Comprehensive DNA Methylation and Mutation Analyses Reveal a Methylation Signature in Colorectal Sessile Serrated Adenomas

Patai, Árpád V.; Barták, Barbara Kinga; Péterfia, Bálint; Micsik, Tamás; Horváth, Réka; Sumánszki, Csaba; Péter, Zoltán; Valcz, Gábor; Kalmár, Alexandra; Tóth, Kinga; Krenács, Tibor; Tulassay, Zsolt; Molnár, Béla

doi:10.1007/s12253-016-0154-6

Cited by 12 publications

(10 citation statements)

References 30 publications

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“…In our study, we found a lower frequency of APC (41.8%) and CTNNB1 (3.3%) mutations, which can be because we did not analyze the whole coding sequence, but the major hotspot regions of both genes. In the serrated polyps pathway, the WNT signaling is reported to be less targeted 27,33 , following our ndings.…”

Section: Discussionsupporting

confidence: 76%

Somatic targeted mutation profiling of colorectal cancer precursor lesions

Santos¹,

Reis²,

Porto³

et al. 2021

Preprint

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Most colorectal cancers (CRC) arise from precursor lesions. We aimed to characterize the mutation profile of CRC precursor lesions in a Brazilian population. In total, 90 FFPE lesions, including 67 adenomas, 7 sessile serrated lesions, and 16 hyperplastic polyps, were analyzed by next-generation sequencing. The genetic ancestry of the patients was estimated. Somatic driver mutations were identified in 66.7% of cases, including alterations in APC (32.2%), TP53 (20.0%), KRAS (18.9%), BRAF (13.3%) and EGFR (7.8%). Adenomas displayed a higher number of mutations, mainly in APC, compared to serrated polyps (73.1% vs. 47.8%, p = 0.039). Advanced adenomas had a higher frequency of mutation in KRAS and GNAS and a high overall mutation rate than early adenomas (92.9% vs. 59%, p = 0.002). Concerning the serrated pathway, a higher frequency of mutations, mainly in BRAF, was observed in sessile serrated lesions (85.7%) compared to hyperplastic polyps (31.3%, p = 0.027). A high degree of ancestry admixture was observed in the population, with a predominance of European followed by African components. The mutation profile of Brazilian colorectal precursor lesions exhibits a similar landscape to other populations. These results bestow the knowledge of CRC's biological history and may contribute to a molecular screening approach.

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Section: Discussionsupporting

confidence: 76%

Somatic targeted mutation profiling of colorectal cancer precursor lesions

Santos¹,

Reis²,

Porto³

et al. 2021

Preprint

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“…Likely as a result of this observed hypermethylation in CRC, the SST mRNA level was decreased in CRC compared to normal tissue, as demonstrated with microarray data [93]. In a small pilot study with only 4 samples collected from patients with pre-neoplastic colorectal sessile serrated adenomas, SST hypermethylation was demonstrated in all examined patients [94]. These results indicate that, among others, the downregulation of SST may be involved in the development of CRC.…”

Section: Epigenetic Regulation Of Sst In Cancersupporting

confidence: 52%

Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer

Klomp

Dalm

Jong

et al. 2020

Rev Endocr Metab Disord

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Both somatostatin (SST) and somatostatin receptors (SSTRs) are proteins with important functions in both physiological tissue and in tumors, particularly in neuroendocrine tumors (NETs). NETs are frequently characterized by high SSTRs expression levels. SST analogues (SSAs) that bind and activate SSTR have anti-proliferative and anti-secretory activity, thereby reducing both the growth as well as the hormonal symptoms of NETs. Moreover, the high expression levels of SSTR type-2 (SSTR2) in NETs is a powerful target for therapy with radiolabeled SSAs. Due to the important role of both SST and SSTRs, it is of great importance to elucidate the mechanisms involved in regulating their expression in NETs, as well as in other types of tumors. The field of epigenetics recently gained interest in NET research, highlighting the importance of this process in regulating the expression of gene and protein expression. In this review we will discuss the role of the epigenetic machinery in controlling the expression of both SSTRs and the neuropeptide SST. Particular attention will be given to the epigenetic regulation of these proteins in NETs, whereas the involvement of the epigenetic machinery in other types of cancer will be discussed as well. In addition, we will discuss the possibility to target enzymes involved in the epigenetic machinery to modify the expression of the SST-system, thereby possibly improving therapeutic options.

