Pathological and molecular features of sporadic rectal cancer in young adults

Background Incidence of early-onset sporadic rectal cancer is rising globally but the reasons are still unclear. Cancer among young adults has different features from late-onset cancer, such as an advanced stage at diagnosis, mucinous differentiation, microsatellite stability and a lower degree of lymphocytic infiltrate. Moreover, this subtype of tumor does not exhibit mutations in the oncogenes typically involved in pathogenesis of rectal cancer, as BRAF, KRAS and NRAS. Therefore, the aim of this study was to analyse biological features of sporadic EORC focusing also on the tumoral microenvironment and immune response. Methods The pathological and molecular records of a series of consecutive rectal cancer patients operated on from 2015 to 2021 were retrieved for this retrospective study. We defined young adults as patients aged 50 years or younger. Histology for the infiltration of intratumoral lymphomononuclear cells, immunohistochemistry for MLH1, PMS2, MSH2, and MSH6, and mutational analysis of BRAF, KRAS, and NRAS were all performed. Sporadic early-onset rectal cancer and late-onset rectal cancer were compared also considering results from TCGA. Moreover, results from Nonparametric tests were used for small sample size comparison. Results 94 patients operated on for rectal cancer at the General Surgery 3 Unit of the Azienda Ospedaliera di Padova from 2015 to 2021 were enrolled in the study. We identified 15 patients with sporadic early-onset rectal cancer, and 79 with late-onset cancer, after ruling out patients with hereditary syndromes, IBD, distant metastasis and undergoing neoadjuvant radiotherapy. Microsatellite instability frequency was similar in early-onset and in late-onset rectal cancer (P = 0.19) even if young patients tended to have mutations in MSH1 and PMS2 (P=0.03). Likewise, the mutation frequency of BRAF and KRAS and NRAS was similar in the two groups (P = 0.40, P =0.70 and P=0.72, respectively). Moreover, in our study the lymphocytic infiltration was similar in the two cohorts (P=0.19). On the contrary, TGCA showed more frequent mutations of SACS and MAP3K21 in the young cohort (P=0.0119 and P=0.0170) and also lower mRNA expression for CD3, CD69 and CD8 beta. Conclusion Our study showed no significative differences in oncogenes mutations and microsatellite instability frequency in early-onset and late-onset sporadic rectal cancer. Our data and results from TCGA suggested that in the young cohort an altered immune infiltrate may play a significative role, as predisposing factor or participating in tumoral progression due an improved capacity by tumoral cells escape the immunosurveillance. A deeper investigation of dysregulation in the immune response and tumoral microenvironment is required to analyse pathogenesis of early-onset rectal cancer.