Somatic mutation profiling in gastric cancer (GC) enables main driver mutations to be identified and their clinical and prognostic value to be evaluated. We investigated 77 tumour samples of GC by next-generation sequencing (NGS) with the Ion AmpliSeq Hotspot Panel v2 and a custom panel covering six hereditary gastric cancer predisposition genes (BMPR1A, SMAD4, CDH1, TP53, STK11 and PTEN). Overall, 47 somatic mutations in 14 genes were detected; 22 of these mutations were novel. Mutations were detected most frequently in the CDH1 (13/47) and TP53 (12/47) genes. As expected, somatic CDH1 mutations were positively correlated with distant metastases (p = 0.019) and tumours with signet ring cells (p = 0.043). These findings confirm the association of the CDH1 mutations with diffuse GC type. TP53 mutations were found to be significantly associated with a decrease in overall survival in patients with Lauren diffuse-type tumours (p = 0.0085), T3-T4 tumours (p = 0.037), and stage III-IV tumours (p = 0.013). Our results confirm that the detection of mutations in the main driver genes may have a significant prognostic value for GC patients and provide an independent GC-related set of clinical and molecular genetic data.Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide after lung cancer and breast cancer. The incidence of GC is particularly high in East Asia, including China, Japan and Korea, and in South America 1 . Based on the Lauren classification, GC is divided into two main types, namely, intestinal and diffuse, which have different epidemiological, morphological and clinical features. Intestinal GC commonly appears in elderly patients with multifocal atrophic gastritis, which is accompanied by intestinal metaplasia or dysplasia. Diffuse GC is more common in younger patients, and its association with atrophic gastritis or intestinal metaplasia is not obvious. Clinical differences between these two types reflect different mechanisms of the development and molecular pathogenesis of tumours 2 . However, Lauren's classification is not closely associated with treatment and prognosis, necessitating the development of a classification combining clinical, morphological, and molecular features of GC in response to certain therapeutic modalities.Comprehensive studies, including analyses of the genome, epigenome, proteome and transcriptome, offered an entirely different view on the tumour, moving it out of a single plane and into a multidimensional spatial image. The ability to determine the tumour-specific spectrum of genetic and epigenetic changes enables us to expand our understanding of the molecular pathogenesis of the tumour and to obtain information about the potential of targeted therapies. Mutational profiling is one way to classify tumours depending on the mutation spectrum into specific molecular subtypes that differ from the standard morphological classification. The results of recent studies, such as TCGA Validation of mutations detected by next-generation sequencing. Validation of th...
To provide a breast cancer (BC) methylotype classification by genome-wide CpG islands bisulfite DNA sequencing. Materials & methods: XmaI-reduced representation bisulfite sequencing DNA methylation sequencing method was used to profile DNA methylation of 110 BC samples and 6 normal breast samples. Intrinsic DNA methylation BC subtypes were elicited by unsupervised hierarchical cluster analysis, and cluster-specific differentially methylated genes were identified. Results & conclusion: Overall, six distinct BC methylotypes were identified. BC cell lines constitute a separate group extremely highly methylated at the CpG islands. In turn, primary BC samples segregate into two major subtypes, highly and moderately methylated. Highly and moderately methylated superclusters, each incorporate three distinct epigenomic BC clusters with specific features, suggesting novel perspectives for personalized therapy.
We have developed an XmaI-RRBS method for rapid and affordable genome-wide DNA methylation analysis, with library preparation taking only 4 days and sequencing possible within 4 h. We have also addressed several challenges in order to further improve the RRBS technology. XmaI-RRBS may be performed on degraded DNA samples and is compatible with the bench-top next-generation sequencing machines.
Extracellular glycoproteins of the laminin family are essential components of basement mem branes involved in a number of biological processes, including tissue differentiation, wound healing, and tum origenesis. We present the first comprehensive study of promoter methylation status of the genes encoding laminin chains in normal tissues (peripheral blood leucocytes, buccal epithelial cells, autopsy breast tissue samples) and in breast carcinoma samples. Based on the results of this study, we divide laminin genes into three categories. Genes, constitutively methylated in breast tissues include LAMA3A, LAMB2, LAMB3, and LAMC2. Genes prone to abnormal methylation in breast carcinoma include LAMA1, LAMA2, LAMA3B, LAMA4, LAMB1, and LAMC3. Genes that are rarely if ever methylated in breast carcinoma include LAMA5 and LAMC1. The constitutively methylated group includes all of the genes that encode subunits of laminin 5 (the historical name of laminin 332), the promoters of which were previously considered unmethylated in normal tissues and prone to abnormal methylation in breast cancer.
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