Mutations in Epigenetic Regulation Genes in Gastric Cancer

Abstract

We have performed mutational profiling of 25 genes involved in epigenetic processes on 135 gastric cancer (GC) samples. In total, we identified 79 somatic mutations in 49/135 (36%) samples. The minority (n = 8) of mutations was identified in DNA methylation/demethylation genes, while the majority (n = 41), in histone modifier genes, among which mutations were most commonly found in KMT2D and KMT2C. Somatic mutations in KMT2D, KMT2C, ARID1A and CHD7 were mutually exclusive (p = 0.038). Mutations in ARID1A were associated with distant metastases (p = 0.03). The overall survival of patients in the group with metastases and in the group with tumors with signet ring cells was significantly reduced in the presence of mutations in epigenetic regulation genes (p = 0.036 and p = 0.041, respectively). Separately, somatic mutations in chromatin remodeling genes correlate with low survival rate of patients without distant metastasis (p = 0.045) and in the presence of signet ring cells (p = 0.0014). Our results suggest that mutations in epigenetic regulation genes may be valuable clinical markers and deserve further exploration in independent cohorts.

Comparison of the mutation patterns between tumor tissue and cell-free DNA in stage IV gastric cancer

“…The four most commonly mutated genes among the three metastatic patterns were TP53, KMT2C, KMT2D and ARID1A, which were also among the top high-frequency mutations for GC reported by the Catalogue of Somatic Mutations in Cancer (COSMIC) database [19]. All four genes mentioned above could be considered tumor suppressor genes [20][21][22][23]. TP53 mutation was associated with lymph node metastasis and distant metastasis in GC, especially in the Asian population [20], which was similar to our results.…”

“…TP53 mutation was associated with lymph node metastasis and distant metastasis in GC, especially in the Asian population [ 20 ], which was similar to our results. ARID1A mutation was reported to be associated with distant metastasis in GC [ 22 ], and ARID1A mutation could serve as a biomarker for immunotherapy in GI tract cancer [ 23 ]. KMT2D and KMT2C mutations in GC were associated with the DNA repair process, and these two genetic mutations were considered targets for cancer treatment using poly ADP-ribose polymerase (PARP) inhibitors [ 22 , 24 ].…”

“…ARID1A mutation was reported to be associated with distant metastasis in GC [ 22 ], and ARID1A mutation could serve as a biomarker for immunotherapy in GI tract cancer [ 23 ]. KMT2D and KMT2C mutations in GC were associated with the DNA repair process, and these two genetic mutations were considered targets for cancer treatment using poly ADP-ribose polymerase (PARP) inhibitors [ 22 , 24 ]. According to our results, some common genetic mutations were identified in different metastatic patterns, and drug therapy might be suitable for stage IV GC treatment, such as PARP inhibitors for mutations of the KMT2 family and immunotherapy for ARID1A mutations.…”

Acute myeloid leukemia associated with CHARGE syndrome

“…The high expression of CHD7 has been reported to contribute to the malignant transformation from glioma to glioblastoma (Machado et al, 2019). Gain‐of‐function CHD7 variants were also found in 13% of primary small cell lung carcinoma (SCLC), 9% of SCLC cell lines, and 6% of gastric carcinoma cells, suggesting the oncogenicity of gain‐of‐function variants of the CHD7 gene (Augert et al, 2017; Nemtsova et al, 2021). In contrast, frameshift pathogenic variants or loss of expression of the CHD7 gene are commonly observed in gastric and colorectal cancers with high microsatellite instability; thus, CHD7 alteration causing a loss of function might also contribute to the pathogenesis of cancer by deregulating CHD7‐mediated chromatin remodeling (Kim et al, 2011).…”

Targeting of the SWI/SNF chromatin remodeling complex in cancer therapy

“…Изменения ARID1A выявлены в различных типах опухолей: в 45 % случаев светлоклеточного рака яичников, в 37 % -рака эндометрия, в 20-30 % -рака желудка, в 20 % -рака мочевого пузыря, в 14 % -гепатоцеллюлярного рака, в 12 % -меланом, в 9 % -колоректального рака, в 8 % -рака легкого, в 4 % -рака поджелудочной железы и в 3 % -рака молочной железы [21]. Исследования соматических мутаций в опухолях желудка, проведенные с помощью высокопроизводительного параллельного секвенирования (next generation sequencing, NGS), показали, что до 47 % случаев аденокарцином желудка имеют мутации хроматинремоделирующих генов, причем соматические мутации ARID1A отличались наибольшей частотой [22]. Дефицит ARID1A в опухолях также часто коррелирует с наличием микросателлитной нестабильности.…”