Spectrum of Somatic Cancer Gene Variations Among Adults With Appendiceal Cancer by Age
Authors: Andreana N. Holowatyj, Cathy Eng, Wanqing Wen, Kamran Idrees, Xingyi Guo
Journal: JAMA Network Open (2020)

<h3>Importance</h3> The incidence of appendiceal cancer (AC) is rising, particularly among individuals younger than 50 years (early-onset AC), with unexplained etiologies. The unique spectrum of somatic cancer gene variations among patients with early-onset AC is largely undetermined. <h3>Objective</h3> To characterize the frequency of somatic variations and genomic patterns among patients with early-onset (age &lt;50 years) vs late-onset (age ≥50 years) AC. <h3>Design, Setting, and Participants</h3> This cohort study included individuals aged 18 years and older diagnosed with pathologically verified AC. Cases with clinical-grade targeted sequencing data from January 1, 2011, to December 31, 2019, were identified from the international clinicogenomic data-sharing consortium American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE). Data analysis was conducted from May to September 2020. <h3>Exposures</h3> Age at clinical sequencing. <h3>Main Outcomes and Measures</h3> Somatic variation prevalence and spectrum in AC patients was determined. Variation comparisons between early-onset and late-onset AC were evaluated using multivariable logistic regression with adjustment for sex, race/ethnicity, histological subtype, sequencing center, and sample type. <h3>Results</h3> In total 385 individuals (mean [SD] age at clinical sequencing, 56.0 [12.4] years; 187 [48.6%] men; 306 [79.5%] non-Hispanic White individuals) with AC were included in this study, and 109 patients (28.3%) were diagnosed with early-onset AC. Race/ethnicity differed by age at sequencing; non-Hispanic Black individuals accounted for a larger proportion of early-onset vs late-onset cases (9 of 109 [8.3%] vs 11 of 276 [4.0%];<i>P</i> = 0.04). Compared with patients aged 50 years or older at sequencing, patients with early-onset AC had significantly higher odds of presenting with nonsilent variations in<i>PIK3CA</i>,<i>SMAD3</i>, and<i>TSC2</i>(<i>PIK3CA</i>: odds ratio [OR], 4.58; 95% CI, 1.72-12.21;<i>P</i> = .002;<i>SMAD3</i>: OR, 7.37; 95% CI, 1.24-43.87;<i>P</i> = .03;<i>TSC2</i>: OR, 12.43; 95% CI, 1.03-149.59;<i>P</i> = .047). In contrast, patients with early-onset AC had a 60% decreased odds of presenting with<i>GNAS</i>nonsilent variations compared with patients with late-onset AC (OR, 0.40; 95% CI, 0.21-0.76,<i>P</i> = .006). By histological subtype, young patients with mucinous adenocarcinomas of the appendix had 65% decreased odds of variations in<i>GNAS</i>compared with late-onset cases in adjusted models (OR, 0.35; 95% CI, 0.15-0.79;<i>P</i> = .01). Similarly, patients with early-onset nonmucinous appendiceal adenocarcinomas had 72% decreased odds of presenting with<i>GNAS</i>variations vs late-onset cases, although these findings did not reach significance (OR, 0.28; 95% CI, 0.07-1.14;<i>P</i> = .08).<i>GNAS</i>and<i>TP53</i>variations were mutually exclusive in ACs among early-onset and late-onset cases (<i>P</i> &lt; .05). <h3>Conclusions and Relevance</h3> In the study, AC among younger individuals harbored a distinct genomic landscape compared with AC among older individuals. Development of therapeutic modalities that target these unique molecular features may yield clinical implications specifically for younger patients.