MicroRNA‐31 expression in relation to <i>BRAF</i> mutation, CpG island methylation and colorectal continuum in serrated lesions

Ito, Miki; Mitsuhashi, Kei; Igarashi, Harukazu; Nosho, Katsuhiko; Naito, Takafumi; Yoshii, Shinji; Takahashi, Hiroaki; Fujita, Masahiro; Sukawa, Yasutaka; Yamamoto, Eiko; Takahashi, Taiga; Adachi, Yasushi; Nojima, Masanori; Sasaki, Yasushi; Tokino, Takashi; Baba, Yoshifumi; Maruyama, Reo; Suzuki, Hiromu; Imai, Kohzoh; Yamamoto, Hiroyuki; Shinomura, Yasuhisa

doi:10.1002/ijc.28920

Cited by 46 publications

(65 citation statements)

References 52 publications

(162 reference statements)

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“…That is, although it was not the emphasis of our study, we note that our mismatch repair and BRAF findings also support the colorectal continuum model. 19,29 As our study was designed to address the WHO 2010 premise that mucinous colorectal cancers can be graded on the basis of mismatch repair/microsatellite instability status, we used the WHO 2010 criteria for the diagnosis of mucinous carcinoma which requires that 450% of the tumour demonstrate mucinous differentiation. 1 However, we accept that tumours with o 50% mucinous differentiation may still demonstrate some or all of the characteristics of mucinous colorectal cancers and that further studies will be required to determine whether tumour with o 50% mucinous differentiation can be graded on the basis of microsatellite instability/ mismatch repair status.…”

Section: Discussionmentioning

confidence: 99%

Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer

et al. 2016

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There is some uncertainty about pathological grading of mucinous colorectal adenocarcinoma, defined as colorectal cancer demonstrating at least 50% mucinous differentiation. Under the WHO 2000 classification mucinous colorectal cancer was considered high grade. However under the current WHO 2010 classification microsatellite unstable/mismatch repair-deficient (MSI/MMRd) mucinous colorectal cancer is considered low grade, whereas microsatellite stable/mismatch repair proficient (MSS/MMRp) tumours are high grade. However there is little empirical evidence for this approach. We therefore compared the long term survival of patients with MSI/MMRd vs MSS/MMRp mucinous colorectal cancer in a large unselected cohort of patients undergoing surgery at our institution from 1998 to 2011. There were 2608 patients in the cohort, of which 264 (10.1%) were mucinous. 95 (36%) of the mucinous tumours were microsatellite unstable. The all-cause 5-year survival of mucinous MSI/MMRd colorectal cancer was similar to that of non-mucinous low-grade colorectal cancer (73 vs 67%, P = 0.368), and significantly better than that of both non-mucinous high-grade (73 vs 53%, Po 0.001) and mucinous MSS/MMRp colorectal cancer (73 vs 57%, P = 0.023). The 5-year survival of mucinous MSS/MMRp colorectal cancer was slightly better than that of non-mucinous high-grade patients (57 vs 53%, P = 0.027), but significantly worse than that of non-mucinous low-grade colorectal cancer (57 vs 67%, P = 0.018). In multivariate Cox regression analysis, conventional histological grade based on glandular differentiation maintained prognostic significance (P = 0.003) whereas MSI/MMRd status just failed to be statistically significant (P = 0.062). Our findings support the WHO 2010 approach that as a group mucinous MSS/MMRp colorectal cancers are biologically aggressive. However, grading based exclusively on MSI/MMR status may be overly simplistic as conventional grading based on the degree of glandular differentiation still holds greater prognostic significance in multivariate analysis.

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Section: Discussionmentioning

confidence: 99%

Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer

et al. 2016

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“…Bisulfite modification of genomic DNA was conducted using the BisulFlash™ DNA Modification Kit (Epigentek, Brooklyn, N.Y., USA) [17]. DNA methylation was quantified for four CIMP-specific promoters [CACNA1G, CDKN2A (p16) , IGF2 and RUNX3] and IGFBP7 , MGMT , MLH1 and RASSF2 using Real-Time PCR (MethyLight) [17,30,31].…”

Section: Methodsmentioning

confidence: 99%

“…In particular, there are many clinical and molecular similarities between SSA and CIMP-high CRC; for example, their proximal tumor location, BRAF mutation status and comparable MLH1 methylation [10,12,16,17,18,25,26]. Therefore, SSAs have been hypothesized to be precursor lesions that develop into CIMP-high CRCs with BRAF mutations in the proximal colon [1,10,12,16,17,18,25,26]. …”

