancreatic cancer." (http://bit.ly/2OH0Z5M)

Dr. Elizabeth Smyth of Cambridge University Hospitals and Dr. Rebecca Fitzgerald of University of Cambridge, UK, coauthors of a related editorial, said in a joint email to Reuters Health, "Immune checkpoint blockade benefits a limited proportion of patients with gastric cancer and there is an unmet need for biomarkers to improve patient selection for treatment."

"In multiple cancers, high tumor mutation burden has been associated with better outcomes from immune checkpoint inhibition," they noted. "However, currently available tests for this are quite complex and expensive."

Given the findings of the current study, "the next step should be to validate MUC16 mutations as a predictor of outcome in patients who have been treated with pembrolizumab or nivolumab, which are the licensed anti-PD-1 antibodies used in gastric cancer," they said.

"If MUC16 mutation did predict for benefit from immune checkpoint blockade, it could be a simple and clinically useful predictive biomarker," they concluded. "However, more research needs to be done to confirm this."

SOURCE: http://bit.ly/2L1w4ir and http://bit.ly/2OHmCmI

JAMA Oncol 2018.