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Genetic Analysis of Gastrointestinal Neuroendocrine Tumors (GI-NET) Identified With Different Risks of Prognosis Multicenter Retrospective Cohort (GARNET)

Gene Alterations for rectum neuroendocrine tumors (GARNET)

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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.

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.

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.

Oct. 22, 2023

June. 30, 2024

No

https://jrct.mhlw.go.jp/latest-detail/jRCT1040210119

Mizuno Nobumasa

Aichi Cancer Center

1-1 Kanokoden Chikusa-ku Nagoya Aichi

nobumasa@aichi-cc.jp

Tadayuki Kawata

Novartis Pharma K.K.

1-23-1 Toranomon Minato-ku Tokyo

+81-80-3436-1621

tadayuki.kawata@novartis.com

Complete

Dec. 26, 2021

Observational

1.Provision of written informed consent prior to any study related procedures.
2.Diagnosed to be suffering from advanced rectal NET (World Health Organization Grade 1 or 2, up to 20% Ki-67).
3.Male or female, aged 18 or older.
4.An archival tissue sample (at the time of initial diagnosis before intervention) of the primary tumor by endoscopic biopsy must be available for molecular testing. If the sample volume is insufficient, surgical specimens or specimens from metastases must be available.
5.Cohort A
T2N1M0 or higher at the first diagnosis (Stage III).
Recurrence-free survival of 5 years or more from initial surgical treatment (at the time of enrollment).
No distant metastases (including regional lymph node metastases).
6.Cohort B
Distant metastases (excluding regional lymph node metastases).
Survival period of 3 years or more after distant metastasis diagnosis (at the time of data cutoff).
7.Cohort C
Distant metastases (excluding regional lymph node metastases).
Survival period of less than 3 years from distant metastasis diagnosis (at the time of data cutoff).
Patients who died due to reason current tumor.

1. Patients diagnosed with NEC and MiNEN.
2. Neuroendocrine tumors that do not originate in the rectum.
3. Patients with NET G3 (Ki-67 > 20).
4. Patients who received peptide receptor radionuclide therapy (PRRT).
5. Patients who died due to reasons other than current tumor reason (e.g. side effects of drugs, suicide).
6. Tissue sample that collected after drug intervention for NET.
7. Cohort A
Patients who have only undergone endoscopic resection (endoscopic sub-mucosal dissection (ESD), endoscopic mucosal resection (EMR) etc.)
Patients who have record of recurrence or death.

Both

neuroendocrine tumore

None

NET NEN GI-NET

the proportion of patients with each type of gene alteration in each cohort by using WES

1. The proportion of patients with each type of gene alteration in each cohort by using CNV analysis, DNA methylation analysis, and RNA expression analysis.
2. Clinical factors at the initial diagnosis in each cohort
3. Clinical factors by type of metastasis (synchronous vs. heterochronous) in Cohort B and Cohort C.
4. Association of different prognosis (Cohorts A, B and C) with the following characteristics
5. The proportion of gene alteration frequencies in Cohort B and Cohort C by type of recurrence (i.e., synchronous and heterochronous).
6. Association of patient survival time with gene alterations and factors

+81-52-762-6111

Nov. 11, 2021

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