Synapse - Genomic profiling reveals germline predisposition and homologous recombination deficiency in pancreatic acinar cell carcinoma

Genomic profiling reveals germline predisposition and homologous recombination deficiency in pancreatic acinar cell carcinoma Journal Article

Authors:	Mandelker, D.; Marra, A.; Zheng-Lin, B.; Selenica, P.; Blanco-Heredia, J.; Zhu, Y.; Gazzo, A.; Wong, D.; Yelskaya, Z.; Rai, V.; Somar, J.; Ostafi, S.; Mehta, N.; Yang, C.; Li, Y.; Brown, D. N.; da Silva, E. M.; Pei, X.; Linkov, I.; Terraf, P.; Misyura, M.; Ceyhan-Birsoy, O.; Ladanyi, M.; Berger, M.; Pareja, F.; Stadler, Z.; Offit, K.; Riaz, N.; Park, W.; Chou, J.; Capanu, M.; Koehler, M.; Rosen, E.; O'Reilly, E. M.; Reis-Filho, J. S.
Article Title:	Genomic profiling reveals germline predisposition and homologous recombination deficiency in pancreatic acinar cell carcinoma
Abstract:	PURPOSE: To determine the genetic predisposition underlying pancreatic acinar cell carcinoma (PACC) and characterize its genomic features. METHODS: Both somatic and germline analyses were performed using an Food and Drug Administration-authorized matched tumor/normal sequencing assay on a clinical cohort of 28,780 patients with cancer, 49 of whom were diagnosed with PACC. For a subset of PACCs, whole-genome sequencing (WGS; n = 12) and RNA sequencing (n = 6) were performed. RESULTS: Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 (n = 1), BRCA2 (n = 12), PALB2 (n = 2), ATM (n = 2), and CHEK2 (n = 1). Thirty-one PACCs displayed pure, and 18 PACCs harbored mixed acinar cell histology. Fifteen of 31 (48%) pure PACCs harbored a germline pathogenic variant affecting HR-/DDR-related genes. BRCA2 germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma (86 of 2,739, 3.1%; P < .001), high-grade serous ovarian carcinoma (67 of 1,318, 5.1%; P < .001), prostate cancer (116 of 3,401, 3.4%; P < .001), and breast cancer (79 of 3,196, 2.5%; P < .001). Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs undergoing WGS, including 100% (n = 6) of PACCs with germline HR-related pathogenic mutations and 1 of 6 PACCs lacking known pathogenic alterations in HR-related genes. Exploratory analyses revealed that in PACCs, the repertoire of somatic driver genetic alterations and the load of neoantigens with high binding affinity varied according to the presence of germline pathogenic alterations affecting HR-/DDR-related genes and/or HRD. CONCLUSION: In a large pan-cancer cohort, PACC was identified as the cancer type with the highest prevalence of both BRCA2 germline pathogenic variants and genomic features of HRD, suggesting that PACC should be considered as part of the spectrum of BRCA-related malignancies.
Keywords:	genetics; pancreatic neoplasms; homologous recombination; genetic predisposition to disease; brca1 protein; brca2 protein; pancreas carcinoma; pancreas tumor; genomics; acinar cell carcinoma; carcinoma, acinar cell; genetic predisposition; germ-line mutation; germline mutation; pancreatic carcinoma; humans; human; male
Journal Title:	Journal of Clinical Oncology
Volume:	41
Issue:	33
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Date Published:	2023-11-20
Start Page:	5151
End Page:	5162
Language:	English
DOI:	10.1200/jco.23.00561
PUBMED:	37607324
PROVIDER:	scopus
PMCID:	PMC10667000
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85177103021&doi=10.1200%2fJCO.23.00561&partnerID=40&md5=93dc9d67c08cf6b4bdfa6048f4ca0b9a
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Jorge Reis-Filho -- Source: Scopus