Clinical and epigenetic features of colorectal cancer patients with somatic POLE proofreading mutations
Autor: | Yoshiko Mori, Yoshiyuki Yamaguchi, Akihiro Nyuya, Kunitoshi Shigeyasu, Takehiro Tanaka, Takashi Kawai, Hiroaki Tanioka, Toshiaki Toshima, Fumitaka Taniguchi, Yuzo Umeda, Makoto Okawaki, Takeshi Nagasaka, Toshiyoshi Fujiwara, Ajay Goel, Kazuya Yasui |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Oncology
Adult Epigenomics Male medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Colorectal cancer MLH1 medicine.disease_cause Methylation Epigenesis Genetic Cohort Studies Internal medicine Genetics medicine Humans Epigenetics Stage (cooking) Poly-ADP-Ribose Binding Proteins Molecular Biology neoplasms Genetics (clinical) Aged business.industry Research Microsatellite instability nutritional and metabolic diseases DNA Polymerase II DNA Methylation Middle Aged medicine.disease Phenotype digestive system diseases POLE Mutation Female KRAS business Colorectal Neoplasms Developmental Biology |
Zdroj: | Clinical Epigenetics |
ISSN: | 1868-7083 1868-7075 |
Popis: | Background Mutations in the POLE gene result in an ultra-hypermutated phenotype in colorectal cancer (CRC); however, the molecular characterisation of epigenetic alterations remains unclear. We examined the genetic and epigenetic profiles of POLE-mutant CRC to elucidate the clinicopathological features of the associated genetic and epigenetic alterations. Results Tumour tissues (1,013) obtained from a cohort of patients with CRC were analysed to determine associations between the proofreading domain mutations of POLE with various clinicopathological variables, microsatellite instability (MSI) status, BRAF and KRAS mutations, and the methylation status of key regions of MLH1, MGMT, and SFRP2 promoters by calculating the methylation scores (range 0–6). Only four cases (0.4%) exhibited pathogenic POLE hotspot mutations (two p.P286R [c.857C > G], one p.V411L [c.1231G > C], and p.S459F [c.1376C > T] each), which were mutually exclusive to BRAF and KRAS mutations and MSI. CRC patients were divided into four subgroups: patients with POLE mutations (POLE, 0.4%, n = 4), patients with both MSI and extensive methylation in MLH1 (MSI-M, 2.9%, n = 29), patients with MSI but no extensive methylation in MLH1 (MSI-U, 3.6%, n = 36), and patients without MSI (non-MSI, 93.2%, n = 944). The POLE group was younger at diagnosis (median 52 years, P P P POLE-mutant tumours was small, the number of CD8-positive cells increased in tumours with partial methylation in the MLH1 gene. Conclusions CRC patients with POLE proofreading mutations are rare. Such mutations are observed in younger individuals, and tumours are primarily located in the right colon. Diagnosis occurs at an earlier stage, and distinct epigenetic alterations may be associated with CD8 cell infiltration. |
Databáze: | OpenAIRE |
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