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.

FIG 1.

Germline genetic alterations in homologous recombination and DNA damage repair genes in PACC. Micrograph depicting the histologic features of (A) pure PACC and PACC admixed with (B) pancreatic ductal carcinoma and (C) pancreatic neuroendocrine. (D-F) Prevalence of germline pathogenic alterations in DDR-/HR-related genes in the MSK-IMPACT cohort samples stratified according to the tumor type. Bubble plots are color-coded and sized according to the legend. ^aPancreas Other refers to pancreatic cancer histologies other than ductal adenocarcinoma and acinar cell carcinoma. DDR, DNA damage response; HR, homologous recombination; MSK-IMPACT, Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets; PACC, pancreatic acinar cell carcinoma; PDAC, pancreatic ductal adenocarcinoma.

FIG 2.

Repertoire of germline and somatic genetic alterations in PACC. (A) OncoPrint depicting the germline and somatic pathogenic mutations, amplifications and deletions, and structural variants affecting cancer-related genes on the basis of clinical tumor-normal MSK-IMPACT sequencing in 49 PACC tumors. TMB, reported as mutations per megabase, is displayed at top. Germline status, histology, stage at diagnosis, and dominant mutational signature are displayed at the bottom and color-coded according to the legend at the right. (B) TMB of PACCs subjected to clinical tumor-normal MSK-IMPACT sequencing in carriers of germline HR/DDR genetic alterations and wild-type. (C) Chromosomal instability as assessed by the FGA on the basis of clinical MSK-IMPACT sequencing of PACCs carrying germline HR/DDR genetic alterations and wild-type. P values are calculated by the Mann-Whitney U test. (D) Volcano plot showing mutation enrichment analysis of somatic genetic alterations in PACCs carrying germline HR/DDR genetic alterations versus wild-type. Results are represented as −log₁₀(P value; y axis) and log₂(OR; x axis) from two-sided Fisher's exact tests. Genes that are differentially altered (P < .05) between the corresponding groups are labeled and highlighted in red. Size of the circle reflects the prevalence of alteration in each displayed subgroup. APOBEC, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide; DDR, DNA damage response; FGA, fraction of genome altered; HR, homologous recombination; HRD, HR deficiency; LOH, loss of heterozygosity; MSK-IMPACT, Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets; OR, odds ratio; PACC, pancreatic acinar cell carcinoma; PDAC, pancreatic ductal adenocarcinoma; TMB, tumor mutational burden; WT, wild type.

FIG 3.

WGS of PACC. (A) OncoPrint of the genomic characteristics of 12 PACCs subjected to tumor-normal WGS, including seven cases with germline genetic alterations of BRCA2 (n = 5) and PALB2 (n = 2) and five germline wild-type. The features that are represented include germline gene, dominant mutational signature by the signal algorithm, whole genome doubling, HRDetect score, fraction of genome altered, SNV type, proportion and load, INDEL size, proportion and load, SV type, proportion and load, and Waddell subtype. Circos plots displaying intervariant distance and classification of SNVs, regions of kataegis, INDELS, copy number alterations, regions of loss of heterozygosity and SVs of PACCs carrying (B) BRCA2 germline alteration, (C) PALB2 germline alteration, and (D and E) germline wild-type. HRD, HR deficiency; INDEL, insertion and deletion; LOH, loss of heterozygosity; PACC, pancreatic acinar cell carcinoma; SNV, single-nucleotide variant; SV, structural variant; WGD, whole-genome duplication; WGS, whole-genome sequencing; WT, wild type.

FIG 3.

WGS of PACC. (A) OncoPrint of the genomic characteristics of 12 PACCs subjected to tumor-normal WGS, including seven cases with germline genetic alterations of BRCA2 (n = 5) and PALB2 (n = 2) and five germline wild-type. The features that are represented include germline gene, dominant mutational signature by the signal algorithm, whole genome doubling, HRDetect score, fraction of genome altered, SNV type, proportion and load, INDEL size, proportion and load, SV type, proportion and load, and Waddell subtype. Circos plots displaying intervariant distance and classification of SNVs, regions of kataegis, INDELS, copy number alterations, regions of loss of heterozygosity and SVs of PACCs carrying (B) BRCA2 germline alteration, (C) PALB2 germline alteration, and (D and E) germline wild-type. HRD, HR deficiency; INDEL, insertion and deletion; LOH, loss of heterozygosity; PACC, pancreatic acinar cell carcinoma; SNV, single-nucleotide variant; SV, structural variant; WGD, whole-genome duplication; WGS, whole-genome sequencing; WT, wild type.

FIG 4.

Repertoire of neoantigens of PACC. (A) Barplots showing the number of neoantigens in PACCs subjected to whole-genome sequencing grouped by HR/DDR germline alteration status (red, BRCA2 and PALB2 carriers; blue, germline wild-type). The bars are color-coded according to legend by the neoantigen type. (B) Comparisons of the number of neoantigens in PACCs with or without genomic features of HRD. Neoantigen type is reported at top of each individual boxplot. Samples are color-coded according to the legend (red, HRD-positive; blue, HRD-negative). ****P < .0001; ***P < .001, **P < .01, *P < .05. P values are calculated using the Mann-Whitney U test. DDR, DNA damage response; HR, homologous recombination; HRD, HR deficiency; ns, not significant; PACC, pancreatic acinar cell carcinoma; WGS, whole-genome sequencing; WT, wild type.