1183MO - Molecular characterization of rectal neuroendocrine tumors (NETs) with unfavorable prognosis by multiomics analysis: A multicenter retrospective cohort study (GARNET)

Background

Most rectal neuroendocrine tumors (NETs) are small indolent G1 tumors with good prognosis. However, a few develop distant metastasis, leading to unfavorable outcome, and its association with molecular features are unknown. This study aimed to identify genomic, transcriptomic, and epigenetic alterations that can contribute to more accurate prediction of prognosis of rectal NET.

Methods

This study was a multicenter, noninterventional cohort study, performing multiomics analysis including whole exome sequencing (WES), single nucleotide polymorphism (SNP) array-based profiling for copy number, gene expression and methylation. Patients were classified into 3 cohorts based on the prognoses (ie, cohort A [no recurrence, alive for ≥5 years from initial surgery], cohort B [alive for ≥3 years since recurrence and/or metastasis], cohort C [alive for <3 years from recurrence and/or metastasis to death]). The primary endpoint was to reveal unique molecular alterations in rectal NETs of cohorts B and C compared with cohort A.

Results

A total of 40 patients with rectal NETs were enrolled and 36 patients were analyzed (14 G1-NETs and 22 G2-NETs; 11 in cohort A, 19 in cohort B, and 6 in cohort C). WES revealed 17% (6 of 35) of recurrent somatic mutations in CDC27, which were only identified in cohorts B and C. Cancer genes were infrequently involved: only SF3B1 was mutated in two cases, with the rest of genes including TP53, SMAD4, and ATM mutated in one case. Copy number analysis revealed 56% (19 of 34) chromosomal gain of 19p13.3 and 29% (10 of 34) loss of 16p11.2, both of which cohorts B and C predominated over cohort A. Gene set enrichment analysis between cohorts A and B showed significant enrichments of oxidative phosphorylation and MYC target gene sets for up-regulated genes in cohort B. Unsupervised hierarchical clustering analysis of DNA methylation revealed 3 subgroups, of which cluster 1 mainly consisted of cohort A and cluster 2 of cohorts B and C.

Conclusions

Rectal NETs with unfavorable outcomes (cohorts B and C) had unique genomic and epigenetic alterations, which might be used as a prognostic marker for risk stratification of rectal NETs.

Clinical trial identification

Editorial acknowledgement

Medical writing support was provided by Yutaka Nakagawa (Novartis Malaysia Sdn Bhd).

Legal entity responsible for the study

Novartis Pharma K.K.

Funding

Novartis Pharma K.K.

Disclosure

N. Mizuno: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca, FUJIFILM Toyama Chemical, Novartis, Taiho Pharmaceutical, Yakult Honsha; Financial Interests, Institutional, Local PI: Incyte, MSD, Ono Pharmaceutical, Seagen; Financial Interests, Institutional, Coordinating PI: Novartis. N. Kobayashi: Financial Interests, Personal, Invited Speaker: PDRadiopharma Inc., Novartis Pharma K.K.. H. Hirano: Financial Interests, Personal, Writing Engagement: Nichi-Iko; Financial Interests, Personal, Invited Speaker: Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Teijin Phama; Non-Financial Interests, Institutional, Research Grant: Amgen, Astellas, BeiGene, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Insyte, Janssen Pharmaceutical, Merck Biopharma, MSD, Novartis, Ono Pharmaceutical, Pfizer, Seagen, Taiho Pharmaceutical. T. Tsuchikawa: Non-Financial Interests, Personal, Expert Testimony: Hokkaido University Hospital. S. Matsumoto: Financial Interests, Personal and Institutional, Full or part-time Employment: Kyoto University Hospital. H. Okuyama: Financial Interests, Personal, Advisory Board: Teijin healthcare, Novartis; Financial Interests, Personal, Invited Speaker: Incyte, Novartis, Taiho Pharmaceutical, Chugai pharmaceutical; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical, Chugai pharmaceutical; Financial Interests, Institutional, Local PI: Hutchison Medipharma. K. Shinjo: Financial Interests, Institutional, Funding: NanoCarrier, Eiken Chemical. R. Yamaguchi: Financial Interests, Personal, Advisory Board: Novartis Pharma K.K.; Financial Interests, Personal, Invited Speaker: Novartis Pharma K.K.. T. Kawata: Financial Interests, Personal, Full or part-time Employment: Novartis Pharma K.K.. W. Hosoda: Financial Interests, Personal, Expert Testimony: Novartis. All other authors have declared no conflicts of interest.