What question did this study set out to answer?

To characterize the genomic differences between early-onset and late-onset gastrointestinal cancers across multiple tumor types.

April 5, 2026

Abstract 4105: Distinct age associated genomic landscapes in colorectal, pancreatic, small bowel, and anal cancers: A pan gastrointestinal analysis of 34,000 tumors from AACR Project GENIE v18.0

Key Points

To characterize the genomic differences between early-onset and late-onset gastrointestinal cancers across multiple tumor types.
Utilized AACR Project GENIE v18.0 dataset with 34,000 GI tumors.
Classified tumors into early-onset (<50 years) and late-onset (≥50 years).
Compared mutation frequencies by cancer type and age group, focusing on key genomic drivers.
Early-onset colorectal cancer had more Wnt pathway alterations (APC, TCF7L2, TP53) compared to late-onset.
Early-onset pancreatic cancer had lower frequencies of typical drivers (KRAS, TP53) but higher rates of MEN1 and other genes.
Small bowel cancers in early-onset patients showed more DNA damage response genes, unlike late-onset tumors that were enriched for KDR and MGA.
Early-onset anal cancer had elevated markers related to chromatin remodeling and DNA repair, whereas late-onset tumors showed instability patterns.

Abstract

Abstract Background: Early-onset gastrointestinal (GI) cancers are increasing globally, yet the genomic basis for age-related differences across multiple tumor types remains poorly defined. We leveraged AACR Project GENIE v18.0 (N≈34,000 GI tumors) to characterize molecular distinctions by age in colorectal, pancreatic, small bowel, and anal cancers with sufficient early-onset representation. Methods: Clinical and genomic data were extracted and tumors classified into early-onset (50 years) and late-onset (≥50 years). Mutation frequencies were compared by cancer type and age group, focusing on recurrent drivers, DNA repair, Wnt signaling, RAS/MAPK, chromatin remodeling genes, and targetable alterations. Results: Early-onset colorectal cancer (N=5,724) showed increased Wnt/β-catenin pathway alterations: APC (+4.9%), TCF7L2 (+4.1%), and TP53 (+5.0%), while late-onset tumors (N=15,807) were enriched for BRAF (−5.4%), RNF43 (−1.9%), and GNAS (−1.1%), indicating divergent tumorigenic pathways. Early-onset pancreatic cancer (N=890) exhibited significantly lower frequencies of canonical drivers—KRAS (−24.7%), TP53 (−15.6%), CDKN2A (−6.9%), SMAD4 (−6.0%)—with enrichment of MEN1 (+3.5%), TSC2 (+3.0%), ATRX (+2.0%), DAXX (+1.9%), and CTNNB1 (+2.4%), consistent with fusion-driven, hereditary, and chromatin remodeling biology. Small bowel cancer (N=99) in early-onset patients demonstrated enrichment in DNA damage response and MAPK/RAS genes including BRCA2 (+7.2%), NF1 (+7.4%), FBXW7 (+8.8%), FLT4 (+6.5%), ARAF (+6.4%), and ALK (+5.1%), whereas late-onset tumors (N=538) were enriched for KDR (−5.1%) and MGA (−5.2%). Early-onset anal cancer (N=62) showed elevated MGA (+7.8%), WHSC1/NSD2 (+6.9%), PBRM1 (+6.2%), FANCA (+5.2%), ERCC5 (+6.2%), and MSH6 (+5.9%), highlighting chromatin remodeling and DNA repair pathways potentially related to HPV biology; late-onset tumors (N=464) had enrichment in ATM (−5.6%), PTEN (−5.5%), STK11 (−5.2%), APC (−5.2%), and KMT2C (−5.0%), reflecting age-associated genomic instability. Conclusions: This pan-GI age-stratified analysis reveals distinctive oncogenic programs in early-onset GI cancers characterized by Wnt/TP53-driven colorectal, fusion- and chromatin remodeling-driven pancreatic, DNA damage response/MAPK-driven small bowel, and chromatin-immune DDR signatures in anal cancers. These findings underscore the need for age-tailored precision oncology and support routine genomic profiling in early-onset GI malignancies to identify targetable alterations enriched in younger patients. Citation: AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through an International Consortium. Cancer Discov. 2017;7(8):818-831. (Data: GENIE Release 18.0-public)Acknowledgement: AACR and Project GENIE registry Citation Format: Ahmed Abdelhakeem, Nency Ganatra, Dina Elantably, Tayo Adeoye, Nayef H. Abdel-Razeq, Mosalem M. Osama, Hani M. Babiker. Distinct age associated genomic landscapes in colorectal, pancreatic, small bowel, and anal cancers: A pan gastrointestinal analysis of 34,000 tumors from AACR Project GENIE v18.0 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4105.

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Abdelhakeem et al. (Fri,) studied this question.

synapsesocial.com/papers/69d1fde4a79560c99a0a44ae https://doi.org/https://doi.org/10.1158/1538-7445.am2026-4105

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