RESUMO
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.
Assuntos
Carcinoma de Células Acinares , Neoplasias Pancreáticas , Masculino , Humanos , Carcinoma de Células Acinares/genética , Neoplasias Pancreáticas/genética , Proteína BRCA2/genética , Proteína BRCA1/genética , Mutação em Linhagem Germinativa , Predisposição Genética para Doença , Recombinação Homóloga , Genômica , Neoplasias PancreáticasRESUMO
Caloric/dietary restriction (CR/DR) can promote longevity and protect against age-associated disease across species. The molecular mechanisms coordinating food intake with health-promoting metabolism are thus of significant medical interest. We report that conserved Caenorhabditis elegans microRNA-80 (mir-80) is a major regulator of the DR state. mir-80 deletion confers system-wide healthy aging, including maintained cardiac-like and skeletal muscle-like function at advanced age, reduced accumulation of lipofuscin, and extended lifespan, coincident with induction of physiological features of DR. mir-80 expression is generally high under ad lib feeding and low under food limitation, with most striking food-sensitive expression changes in posterior intestine. The acetyltransferase transcription co-factor cbp-1 and interacting transcription factors daf-16/FOXO and heat shock factor-1 hsf-1 are essential for mir-80(Δ) benefits. Candidate miR-80 target sequences within the cbp-1 transcript may confer food-dependent regulation. Under food limitation, lowered miR-80 levels directly or indirectly increase CBP-1 protein levels to engage metabolic loops that promote DR.
