Citations

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.

Abstract Background: PARP inhibitors are restricted to a subset of BRCA-associated cancers, but homologous recombination repair (HRR) deficiency signifies a broader genomic vulnerability that may extend therapeutic opportunities across diverse malignancies. We utilized AACR Project GENIE v18.0-public to define the pan-cancer prevalence of HRR gene alterations. Methods: Somatic mutation and clinical sample data from GENIE v18.0-public were analyzed. HRR genes included BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51B/C/D, RAD51L1, BARD1, BRIP1, and core FANC genes. HRR alteration rates were calculated by tumor type using unique samples; only de-identified aggregate results are reported. Results: Among 101,240 tumors, HRR gene alterations were frequent in multiple non-BRCA-associated cancers. Highest rates were seen in sialoblastoma (100%), large cell medulloblastoma (50%), malignant glomus tumor (50%), lung cancer (46.0%), infantile fibrosarcoma (42.9%), liver (40%), kidney (40%), non-melanoma skin (36.9%), colorectal (36.6%), melanocytoma (34.2%), biliary tract (33.3%), bladder (31.5%), and ovarian/fallopian tube (30.2%). Notably, lung, bladder, hepatobiliary, renal, gastrointestinal, and some sarcoma subtypes showed HRR mutation prevalence equal or higher than current PARP indications, yet lack FDA approval. Conclusions: HRR alterations are widespread across solid tumors, often surpassing rates in cancers eligible for PARP treatment. These findings support expanding tumor-agnostic HRR genomic testing beyond BRCA-linked malignancies and warrant prospective trials of PARP inhibitors in HRR-enriched tumor types such as lung, bladder, hepatobiliary, renal, gastrointestinal, and pediatric/rare cancers. Impact: Large-scale genomic profiling from AACR Project GENIE demonstrates that HRR gene alterations are common across diverse solid tumors, with prevalence in multiple cancer types surpassing those currently eligible for PARP inhibitor therapy. These findings support broad implementation of HRR genomic testing in routine molecular diagnostics and provide a rationale for expanding PARP inhibitor use beyond BRCA-associated malignancies. The data justify prospective tumor-agnostic clinical trials of PARP inhibitors in HRR-enriched cancers such as lung, bladder, hepatobiliary, renal, gastrointestinal, and select pediatric and rare tumors; this could transform therapeutic decision-making and accelerate development of synthetic lethality-based targeted therapies Citation: AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831 Acknowledgement: AACR and Project GENIE Citation Format: Ahmed Abdelhakeem, Nency Ganatra, Dina Elantably, Tayo Adeoye, Nayef H. Abdel-Razeq, Osama M. Mosalem, Hani M. Babiker. Pan cancer enrichment of homologous recombination repair (HRR) gene alterations in 101,240 tumor samples from AACR Project GENIE: Implications for tumor-agnostic PARP inhibitor expansion [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 4106.

INTRODUCTION: Non-Hodgkin's Lymphoma (NHL) survival is influenced by various factors, including marital status and sex. This study explores how these intersecting factors affect cancer-specific (CSS) and overall survival (OS) in NHL patients. OBJECTIVE: To examine the intersection of sex and marital status on survival outcomes among individuals with NHL. METHODOLOGY: We conducted a retrospective cohort study using SEER registry data for individuals aged 18-85 diagnosed with NHL. Cox regression models assessed the influence of marital status and sex on CSS and overall survival OS, adjusting for age, race, household income, disease stage, primary site, and treatment (chemotherapy, radiotherapy, surgery). Kaplan-Meier curves and log-rank tests compared survival distributions. RESULT: The study analyzed 319,013 individuals with NHL from 2000 to 2020. Participants were predominantly white (73.0%) and female (54.7%), with 54.6% married and a median age of 66 years (IQR 55-76). Females exhibited a 33% higher hazard of death for cancer-specific survival (HR = 1.34, 95% CI: 1.30-1.38) and a 40% higher hazard for overall survival (HR = 1.40, 95% CI: 1.37-1.44). The interaction of marital status and sex significantly impacts both CSS and OS among individuals with NHL. Widowed individuals, regardless of sex, showed the highest risk of death; males had a cancer-specific hazard ratio (HR) of 2.50 (95% CI: 2.35-2.65) and overall HR of 2.31 (95% CI: 2.21-2.41), while females had a cancer-specific HR of 3.09 (95% CI: 2.87-3.31) and overall HR of 2.97 (95% CI: 2.82-3.12). Divorced and separated individuals also exhibited elevated risk. Notably, married males had the lowest hazard ratios, with cancer-specific HR of 1.07 (95% CI: 1.03-1.12) and overall HR of 0.87 (95% CI: 0.84-0.89). CONCLUSION: This study highlights that marital status and sex significantly influence survival outcomes in NHL patients. Widowed individuals have the highest mortality risk, while being married is associated with better survival, especially for males. These findings emphasize the role of social support and gender-specific factors in NHL prognosis.

INTRODUCTION Medicaid expansion under the Affordable Care Act (ACA) has aimed to improve healthcare access and outcomes for low-income individuals across the United States. Acute Lymphoblastic Leukemia (ALL), a rapidly progressing hematological malignancy, demands timely and comprehensive medical intervention to optimize patient survival rates. Despite advancements in treatment, disparities in cancer-specific survival persist (CSS), particularly among socioeconomically disadvantaged populations. OBJECTIVE This study investigates the impact of Medicaid expansion on CSS among individuals diagnosed with ALL, aiming to explore the extent to which increased healthcare access through Medicaid expansion may influence survival outcomes in this vulnerable patient population. METHODOLOGY We utilized the Surveillance, Epidemiology, and End Results (SEER) cancer registry to examine the impact of Medicaid expansion on CSS among individuals diagnosed with ALL. A difference-in-difference analysis (DID) was conducted to evaluate the effect of the policy on survival outcomes. Texas, a state that has not implemented Medicaid expansion, was compared with California, which adopted the policy in 2014. The analysis adjusted for significant covariates including age, sex, race/ethnicity, socioeconomic status, and treatment modalities. By comparing pre- and post-expansion periods in these two states, we aimed to isolate the impact of Medicaid expansion on CSS in ALL patients. RESULT Among 22,303 patients, 60.0% were in California (13,384), while 40.0% were in Texas (8,919). The pre-ACA period included 14,129 patients (62.0% in California and 38.0% in Texas), and 8,174 patients were in the post-ACA period (56.6% in California and 43.4% in Texas). In the post-ACA implementation period, there was a 23.5% reduction in the hazard of deaths (HR=0.77, 95% CI 0.70-0.85). Medicaid expansion significantly improved cancer-specific survival among individuals with ALL across different race/ethnicity and income levels (DID=-0.69, 95% CI -1.18 to -0.19). The most significant improvements were observed among minority groups: Blacks (DID=-0.80, 95% CI -1.39 to -0.21) and Hispanics (DID=-0.72, 95% CI -1.35 to -0.22), as well as individuals with lower income levels (DID=-0.66, 95% CI -1.14 to -0.18). CONCLUSION The implementation of the ACA and its Medicaid expansion component led to a substantial improvement in cancer-specific survival among individuals with acute lymphoblastic leukemia in California compared to non-expansion Texas.