Evidence for the role of aberrant DNA methylation in the pathogenesis of Lynch syndrome adenomas

Kaz, Andrew M.; Kim, Young Ho; Dzieciatkowski, Slavomir; Lynch, Henry T.; Watson, Patrice; Washington, Mary Kay; Li, Lin; Grady, William M.

doi:10.1002/ijc.22544

Cited by 33 publications

(29 citation statements)

References 46 publications

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“…However, the loss of p16/p14 alone was not sufficient for tumor development in this model. In the present study, we observed recurrent alterations of p16 INK4A in human (Kaz et al 2007).…”

Section: Discussionsupporting

confidence: 65%

Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas

Kiss¹,

Geli²,

Lundberg³

et al. 2008

Endocrine Related Cancer

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Pheochromocytomas and abdominal extra-adrenal paragangliomas are related to endocrine tumors of the sympathetic nervous system. Studies in animal models have shown that inactivation of the products of the cyclin dependent kinase inhibitor 2A (CDKN2A) gene locus, p16INK4A and p14 ARF , promotes the development of pheochromocytoma, especially in malignant form. The present study evaluated the involvement of CDKN2A in human pheochromocytomas and abdominal extra-adrenal paragangliomas from 55 patients. Promoter methylation was assessed using quantitative Pyrosequencing and methylation-specific PCR, and mRNA expression was measured by quantitative real-time PCR. For p16, western blot analysis and sequencing were also performed. succinate dehydrogenase complex subunit B (SDHB) sequencing analysis included extra-adrenal paragangliomas, all tumors classified as malignant, and cases diagnosed at 30 years or younger. The p16INK4A promoter was heavily methylated in a subset of paragangliomas, and this was significantly associated with malignancy (P!0.0043) and SDHB mutation (P!0.002). p16INK4A mRNA expression showed moderate suppression in malignant cases (P!0.05). In contrast, very little p14 ARF promoter methylation was seen and there was no significant difference in p14 ARF expression between tumors and normal samples. The p16 protein expression was reduced in 16 tumors, and sequence variations were observed in four tumors including the missense mutation A57V and the single nucleotide polymorphism (SNP) A148T. The results suggest that p16 INK4A, and not p14 ARF , is a subject of frequent involvement in these tumors. Importantly, hypermethylation of the p16 INK4A promoter was significantly associated with malignancy and metastasis, and SDHB gene mutations. This finding suggests an etiological link and could provide a clinical utility for diagnostic purposes.

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“…However, the loss of p16/p14 alone was not sufficient for tumor development in this model. In the present study, we observed recurrent alterations of p16 INK4A in human (Kaz et al 2007).…”

Section: Discussionsupporting

confidence: 65%

Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas

Kiss¹,

Geli²,

Lundberg³

et al. 2008

Endocrine Related Cancer

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“…MMR-D tumors, both familial and sporadic, compared to traditional carcinomas vary in tumor characteristics, clinical surveillance, have lesser likelihood for metastasis and show a superior disease-free survival [47,48,49,50]. It is important to identify patients with MMR-D tumors in everyday clinical practice to provide patients the best available treatment.…”

Section: Discussionmentioning

confidence: 99%

Tumor and Patient Characteristics of Individuals with Mismatch Repair Deficient Colorectal Cancer

et al. 2015

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Aims: To investigate tumor and patient characteristics of individuals with mismatch repair (MMR)-deficient colorectal carcinomas. Methods: We immunhistochemically investigated tissue samples of 307 consecutive patients with colorectal cancer for defects in DNA MMR proteins (hMLH1, hMSH2, hMSH6, hPMS2) and those with mutations further for microsatellite instability (MSI) and BRAF V600E mutations. Results: 32/308 (10.4%) tumors showed MMR deficiency. Seventy five percent (n = 24) had loss of hMLH1 and hPMS2 expression, 3% (n = 1) of hPMS2 alone, 18.8% (n = 6) of hMSH6 and hMSH2, 3% (n = 1) of hMSH2 alone. All MMR-deficient tumors showed high MSI. These tumors occurred preferably in the right-sided colon, in women and showed specific histological features. We obtained the family history of 18/32 patients; 2 (11.1%) met Amsterdam Criteria, 5 (27.8%) Bethesda Guidelines and 6 (33.3%) revised Bethesda Guidelines. BRAF V600E mutations were found in 16 (67%) of hMLH1 and none of the hMSH2 deficient tumors. Conclusion: We suggest using immunhistochemical testing of tumor tissues with subsequent MSI analysis, which may be justified as a screening method for MMR deficiency in colorectal cancer, since it identifies patients with possibly hereditary defects and unalike response to chemotherapy.

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“…34, No. 1, [255][256][257][258][259][260][261][262][263][264][265]2013 describing the relationship between the lowest versus all higher categories of the dependent variable are the same as those that describe the relationship between the next lowest category and all higher categories, and so on. The second is that converting the resulting calibration from LRs to probabilities assumes an underlying overall prior probability for the dataset.…”

Section: Discussionmentioning

confidence: 99%

“…Akin to BRAF V600E, mutation carriers demonstrating MLH1 methylation have been identified rarely. In these carriers, MLH1 promoter methylation is likely the "second hit" 128,264 . Further, there is increasing evidence for a role of constitutional epimutations in LS 129,139,265 .…”

Section: Mlh1 Promoter Methylation and Braf V600ementioning

confidence: 99%

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Interpreting the clinical significance of mismatch repair gene sequence variants

Thompson¹

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The clinical classification of inherited nucleotide sequence variants identified in disease-related genes has a direct impact on the clinical management of patients and their families. Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2). However, ~30% of MMR gene variants identified in suspected Lynch cases are of uncertain clinical significance, which constitutes a challenge for genetic counselling and clinical management of families. In the past there has been no uniform system to tackle these variants, and mainly ad hoc methods have been utilized to determine if they are disease causing. The multifactorial likelihood model approach was initially developed for the evaluation of sequence variants in the BRCA1/2 cancer predisposition genes. It was adapted for MMR gene variants to provide a quantitative measure of risk in the form of probability of pathogenicity. Estimates of prior probability of pathogenicity based on evolutionary sequence conservation and physicochemical characteristics of predicted alterations were combined with variant segregation information and tumour features. Microsatellite instability (MSI) and somatic BRAF V600E tumour data for unselected colorectal cancer probands of known pathogenic variant status were used to derive likelihood ratios (LR) for tumour characteristics using the Colon Cancer Family Registry resource.The LR in favour of pathogenicity was estimated to be ~12-fold for a MSI and BRAF V600E mutation-negative colorectal tumour. Our findings provide a working multifactorial likelihood model for classifications that carefully considers mode of ascertainment for gene testing.

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Evidence for the role of aberrant DNA methylation in the pathogenesis of Lynch syndrome adenomas

Cited by 33 publications

References 46 publications

Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas

Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas

Tumor and Patient Characteristics of Individuals with Mismatch Repair Deficient Colorectal Cancer

Interpreting the clinical significance of mismatch repair gene sequence variants

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