Patterns of germline and somatic mutations in 16 genes associated with mismatch repair function or containing tandem repeat sequences

Autor: Wen Yi Liang, Shung Haur Yang, Pei Ching Lin, Chien Hsing Lin, Wei Shone Chen, Yuan Tzu Lan, Jeng Kai Jiang, Shih Ching Chang, Jen Kou Lin
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Cancer Research
congenital
hereditary
and neonatal diseases and abnormalities
Somatic hypermutation
colorectal cancer
Biology
MLH1
medicine.disease_cause
lcsh:RC254-282
DNA Mismatch Repair
Germline
EMAST
03 medical and health sciences
0302 clinical medicine
Germline mutation
Mutation Rate
medicine
Biomarkers
Tumor
Humans
Radiology
Nuclear Medicine and imaging
Prospective Studies
MSI
Aged
Original Research
Mutation
POLD1
Microsatellite instability
Clinical Cancer Research
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Prognosis
MMR
digestive system diseases
MSH6
030104 developmental biology
DNA Repair Enzymes
Oncology
Tandem Repeat Sequences
030220 oncology & carcinogenesis
Cancer research
Female
Colorectal Neoplasms
Follow-Up Studies
Zdroj: Cancer Medicine
Cancer Medicine, Vol 9, Iss 2, Pp 476-486 (2020)
ISSN: 2045-7634
Popis: Background We assumed that targeted next‐generation sequencing (NGS) of mismatch repair‐associated genes could improve the detection of driving mutations in colorectal cancers (CRC) with microsatellite instability (MSI) and microsatellite alterations at selected tetranucleotide repeats (EMAST) and clarify the somatic mutation patterns of CRC subtypes. Material and methods DNAs from tumors and white blood cells were obtained from 81 patients with EMAST(+)/MSI‐high (MSI‐H), 78 patients with EMAST(+)/microsatellite stable (MSS), and 72 patients with EMAST(−)/MSI‐H. The germline and somatic mutations were analyzed with a 16‐genes NGS panel. Results In total, 284 germline mutations were identified in 161 patients. The most common mutations were in EPCAM (24.8%), MSH6 (24.2%), MLH1 (21.7%), and AXIN2 (21.7%). Germline mutations of AXIN2, POLE, POLD1, and TGFBR2 also resulted in EMAST and MSI. EMAST(+)/MSI‐H tumors had a significant higher mutation number (205.9 ± 95.2 mut/MB) than tumors that were only EMAST(+) or MSI‐H (118.6 ± 64.2 and 106.2 ± 54.5 mut/MB, respectively; both P
For patients with microsatellite instability or microsatellite alterations at selected tetranucleotide repeats, the somatic mutation burden occurs due to the dysfunction of downstream effectors but not the affected gene with germline mutation. The dysfunction of AXIN2 might affect both the canonical APC pathway and the hypermutation mechanism.
Databáze: OpenAIRE
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