domingo, 29 de septiembre de 2019

An updated review of microsatellite instability in the era of next-generation sequencing and precision medicine. - PubMed - NCBI

2019 Sep 11. pii: S0093-7754(18)30185-4. doi: 10.1053/j.seminoncol.2019.08.003. [Epub ahead of print]

An updated review of microsatellite instability in the era of next-generation sequencing and precision medicine.

Author information

1: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan. Electronic address: h-yama@marianna-u.ac.jp.
2: The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract

Deficient DNA mismatch repair causes a robust mutator phenotype known as microsatellite instability (MSI). MSI is a feature of Lynch syndrome-related cancers and is also found in approximately 15% of sporadic gastric, colorectal, and endometrial cancers. Epigenetic inactivation of the MLH1 gene is often associated with sporadic MSI cancers. Recent next-generation sequencing (NGS)-based analyses have comprehensively characterized MSI-positive (MSI+) cancers, and several approaches for detecting the MSI phenotype of tumors using NGS have been developed. The FDA has recently granted accelerated approval to an anti-PD-1 antibody, pembrolizumab, for use in pediatric and adult patients with MSI+ solid tumors. Genome-wide analyses using NGS have revealed that hypermutation defined as >10 somatic mutations per megabase appears to be more prevalent than previously estimated, affecting approximately 17% of adult cancers. These results potentially expand the use of immunotherapy, which is thought to be effective in cancers with an increased mutational burden. Therefore, evaluation of MSI and MSI-associated molecular changes in tumors has emerged as clinically important. MSI is a valuable diagnostic marker of Lynch syndrome and a potential predictive marker for chemotherapy and immunotherapy efficacy. Here, we provide an update on MSI-associated cancers, focusing on findings obtained by genome-wide analyses using NGS, and the predictive role of MSI in immune checkpoint immunotherapy.