Genomic Profiling Reveals Germline Predisposition and Homologous Recombination Deficiency in Pancreatic Acinar Cell Carcinoma.

Autor:	Mandelker D; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Marra A; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Zheng-Lin B; Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Selenica P; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Blanco-Heredia J; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Zhu Y; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Gazzo A; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Wong D; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Yelskaya Z; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Rai V; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Somar J; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Ostafi S; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Mehta N; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Yang C; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Li Y; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Brown DN; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., da Silva EM; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Pei X; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Linkov I; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Terraf P; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Misyura M; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Ceyhan-Birsoy O; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Ladanyi M; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Berger M; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Pareja F; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Stadler Z; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Offit K; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Riaz N; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Park W; Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Chou J; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY., Capanu M; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY., Koehler M; Repare Therapeutics, Cambridge, MA., Rosen E; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., O'Reilly EM; Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY.; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY., Reis-Filho JS; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2023 Nov 20; Vol. 41 (33), pp. 5151-5162. Date of Electronic Publication: 2023 Aug 22.
DOI:	10.1200/JCO.23.00561
Abstrakt:	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.
Databáze:	MEDLINE
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