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Genomic and Immune Landscape of Pancreatic Ductal Adenocarcinoma Associated with Germline Pathogenic Variants in ATM.

S. Yadav,R. Bao,R. Graham,Chunling Hu,S. Hart,Jie Na,N. Boddicker,Rohan D Gnanaolivu,James Smadbeck,Li Ding,D. Billadeau,Aaron T. Mayer,Shounak Majumder,Paulo Cilas Morais Lyra,Adrian V. Lee,A. N. Monteiro,J. Villasboas,Robert R. McWilliams,F. Couch

Published 2025 in Clinical Cancer Research

ABSTRACT

BACKGROUND Germline pathogenic variants (PVs) in ATM increase the risk of pancreatic ductal adenocarcinoma (PDAC) but the underlying tumor biology of PDAC associated with germline PVs in ATM have not been adequately explored. EXPERIMENTAL DESIGN Whole-genome (WGS), whole-exome (WES), and RNA-sequencing were performed on PDAC tumors from 25 germline ATM PVs carriers diagnosed at Mayo Clinic between 2007 and 2017. Somatic and copy number alterations, mutational signatures, transcriptomic subtypes, and the immune landscape were evaluated. RESULTS High-quality WES and WGS sequencing were obtained from 21 and 15 tumors, respectively. Biallelic inactivation of ATM was observed in 87%, KRAS PVs in 90%, CDKN2A homozygous loss in 60%, and TP53 alterations in <10% of these tumors. A predominant clock-like mutational signature was present in all samples. Whole transcriptome analysis identified that the Aberrantly Differentiated Endocrine Exocrine (ADEX) subtype accounted for 18% of PDACs and was consistently associated with >5-year overall survival. In addition, a 28-gene expression-based signature associated with OS was identified and further validated in the TCGA cohort. Immune landscape analysis through CODEX identified enriched CD4 T-helper cell/tumor interactions and reduced B7H3 high cell/tumor interactions in ATM PV carriers compared to non-carriers. CONCLUSIONS The observed absence of TP53 PVs and enrichment for CDKN2A alterations in ATM tumors, along with differences in the mutational signatures, transcriptomic subtypes and immune landscape, improve our understanding of the mechanistic pathways involved in PDAC development in germline ATM PV carriers and help identify potential targeted therapeutic strategies.

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