Abstract 7471: Mutational profiles of pancreatic cancer patients from Eastern Asia using somatic exome sequencing
Authors: Jacquelyn Reuther, Taro Shibuki, Megan Hawley, Hideaki Bando, Keir Violaceae, Makoto Ueno, Kenji Ikezawa, Takuji Okusaka, Teiichi Sugiura, Keiko Kamei, Yoshito Komatsu, Michiaki Unno, Hiroki Yukami, Takuji Iwashita, Emily Westheimer, Kumiko Umemoto, Robert Daber, Takayuki Yoshino, Jianhua Zhao, Masafumi Ikeda
Journal: Cancer Research (2025)

Abstract Introduction: Pancreatic adenocarcinoma (PC) is one of the most lethal diseases. The incidence of PC is rising in the Asia-Pacific population, with some of the highest rates in Japan. As such, the utilization of molecular testing has increased, especially for advanced disease, to identify molecular drivers and therapeutic targets. Methods: 146 patients from Japan (ages 45-81) who were diagnosed with PC underwent exome-based, tumor molecular profiling (TMP) (Labcorp Genetics Inc). 96/146 (65.8%) patients had unresectable tumors. Results were correlated with clinical information. Variants were interpreted according to the AMP/ASCO/CAP guidelines. Signaling pathway analysis was conducted using the Reactome database, with significance determined by binomial test with corrected p-values (FDR; Benjamini-Hochberg procedure). Fisher’s exact test was utilized for statistical assessment of clinical parameters. Results: TMP detected 404 Tier 1/2 somatic variants in 135 (92.5%) patients. Genes known to be frequently mutated in PC were identified in the cohort: KRAS (122/146; 83.6%), TP53 (108/146; 74.0%), SMAD4 (35/146; 24.0%) and CDKN2A (25/146; 17.1%). A potential enrichment of hotspot U2AF1 (5/146; 3.4%) codon 34 mutations was identified, compared to published frequencies in PC in cancer databases (1%) that trended toward statistical significance (p=0.07). Pathway analysis identified a statistically significant enrichment of mutations in several kinase signaling pathways including PI3K/AKT (p-value: 2.1e-11; FDR: 9.8e-09), ERBB2 (p-value: 5.3e-07; FDR: 1.2e-04), and RAS/MAPK (p-value: 4.2e-06; FDR: 5.5e-04). Mutations associated with homologous recombination or mismatch repair pathways were statistically associated with early age of onset (&amp;lt;50 years of age; p= 0.036). Hotspot KRAS mutations were associated with unresectability (p=0.002), late tumor stage (stages 3-4, p=0.026), and metastasis (p=0.010). Conclusion: Alterations enriched in targetable pathways were identified in the patient cohort in addition to statistically significant findings associated with more aggressive PC. TMP testing can aid in the identification of alterations that are pertinent to the identification of relevant therapies and clinical trials as well as identify PC patients with potentially more aggressive disease. Citation Format: Jacquelyn Reuther, Taro Shibuki, Megan Hawley, Hideaki Bando, Keir Violaceae, Makoto Ueno, Kenji Ikezawa, Takuji Okusaka, Teiichi Sugiura, Keiko Kamei, Yoshito Komatsu, Michiaki Unno, Hiroki Yukami, Takuji Iwashita, Emily Westheimer, Kumiko Umemoto, Robert Daber, Takayuki Yoshino, Jianhua Zhao, Masafumi Ikeda. Mutational profiles of pancreatic cancer patients from Eastern Asia using somatic exome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7471.