Prevalence of<i>MLH1</i>constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer

Castillejo, Adela; Hernández‐Illán, Eva; Rodríguez–Soler, María; Pérez–Carbonell, Lucía; Egoavil, Cecilia; Barberá, Víctor Manuel; Guarinós, Carla; Martínez-de-Dueñas, Eduardo; Juan, María José; Sánchez-Heras, Ana Beatriz; García-Casado, Zaida; Ruíz-Ponte, Clara; Brea‐Fernández, Alejandro; Juárez, Míriam; Bujanda, Luís; Clofent, Juan; Llor, Xavier; Andreu, Montserrat; Castells, Antoni; Carracedo, Ángel; Alenda, Cristina; Payá, Artemio; Jover, Rodrigo; Soto, José Luís

doi:10.1136/jmedgenet-2015-103076

Cited by 29 publications

(25 citation statements)

References 14 publications

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“…Epimutation was first reported in 2002 in a case of colorectal cancer by Gazzoli et al, based on methylation in a single allele of the MLH1 promoter in peripheral blood DNA [9]. Multiple cases of epimutation in MMR genes have subsequently been described [10,11,12,13,14,15,16,17,18,19]. Based on these cases, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) suggest additional tests for epimutation in some cases of colorectal cancers [26].…”

Section: Discussionmentioning

confidence: 99%

“…Mangold et al found germline mutations of MLH1 or MSH2 in 62% of patients who fulfilled the revised Bethesda guidelines and had MSI-H [28]. Colorectal cancer patients with suspected Lynch syndrome, who were selected for epimutation tests because of negative germline tests for MMR genes, had MSI and IHC loss of MLH1 due to epimutation at rates of 3%–10% [11,13,14,16,17,29,30,31,32,33]. The current study suggests that similar findings may occur in endometrial cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we are unable to infer the frequency of MLH1 epimutation among cases whose cancer exhibited MSI. In patients with colorectal cancer, Castillejo et al [17] found MLH1 constitutional epimutation in five of 847 patients who met the revised Bethesda guidelines (0.59%), but in zero of 2123 patients who did not meet the guidelines. For comparison, MLH1 germline mutation was detected in 18 of the cases that met the guidelines (2.13%).…”

Section: Discussionmentioning

confidence: 99%

“…For comparison, MLH1 germline mutation was detected in 18 of the cases that met the guidelines (2.13%). Among 106 patients who met the guidelines and showed a loss of MLH1 on IHC, five had MLH1 constitutional epimutation (4.7%) [17]. This result indicates that constitutional MLH1 epimutation may be found more frequently in a subgroup showing MSI-H or IHC loss of MMR, meeting the guidelines with endometrial cancer, or all three.…”

Section: Discussionmentioning

confidence: 99%

“…Errors in epigenetic gene repression, including methylation, are referred to as epimutation. Epimutation in MMR genes, especially in MLH1 and MSH2 , has been reported in colorectal cancers, and these cases show an early-onset Lynch syndrome-like phenotype [9,10,11,12,13,14,15,16,17,18,19]. MSH6 and PMS2 epimutation has never been reported.…”

Section: Introductionmentioning

confidence: 99%

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Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis

Takeda

Banno

Yanokura

et al. 2016

Genes

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Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%)—1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis

Takeda

Banno

Yanokura

et al. 2016

Genes

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Epigenetic Mechanisms in Lynch Syndrome

Nieminen

Niskakoski

Peltomäki

2016

Encyclopedia of Life Sciences

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Lynch syndrome (LS) has been known for a century. The syndrome was originally recognised as a dominant predisposition to cancers of multiple organs, including those of the gastrointestinal tract and female reproductive organs. In 1993–1995, LS was linked to germline mutations in DNA (deoxyribonucleic acid) mismatch repair (MMR) genes MLH1 , MSH2 , MSH6 and PMS2 . Soon thereafter, promoter methylation as an alternative mechanism of DNA MMR gene inactivation was discovered. Such ‘epigenetic mutations’ (epimutations) may be somatic (e.g. biallelic methylation of MLH1 in sporadic microsatellite‐unstable cancers) or constitutional (monoallelic methylation of MLH1 or MSH2 in normal tissue, involving cells derived from all three germ layers and causing predisposition to LS cancers). To date, epigenetic mechanisms are known to operate at all stages of LS tumourigenesis, from constitutional predisposition to cancer initiation and progression, and involve DNA MMR genes as well as multiple other growth‐regulatory genes. This review discusses the role of epigenetic mechanisms in the pathogenesis of LS and more broadly, LS as a model of epigenetic mechanisms underlying common human cancers. Key Concepts Lynch syndrome (LS) is caused by mutations in one of the DNA mismatch repair genes; MLH1 , MSH2 , MSH6 or PMS2 . DNA methylation, miRNAs and histone modifications are involved in epigenetic regulation of MMR genes. Epigenetic regulation has been linked to constitutional predisposition, cancer initiation and progression in LS. MLH1 gene may be constitutionally affected by primary epimutation (has no known genetic basis and is usually not inherited) or secondary epimutation (associated with genetic cis ‐ or trans ‐acting alteration, which can be transmitted to offspring). EPCAM deletions may induce secondary epimutations of the MSH2 gene. MMR genes typically, but not always, require two hit inactivation for tumour initiation. LS spectrum tumours have epigenetic profiles characteristic of tumour type. Environmental factors interact with genetic and epigenetic factors, influencing LS phenotype.

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Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation

Pinto

Guerra

et al. 2018

Cancer Medicine

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Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) in various biological samples. We found four (4/38; 10.5%) patients with constitutional methylation in the MLH1 gene promoter. RNA studies demonstrated decreased MLH1 expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH1 constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH1 methylation occurs in a significant proportion of patients who have loss of MLH1 protein expression in their tumors and no MLH1 pathogenic germline mutation. Furthermore, we provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history.

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Prevalence ofMLH1constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer

Abstract: Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1.

Cited by 29 publications

References 14 publications

Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis

Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis

Epigenetic Mechanisms in Lynch Syndrome

Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation

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