Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas

Berkhout, Marloes; Nagtegaal, Irıs D.; Cornelissen, S.J.B.; Dekkers, Marieke; Molengraft, F. J. J. M. Van De; Peters, Wilbert H.M.; Nagengast, Fokko M.; Krieken, J. Han J.M. van; Jeuken, Judith

doi:10.1038/modpathol.3800952

Cited by 25 publications

(18 citation statements)

References 61 publications

(79 reference statements)

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“…The definition of clinically meaningful cutoff values is crucial. The arbitrary 20% cutoff value 33,34 has been validated in our series, whereas the 15% threshold 21 would have resulted in an increase of false-negative results. Also, we have confirmed that considering only C-and D-regions of MLH1 promoter, 36,40 yields the best performance in the diagnostic setting.…”

Section: Discussionmentioning

confidence: 79%

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MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

et al. 2012

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The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent.

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Section: Discussionmentioning

confidence: 79%

“…A similar value has been proposed as a meaningful cutoff value in previous studies. 33,34 Ten replicates in two independent experiments were analyzed.…”

Section: Detection Of Somatic Alterationsmentioning

confidence: 99%

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

et al. 2012

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“…All three enzymes, DNMT1, DNMT3a, and DMNT3b, have been shown to be overexpressed in several tumor types, including colorectal cancer (14,19). Interestingly, both sporadic and FAP-related colon adenocarcinomas have common, for example, p16 and MGMT, as well as different, for example, PAX3, tumor-suppressor genes that are methylated, and hypermethylation seems to be a general feature of both sporadic and FAP-related carcinomas (20,21). In this study, we determined whether BRBs administered in the form of a rectal suppository and/or in combination with oral administration cause suppression of polyp development in subjects with FAP, and whether BRBs affect DNA methylation in tissues collected from these patients.…”

Section: Introductionmentioning

confidence: 99%

A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis

Wang¹,

Burke

Hasson

et al. 2014

Cancer Prevention Research

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Familial adenomatous polyposis (FAP) is characterized by the early onset of colonic polyposis and a high risk for colorectal cancer. FAP is treated by colectomy followed by lifelong removal of rectal polyps. This study determined whether black raspberries (BRBs) might regress rectal polyps in patients with FAP. Fourteen patients with FAP were treated with BRBs daily for 9 months. Seven patients received BRB powder orally plus two BRB suppositories inserted into the rectum at bedtime. The other 7 received an oral placebo plus the suppositories. Rectal polyp counts and polyp sizes were obtained at time zero and after 9 months of BRB treatment. Polyps and adjacent normal tissue were collected at both time points. The burden (P ¼ 0.036) but not number (P ¼ 0.069) of rectal polyps was significantly decreased. No benefit was noted with the addition of oral BRBs. Three patients were nonresponders. BRBs significantly decreased cellular proliferation, DNA methylation methyl transferase 1 protein expression, and p16 promoter methylation, but not promoter methylation of the Wnt pathway antagonists, SFRP2 and WIF1, in rectal polyps (adenomas) from responders but not from nonresponders. The MBD-seq assay revealed more demethylated transcription start sites (TSS), including those for miRNAs, in BRB-treated adenomas from the responders. In conclusion, BRB suppositories seem sufficient for regressing rectal polyps in patients with FAP. Cancer Prev Res; 7(7); 666-74. Ó2014 AACR.

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“…Several studies have also documented mutations of SMAD4, APC, KRAS, and β-catenin (13,(16)(17)(18), as well as epigenetic silencing of APC and gains on chromosomes 7, 8, 12, 13q, and 20q, and losses on chromosomes 2, 4, 5q, 6q, 8, 9, 15q, 17p, 18, and 21 (19,20). Studies evaluating the chromosomal aberrations in patients with concomitant small bowel adenocarcinoma and Crohn's disease or familial adenomatous polyposis have shown that the chromosomal aberrations of sporadic small bowel adenocarcinoma do not differ from patients with these predisposing conditions (19,20).…”

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confidence: 99%

High-Resolution Array Comparative Genomic Hybridization in Sporadic and Celiac Disease–Related Small Bowel Adenocarcinomas

Diosdado

Buffart

Watkins

et al. 2010

Clinical Cancer Research

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Purpose: The molecular pathogenesis of small intestinal adenocarcinomas is not well understood. Understanding the molecular characteristics of small bowel adenocarcinoma may lead to more effective patient treatment.Experimental Design: Forty-eight small bowel adenocarcinomas (33 non-celiac disease related and 15 celiac disease related) were characterized for chromosomal aberrations by high-resolution array comparative hybridization, microsatellite instability, and APC promoter methylation and mutation status. Findings were compared with clinicopathologic and survival data. Furthermore, molecular alterations were compared between celiac disease-related and non-celiac disease-related small bowel adenocarcinomas.Results: DNA copy number changes were observed in 77% small bowel adenocarcinomas. The most frequent DNA copy number changes found were gains on 5p15. 33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2, and 20p13-20q13.33, and losses on 4p13-4q35.2, 5q15-5q21.1, and 21p11.2-21q22.11. Seven highly amplified regions were identified on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1, and 19q13.2. Celiac disease-related and non-celiac disease-related small bowel adenocarcinomas displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non-celiac disease-related and 73% celiac disease-related small bowel adenocarcinomas. No nonsense mutations were found. Thirty-three percent of non-celiac disease-related small bowel adenocarcinomas showed microsatellite instability, whereas 67% of celiac disease-related small bowel adenocarcinomas were microsatellite unstable.Conclusions: Our study characterized chromosomal aberrations and amplifications involved in small bowel adenocarcinoma. At the chromosomal level, celiac disease-related and non-celiac disease-related small bowel adenocarcinomas did not differ. A defect in the mismatch repair pathways seems to be more common in celiac disease-related than in non-celiac disease-related small bowel adenocarcinomas. In contrast to colon and gastric cancers, no APC nonsense mutations were found in small bowel adenocarcinoma. However, APC promoter methylation seems to be a common event in celiac disease-related small bowel adenocarcinoma. Clin Cancer Res; 16(5); 1391-401. ©2010 AACR.

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Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas

Cited by 25 publications

References 61 publications

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis

High-Resolution Array Comparative Genomic Hybridization in Sporadic and Celiac Disease–Related Small Bowel Adenocarcinomas

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