Clinico-genomic characterization of ATM and HRD in pancreas cancer: Application for practice Journal Article
| Authors: | Park, W.; O'Connor, C. A.; Bandlamudi, C.; Forman, D.; Chou, J. F.; Umeda, S.; Reyngold, M.; Varghese, A. M.; Keane, F.; Balogun, F.; Yu, K. H.; Kelsen, D. P.; Crane, C.; Capanu, M.; Iacobuzio-Donahue, C.; O’Reilly, E. M. |
| Article Title: | Clinico-genomic characterization of ATM and HRD in pancreas cancer: Application for practice |
| Abstract: | Purpose: Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated. Results: Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3-not reached (NR)], 27.1 months (95% CI: 22.7-NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9-NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2-29) relative to breast (18, 3-55) or ovarian (25, 3-56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC. Conclusions: ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease. ©2022 American Association for Cancer Research. |
| Keywords: | genetics; pancreatic neoplasms; cohort studies; carcinoma, pancreatic ductal; cohort analysis; pathology; pancreas carcinoma; pancreas tumor; atm protein; genomics; humans; human; ataxia telangiectasia mutated proteins; atm protein, human |
| Journal Title: | Clinical Cancer Research |
| Volume: | 28 |
| Issue: | 21 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-11-01 |
| Start Page: | 4782 |
| End Page: | 4792 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-22-1483 |
| PUBMED: | 36040493 |
| PROVIDER: | scopus |
| PMCID: | PMC9634347 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
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