Vanderbilt University Medical Center Nashville, TN
Award: Presidential Poster Award
Andreana N. Holowatyj, PhD, MSCI, Cathy Eng, MD, Wanqing Wen, MD, Kamran Idrees, MD, MS, Xingyi Guo, PhD; Vanderbilt University Medical Center, Nashville, TN
Introduction: The incidence of appendiceal cancer (AC) is rising with etiologies unknown, particularly among individuals age younger than 50 years (early-onset AC). In addition, early-onset AC harbors distinct clinicopathologic features compared to cases age 50 years and older at diagnosis (late-onset AC). We sought to characterize genomic patterns among patients with early-onset versus late-onset AC. Methods: Using the international clinicogenomic data-sharing consortium—AACR Project GENIE, a total of 385 AC cases with targeted clinical-grade sequencing data were identified. Mutation comparisons between early-onset and late-onset AC were evaluated using multivariable logistic regression models adjusted for sex, race/ethnicity, histological subtype, sequencing center, metastasis status and sample type. Results: A total of 39 genes in ACs had a mutation frequency of >2% among all patients. GNAS and PIK3CA had distinct mutation frequencies between early-onset (n=109) and late-onset (n=276) ACs. Eighteen percent of young patients had ACs with GNAS mutations, whereas nearly one-third of late-onset cases (29%) had mutations in GNAS. In contrast, one in every eight early-onset ACs had PIK3CA mutations, versus 4% of late-onset tumors. Compared to late-onset cases, young AC patients were more likely to present with non-silent mutations in PIK3CA, SMAD3 and TSC2 (PIK3CA: odds ratio [OR] 4.69, 95% confidence interval [CI] 1.72-12.82; SMAD3: OR 7.07, 95%CI 1.19-42.11; TSC2: OR 13.27, 95%CI 1.09-161.60). In contrast, young AC patients were 63% less likely to present with GNAS non-silent mutations compared with late-onset cases (OR 0.37, 95%CI 0.19-0.73). By histological subtype, young patients with mucinous adenocarcinomas of the appendix were 7-fold more likely to present with SMAD3 mutations (OR 7.33, 95%CI 1.22-43.82) and 68% less likely to have GNAS mutations (OR 0.32, 95%CI 0.13-0.75) versus late-onset cases in adjusted models. Similarly, patients with early-onset non-mucinous appendiceal adenocarcinomas were 83% less likely to present with GNAS mutations versus late-onset cases (OR 0.17, 95%CI 0.03-0.93). Discussion: This international study is the first to examine molecular features of AC by age of disease-onset, and the first to report SMAD3 and TSC2 mutations in AC cases. AC among young individuals harbors a distinct genomic landscape compared with late-onset AC cases. Development of therapeutic modalities that target these unique molecular features may yield clinical implications for young AC patients.
Disclosures: Andreana Holowatyj indicated no relevant financial relationships. Cathy Eng indicated no relevant financial relationships. Wanqing Wen indicated no relevant financial relationships. Kamran Idrees indicated no relevant financial relationships. Xingyi Guo indicated no relevant financial relationships.