Among patients with pancreatic ductal adenocarcinoma (PDAC), the use of gene signature-based subtyping may guide personalized therapy, according to a study published in JAMA Oncology.1
Researchers led by Ashton Connor, MD, of the University of Toronto in Canada performed a retrospective cohort study of patients with resected PDAC to examine mutational processes among these patients and their effect on outcomes.
Observed patients included a discovery cohort of 160 PDAC cases from 154 patients who had undergone whole-genome as well as RNA sequencing followed by tumor enrichment. They also looked at a replication cohort of 95 primary cases of PDAC, where patients had undergone whole-genome sequencing as well as expression microarray on bulk biospecimens.
They measured how each signature contributed to carcinogenesis through the use of non-negative matrix factorization to examine the antitumor immunity gene expression across the different subtypes and determine specific biomarkers that would be predictive to therapy.
The researchers identified 5 predominant mutational subtypes that subsequently categorized PDAC into 4 major subtypes of age-related, double-strand break repair, mismatch repair, and 1 with an unknown etiology. Signatures were matched from primary to metastatic tumors, suggesting stability throughout carcinogenesis.
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Additionally, 12 of 27 cases with double-strand break repair were missing germline or somatic events in the canonical homologous recombination genes BRCA1, BRCA2, or PALB2. Patients with double-string break repair and mismatch repair subtypes were associated with an increased expression of antitumor immunity, which corresponded with a higher frequency of tumor-specific neoantigens as well as somatic mutations.
- Connor AA, Denroche RE, Jang GH, et al. Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. JAMA Oncol. 2016 Oct 20. doi:10.1001/jamaoncol.2016.3916 [Epub ahead of print]