Section: Introductionmentioning

confidence: 99%

“…The CpG island methylator phenotype (CIMP) is a distinct form of epigenomic instability [2,17,20,21,22,23], which causes most sporadic microsatellite instability (MSI)-high CRCs by epigenetically inactivating MLH1 [24]. Independent of MSI, CIMP-high CRCs are associated with proximal tumor location, older age of onset, female gender and BRAF mutation [7,22,23].…”

Section: Introductionmentioning

confidence: 99%

“…The serrated neoplasia pathway has attracted considerable attention as an alternative pathway for CRC development, and serrated lesions exhibit unique clinical, pathological or molecular features [1,8,9,10,11,12,13,14,15,16,17,18,19]. Sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs) are premalignant lesions, although an SSA is the principal serrated precursor of CRC [18].…”

Section: Introductionmentioning

confidence: 99%

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Clinicopathological and Molecular Characteristics of Serrated Lesions in Japanese Elderly Patients

et al. 2015

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Background: The population in Japan is aging more rapidly than in any other country. However, no studies have determined the characteristics of the large population of elderly patients with colorectal tumors. Therefore, we examined the clinicopathological and molecular features of these tumors in elderly patients. Methods: In total, 1,627 colorectal tumors (393 serrated lesions, 277 non-serrated adenomas and 957 colorectal cancers) were acquired from patients. Tumor specimens were analyzed for BRAF and KRAS mutations, CpG island methylator phenotype-specific promoters (CACNA1G, CDKN2A, IGF2 and RUNX3), IGFBP7, MGMT, MLH1 and RASSF2 methylation, microsatellite instability (MSI) and microRNA- 31 (miR-31). Results: The frequency of elderly patients (aged ≥75 years) with sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that of those with other serrated lesions and non-serrated adenomas (p < 0.0001). In elderly patients, all SSAs were located in the proximal colon (particularly the cecum to ascending colon). High miR-31 expression, MLH1 methylation and MSI-high status were more frequently detected in SSAs from elderly patients than in those from non-elderly patients. In contrast, no significant differences were found between older age of onset and high-grade dysplasia for traditional serrated adenomas or non-serrated adenomas in any of these molecular alterations. Conclusion: In elderly patients, all SSAs were located in the proximal colon. Furthermore, cytological dysplasia and molecular alterations were more frequently detected in elderly patients with SSAs than in non-elderly patients. Thus, careful colonoscopic examinations of the proximal colon are necessary for elderly patients because SSAs in those patients may exhibit malignant potential.

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Inflammatory response in serrated precursor lesions of the colon classified according to WHO entities, clinical parameters and phenotype–genotype correlation

Rau

Atreya

Aust

et al. 2016

The Journal of Pathology CR

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Studies on traditional serrated adenoma (TSA) and sessile serrated adenoma with dysplasia (SSA‐D) are rare due to the low frequency of these lesions, which are well defined by the latest WHO classification. However, introducing new morphological criteria such as intra‐epithelial lymphocytes (IELs) might facilitate colorectal polyp diagnoses. Additionally, the phenotype–genotype correlation needs to be updated as the terminology has repeatedly changed. This study analysed 516 polyps, consisting of 118 classical adenomas (CAD), 116 hyperplastic polyps (HPP), 179 SSAs, 41 SSA‐Ds, and 62 TSAs. The lesions were analysed in relation to the patients’ clinical parameters including gender, age, localisation, and size. The inflammatory background of the polyps was quantified and BRAF and KRAS mutations as well as MLH1 and CDKN2A promoter methylation were assessed. In multivariate analyses, an increase in IELs was an independent and robust new criterion for the diagnosis of SSA‐D (p < 0.001). Superficial erosions and acute neutrophil granulocytes led to reactive changes potentially resembling dysplasia. KRAS and BRAF mutations were associated with CAD/TSA and HPP/SSA, respectively. However, almost half of TSAs had a BRAF mutation and were KRAS wild type. CDKN2A seems to precede MLH1 hyper‐methylation within the serrated carcinogenesis model. The genotyping of WHO‐based entities – and especially SSA – has sharpened in comparison to previously published data. TSAs can be sub‐grouped according to their mutation status. Of note, the higher number of IELs in SSA‐D reflects their close relationship to colorectal cancers with micro‐satellite instability. Therefore, IELs might represent a new diagnostic tool for SSA‐D.

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MicroRNA‐31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions

Cited by 46 publications

References 52 publications

Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer

Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer

Clinicopathological and Molecular Characteristics of Serrated Lesions in Japanese Elderly Patients

Inflammatory response in serrated precursor lesions of the colon classified according to WHO entities, clinical parameters and phenotype–genotype correlation

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