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“…Since neurokinin A inhibits cell proliferation in normal cell (37), TAC1 is therefore considered a tumor-suppressor gene, and hypermethylation of the TAC1 CpG island promoter has been observed in various types of cancer, including lung (non-small cell type) cancer (14), colon cancer (15), head and neck cancer (16), uterus cancer (17) and pancreatic cancer (27,28). Patai et al (38) reported that TAC1 promoter is hypermethylated in the precancerous condition of colorectal sessile serrated adenomas. Subsequently, TAC1 gene methylation is likely to occur during the early stage of tumorigenesis in colorectal cancer (38).…”

Section: Discussionmentioning

confidence: 99%

“…Patai et al (38) reported that TAC1 promoter is hypermethylated in the precancerous condition of colorectal sessile serrated adenomas. Subsequently, TAC1 gene methylation is likely to occur during the early stage of tumorigenesis in colorectal cancer (38). In the present study, TAC1 promoter methylation was higher in pancreatic cancer tissues compared with that in adjacent non-cancerous tissues.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer

et al. 2020

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No difference in the gene methylation status of tumor-suppression genes between pancreatic cancer tissues and adjacent non-cancer tissues is observed. The present study investigated whether the promoter CpG islands of the cysteine dioxygenase 1 (CDO1), tachykinin precursor 1 (TAC1) and checkpoint with forkhead and ring finger domains (CHFR) genes were methylated in pancreatic cancer and adjacent non-cancerous pancreatic tissue in order to determine if they could be considered as markers for the detection of pancreatic cancer. A total of 38 Formalin-fixed and paraffin-embedded pancreatic adenocarcinoma tissues and their adjacent non-cancerous specimens from patients with pancreatic cancer, as well as 9 non-cancerous pancreatic samples from patients without pancreatic adenocarcinoma were obtained following surgical resection. The hypermethylation of CpG islands was detected using a methylation-specific quantitative PCR. The methylation values were calculated using the ∆Cq method and were expressed as 2-ΔCq. The 2-ΔCq value of the CDO1 promoter from pancreatic adenocarcinoma specimens was significantly higher compared with that of adjacent non-cancerous and tumor-free pancreatic tissues (P<0.0001 and P= 0.0008, respectively). The 2-ΔCq value of the TAC1 promoter of pancreatic adenocarcinoma was also significantly higher compared with that of adjacent non-cancerous tissues and tumor-free pancreatic samples (both P<0.0001). However, there was no significant difference in the 2-ΔCq value of the CHFR promoter among the pancreatic cancer, adjacent non-cancer tissue and tumor-free pancreatic samples. Furthermore, 12 out of the 38 pancreatic adenocarcinoma cases (31.6%) presented some methylation in the CHFR promoter. The results from Kaplan-Meier analysis between CHFR promoter methylation values and the clinicopathological characteristics of patients with pancreatic adenocarcinoma demonstrated that CHFR promoter methylation was significantly associated with lymph node metastasis. The methylation values of CDO1 and TAC1 promoters in cancer tissues were higher compared with adjacent tissues. However, whether hypermethylation of CDO1 and TAC1 promoters may serve as a biomarker in the diagnosis of pancreatic adenocarcinoma remains unclear.

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Comprehensive DNA Methylation and Mutation Analyses Reveal a Methylation Signature in Colorectal Sessile Serrated Adenomas

Cited by 12 publications

References 30 publications

Somatic targeted mutation profiling of colorectal cancer precursor lesions

Somatic targeted mutation profiling of colorectal cancer precursor lesions

Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer

Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer

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