In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 5_suppl ( 2018-02-10), p. 22-22
Abstract:
22 Background: Tumor genomic instability is positively correlated with immunotherapy response. It confers different tumor phenotypes, including high TMB (TMB-H) and high MSI (MSI-H). Recently the US Food and Drug Administration approved MSI-H phenotype as a biomarker for immunotherapy, highlighting its importance, but also bringing up the question of how TMB as another promising biomarker is going to add value in the field. Here, we characterized TMB and MSI profiles to better understand the potential TMB contribution and identify genomic markers for it. Methods: 734 solid tumor were collected, with 462 CRC, and 272 GA samples. Large panel Next-Generation Sequencing assay with the ability to determine TMB and MSI, was performed on each sample. Based on the TMB and MSI status, patients were grouped into four categories: THMH (TMB-H and MSI-H), THMS (TMB-H and MSI-Stable), TLMH (TMB-Low and MSI-H), and TLMS (TMB-Low and MSI-Stable). To identify genes that are related to the interplay of TMB and MSI, Random Forest and Lasso Regression models were applied to identify genes most predictive of the four categories. Results: TMB and MSI are highly correlated in our cohort of CRC and GA tumors. However, 5.8% CRC and 12.9% GA samples are under THMS (Table 1). In these samples, alternate DNA repair pathways are potentially dysregulated, including the nucleotide excision pathway (ATRX, APC), DNA double strand break repair (FANCF, SETD2), and the previously described proofreading pathway (POLD1). We hypothesize that these patients may also derive clinical benefit from immunotherapy. Conclusions: Immunotherapy benefits could be extended to more patients by jointly measuring MSI and TMB. The corresponding marker genes could also be extended beyond the commonly known POLE/POLD1 genes. Orthogonal validation by Whole Exome Sequencing data of the in silico mined marker genes is currently underway. [Table: see text]
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2018.36.5_suppl.22
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2018
detail.hit.zdb_id:
2005181-5
