The therapeutic approach in pancreatic ductal adenocarcinoma (PDAC) must characterize the zygosity of germline and somatic ATM variants (gATMm, sATMm) and their contribution to homologous recombination deficit (HRD). To better understand the role of ATM mutations in PDAC and other malignancies, clinico-genomic data from these patients were extracted. The overall survival (OS) of patients with tumors harboring the ATM mutation was calculated using genomic instability scores (GIS). Among the 46 patients with PDAC, 24 (52%) were diagnosed with stage III/IV and were found to have gATMm (N = 24) or sATM (N = 22) as pathogenic ATM variations. 

Researchers found 27 cases with biallelic variants, 15 cases with monoallelic variants, and 4 cases with ambiguous variants (8%). N = 11 had gATMm (95% CI: 22.7-NR), N = 13 had sATMm (95% CI: 11.9-NR), and the median OS for the advanced-stage cohort at diagnosis was 19.7 months [95% CI: 12.3-not reached (NR)]. About 33 PDAC patients had their GIS calculated and compared to other tumors that were enriched for HRD due to ATM mutations. When compared to the breast (median: 18; range: 3-55) and ovarian (median: 25; range: 3-56) tumors with ATM mutations, the median for these malignancies was lower (median: 11; range: 2-29) (P < 0.001 and P = 0.003, respectively). 

Biallelic pathogenic mutations of ATM were incompatible with TP53. When compared to PDAC with an ATM mutation, PDAC with a mutation in any of the other conventional driver genes (KRAS, CDKN2A, or SMAD4) was less common. The ATM mutations in PDAC belong to a separate biological subgroup that has a better overall survival rate. While ATM should be regarded as a non-core HR gene in PDAC, pathogenic ATM mutations do not impart an HRD signature in this disease.