Genetic and epigenetic analysis of the beta-2-microglobulin gene in microsatellite instable colorectal cancer

Autor: Marian Grendar, Rachele Ciccocioppo, Zora Lasabova, Peter Kruzliak, Peter Mikolajčík, Zuzana Snahnicanova, Luis Rodrigo, Michal Kalman, Laca L, Lukáš Plank, Ivana Kasubova, Eva Gabonova, Martin Caprnda
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Compound heterozygosity
medicine.disease_cause
Epigenesis
Genetic
Beta-2-microglobulin
0302 clinical medicine
80 and over
Promoter Regions
Genetic
Aged
80 and over
General Medicine
Methylation
Middle Aged
Gene Expression Regulation
Neoplastic
CpG site
030220 oncology & carcinogenesis
Female
Microsatellite Instability
KRAS
Colorectal Neoplasms
Adult
Down-Regulation
Human leukocyte antigen
Biology
General Biochemistry
Genetics and Molecular Biology
Promoter Regions
03 medical and health sciences
Genetic
medicine
Humans
Epigenetics
neoplasms
Gene
Aged
Neoplasm Staging
Neoplastic
Microsatellite instability
DNA Methylation
Promoter methylation
medicine.disease
Colorectal cancer
Cancer immunogenicity
digestive system diseases
030104 developmental biology
Gene Expression Regulation
Mutation
Cancer research
CpG Islands
beta 2-Microglobulin
Epigenesis
Zdroj: Clinical and experimental medicine. 20(1)
ISSN: 1591-9528
Popis: One of the most common mechanisms of immune evasion in MSI colorectal cancers (CRCs) is loss of HLA class I expression due to mutations in B2M gene which can become a negative predictor for checkpoint blockade therapy. The aim of this study was the determination of prevalence of B2M somatic mutations in MSI CRC patients and relationship between B2M mutations and lymphocytes infiltration and other clinicopathological features as well as detection of methylation changes in B2M promoter region which can be another mechanism of immune escape. In our study, 37 MSI-H and 5 MSI-L patients were selected for screening of B2M mutational and methylation status. The characterization of patients was based on standard histopathological diagnosis and TNM classification; BRAF, KRAS mutations, tumor-infiltrating lymphocytes and peritumoral lymphoid reaction were also determined. MSI analysis was performed using fragment analysis. B2M mutations were identified by Sanger sequencing, and methylation of CpG islands in promoter region was detected by methylation-specific PCR. Heterozygous mutations in the B2M gene were detected in five MSI-H patients (13.5%), while the mutation c.45_48delTTCT was determined in four patients and mutation c.276delC was found in two patients. One of these five patients was compound heterozygote harboring both mutations. Methylation of the promoter region of the B2M gene was observed in one patient with MSI-H colorectal cancer. Detection of genetic and epigenetic changes in B2M gene could be important in personalized therapy for CRC patients as these changes may be one of the mechanisms of secondary resistance of MSI positive tumors to immunotherapy.
Databáze: OpenAIRE
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