In a study reported in the Journal of Clinical Oncology, Mandelker et al found that pancreatic acinar cell carcinoma was associated with a high prevalence of BRCA2 germline pathogenic variants and genomic features of homologous recombination deficiency (HRD).
The study involved somatic and germline analyses in a clinical cohort of 28,780 patients with cancer at Memorial Sloan Kettering Cancer Center, of whom 49 were diagnosed with pancreatic acinar cell carcinoma. Whole-genome sequencing was performed in a subset of 12 patients with pancreatic acinar cell carcinoma.
Key Findings
Among 49 patients with pancreatic acinar cell carcinoma, 18 (36.7%) harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 in 1 patient, BRCA2 in 12, PALB2 in 2, ATM in 2, and CHEK2 in 1.
In a large pan-cancer cohort, pancreatic acinar cell carcinoma was identified as the cancer type with the highest prevalence of both BRCA2 germline pathogenic variants and genomic features of HRD, suggesting that pancreatic acinar cell carcinoma should be considered as part of the spectrum of BRCA-related malignancies.— Mandelker et al
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Thirty-one pancreatic acinar cell carcinoma cases displayed pure acinar cell histology and 18 had mixed acinar cell histology. Of the 31 pure pancreatic acinar cell carcinomas, 15 (48%) harbored germline pathogenic variants affecting HR-related or DDR-related genes. BRCA2 germline pathogenic variants were found in 11 (35%) pure pancreatic acinar cell carcinomas—significantly more commonly found than in pancreatic adenocarcinoma (86/2,739 = 3.1%; P < .001), high-grade serous ovarian carcinoma (67/1,318 = 5.1%; P < .001), prostate cancer (116/3,401 = 3.4%; P < .001), and breast cancer (79/3,196 = 2.5%; P < .001).
Genomic features of HRD were detected in 7 of 12 patients with pancreatic acinar cell carcinoma undergoing whole-genome sequencing, including 6 of 6 with germline HR-related pathogenic mutations and 1 of 6 with no known pathogenic alterations in HR-related genes. Exploratory analyses indicated that the repertoire of somatic driver genetic alterations and the load of neoantigens with high binding affinity in pancreatic acinar cell carcinomas varied according to the presence of germline pathogenic alterations affecting HR- or DDR-related genes and/or HRD.
The investigators concluded, “In a large pan-cancer cohort, pancreatic acinar cell carcinoma was identified as the cancer type with the highest prevalence of both BRCA2 germline pathogenic variants and genomic features of HRD, suggesting that pancreatic acinar cell carcinoma should be considered as part of the spectrum of BRCA-related malignancies.”
Jorge S. Reis-Filho, MD, PhD, of the Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by National Cancer Institute grants, Cycle for Survival, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, and Repare Therapeutics. For full disclosures of the study authors, visit ascopubs.org.
