Signature Subtyping May Guide Personalized Therapy in PDAC

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Among patients with pancreatic ductal adenocarcinoma, the use of gene signature-based subtyping may guide personalized therapy.
Among patients with pancreatic ductal adenocarcinoma, the use of gene signature-based subtyping may guide personalized therapy.

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.

RELATED: Surveillance of CDNK2A Mutation Carriers Can Detect Pancreatic Ductal Adenocarcinoma at Early Stage

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.

Reference

  1. 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]

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