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MUC16 mutation associated with better gastric cancer survival

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August 9, 2018

Patients with gastric cancer and MUC16-mutant tumors had longer median OS than patients with wild-type MUC16, according to study results published in JAMA Oncology.

MUC16 mutations appear to be associated with tumor mutation load and can be used to stratify patients with gastric cancer into prognostically distinct groups. ...This finding may have implications for prognostic prediction and therapeutic guidance for gastric cancer,” Xiangchun Li, PhD, of Tianjin Medical University Cancer Institute and Hospital, and colleagues wrote.

Gastric cancer is genomically heterogeneous, with varying tumor mutation loads, which is an important determinant in molecular subtyping of gastric cancer.

MUC16 — a type I transmembrane mucin protein that encodes cancer antigen 125 — is commonly observed in gastric cancer; however, its association with tumor mutation load and patient outcomes has remained unknown.

Li and colleagues evaluated samples from 437 patients (median age, 67.6 years; 64.1% men) from The Cancer Genome Atlas — established as the discovery cohort — and 256 patients (median age, 63 years; 55.1% men) from an Asian validation cohort.

Researchers used SignatureAnalyzer — which uses Bayesian-based nonnegative matrix factorization to determine the optimal number of mutational signatures — to extract mutational signatures by combining somatic mutation data from both cohorts rather than doing so separately.

A multivariate regression model measured associations between MUC16 mutation and tumor mutation load — defined as defined as log2 transformation of mutation rate per megabase — by including them as confounding factors.

Mutation frequency, OS and tumor mutation load served as the primary outcomes.

Researchers observed MUC16 mutation among 168 patients (38.4%) in the discovery cohort, representing one of the most common mutated genes in the cohort. Samples with MUC16 mutations had higher tumor mutation load than samples without MUC16 mutation (median mutation count, 264 vs. 115; P < .001).

Of the samples with MUC16 mutations, 44.2% harbored mutations in genes related to maintenance of genomic integrity, DNA replication proofreading and mismatch repair, such as BRCA1/2, POLE and MLH3.

Researchers detected six mutational signatures in the samples: defects in DNA proofreading owing to recurrent somatic mutations in POLE13 (signature 10, 4.8%), overactivity of messenger RNA-editing enzyme APOBEC (signature 2, 10.9%), reflux of gastric acid (signature 17, 6.6%), age-related accumulation of C>T at cytosine-phosphate-guanine dinucleotide (signature

1, 41.8%) and defective mismatch repair (signature 15, 24.3% and signature 21, 11.6%).

To avert any possibility that confounding variables impacted associations between MUC16 mutations and tumor mutation load, researchers included all mutational signatures — except signature 10 — and mutations in BRCA1/2 and POLE in the multivariate model. Results showed associations between MUC16 mutations and tumor mutation load remained significant (OR = 1.87; 95% CI, 1.49-2.36).

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Kaplan-Meier survival analysis showed MUC16 mutation was associated with longer survival in the discovery cohort (median OS, 46.9 months; 95% CI, 26.4-not available vs. 26.7 months; 95% CI, 20.2-43.1; P = .007).

The association remained significant after adjustment for age, sex, mutations in BRCA1/2 and POLE, and other confounding factors (HR = 0.61; 95% CI, 0.42-0.89).

Researchers detected MUC16 mutations in 22.3% of the Asian cohort. These patients also had a significantly greater median mutation count (134 vs. 76; P < .001), an association that persisted in the multivariate model (OR = 1.69; 95% CI, 1.25-2.29).

Signatures 1 (37.9%) and 2 (25.3%) appeared the most prevalent in this cohort.

Kaplan-Meier survival analyses also showed MUC16 mutations were associated with longer survival in the validation cohort; however, median OS of patients with MUC16 mutations could not be calculated because more than half remained alive (not calculable vs. 36.8 months; P = .04).

This association persisted after controlling for confounding factors and mutational signatures (HR = 0.26; 95% CI, 0.07-1.02).

“The association of MUC16 mutation with tumor mutation load was independent of a significant presence of mutational signatures and of mutations in BRCA1/2 and POLE,” the researchers wrote. “Gastric cancer samples with MUC16 mutations were characterized by upregulation of signaling pathways involved in immune response, antigen processing, cell cycle checkpoints, and DNA replication and repair.”

If MUC16 predicts greater tumor mutation load, these data may have important clinical implications, Elizabeth C. Smyth, MB BCh, MSc, from the department of oncology at Cambridge University Hospitals NHS Foundation Trust in the United Kingdom, and Rebecca C. Fitzgerald, MBBChir MD, FRCP, FMedSci, of the Hutchison-MRC Research Centre at University of Cambridge in the United Kingdom, wrote in a related editorial.

“The most obvious use of MUC16 mutation as a surrogate for tumor mutation load in gastric cancer would be to identify patients who might benefit from immune checkpoint blockade,” they wrote. “Because one in six patients with programmed cell death 1 ligand 1-selected gastroesophageal cancer respond to anti-PD-1 therapy, identifying better enrichment biomarkers is a priority.”– by Melinda Stevens

Disclosures: The authors report no relevant financial disclosures. Smyth reports honoraria for advisory roles with Bristol-Myers Squibb, Celgene, Five Prime Therapeutics, Gritstone Oncology and Servier Oncology. Fitzgerald reports being named inventor on patents pertaining to the Cytosponge; the Cytosponge-TFF3 technology has been licensed to Covidien GI solutions (now owned by Medtronic) by the Medical Research Council.