Somatic Mutations in MLH1 and MSH2 Are a Frequent Cause of Mismatch-Repair Deficiency in Lynch Syndrome-Like Tumors

Mensenkamp, Arjen R.; Vogelaar, Ingrid P.; Zelst-Stams, Wendy A. G. van; Goossens, Monique; Ouchene, Hicham; Hendriks-Cornelissen, Sandra J. B.; Kwint, Michael; Hoogerbrugge, Nicoline; Nagtegaal, Irıs D.; Ligtenberg, Marjolijn J. L.

doi:10.1053/j.gastro.2013.12.002

Cited by 296 publications

(265 citation statements)

References 32 publications

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“…Indeed extended analysis by NGS has demonstrated that in some instances this is the case (Rodriguez-Soler et al, 2013). An alternative cause is somatic mutations in an allele of a DNA MMR gene coupled with loss of heterozygosity (LOH) of the other allele (Geurts-Giele et al, 2014;Mensenkamp et al, 2014). However, up to 50% of LLS CRC exhibits biallelic somatic inactivation of DNA MMR genes within the tumor (Geurts-Giele et al, 2014;Haraldsdottir et al, 2014;Kang et al, 2015;Rodriguez-Soler et al, 2013;Sourrouille et al, 2013).…”

Section: "Lynch-like Syndrome" and Novel Aetiologies Of Msi Colorectamentioning

confidence: 99%

“…Consequently, the interpretation of the IHC results may be used to guide any further genetic analysis that may be required. When used in this fashion it is important to remember that IHC is only a pointer and that deficiency in specific MMR proteins may be due to mutations in a different MMR gene (Frayling and Arends, 2015;Mensenkamp et al, 2014) or in other genes associated with CRC (Castillejo et al, 2014;Cohen et al, 2016;Hansen et al, 2017;Haraldsdottir et al, 2014;Palles et al, 2013;Syngal et al, 2015;Yurgelun et al, 2015). It is also important to remember that in the subset of Lynch syndrome due to deletion of EpCAM somatic hypermethylation of MSH2 leads to loss of expression by IHC.…”

Section: Ihc For Dmmr Tumours As a Surrogate For Pcrmentioning

confidence: 99%

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The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Ryan

Sheahan

Creavin

et al. 2017

Critical Reviews in Oncology/Hematology

118

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Section: "Lynch-like Syndrome" and Novel Aetiologies Of Msi Colorectamentioning

confidence: 99%

Section: Ihc For Dmmr Tumours As a Surrogate For Pcrmentioning

confidence: 99%

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Ryan

Sheahan

Creavin

et al. 2017

Critical Reviews in Oncology/Hematology

118

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“…A recent study has found somatic mutations in at least two of these genes in almost 70% of patient tumors 95 . In another study, two acquired mutations in MLH1 and MSH2 have been observed in 52% (13/25) of the patients studied 96 .…”

Section: Microsatellite Instabilitymentioning

confidence: 99%

Colorectal cancer carcinogenesis: a review of mechanisms

Tariq¹,

Ghias²

2016

Cancer Biology &Amp; Medicine

220

138

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Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men globally. CRC arises from one or a combination of chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Genetic instability is usually caused by aneuploidy and loss of heterozygosity. Mutations in the tumor suppressor or cell cycle genes may also lead to cellular transformation. Similarly, epigenetic and/or genetic alterations resulting in impaired cellular pathways, such as DNA repair mechanism, may lead to microsatellite instability and mutator phenotype. Non-coding RNAs, more importantly microRNAs and long non-coding RNAs have also been implicated at various CRC stages. Understanding the specific mechanisms of tumorigenesis and the underlying genetic and epigenetic traits is critical in comprehending the disease phenotype. This paper reviews these mechanisms along with the roles of various non-coding RNAs in CRCs.

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“…MMR DNA sequencing was performed as previously described in the case of PT3. 19 Somatic KRAS and BRAF hotspot mutations (KRAS exons 2 and 3 and BRAF p.V600E were tested as described previously. 20 Somatic mutations are submitted to the COSMIC database (ID # 616).…”

Section: Somatic Mutation Screeningmentioning

confidence: 99%

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

et al. 2014

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Germline variants affecting the exonuclease domains of POLE and POLD1 predispose to multiple colorectal adenomas and/or colorectal cancer (CRC). The aim of this study was to estimate the prevalence of previously described heterozygous germline variants POLE c.1270C4G, p.(Leu424Val) and POLD1 c.1433G4A, p.(Ser478Asn) in a Dutch series of unexplained familial, early onset CRC and polyposis index cases. We examined 1188 familial CRC and polyposis index patients for POLE p.(Leu424Val) and POLD1 p.(Ser478Asn) variants using competitive allele-specific PCR. In addition, protein expression of the POLE and DNA mismatch repair genes was studied by immunohistochemistry in tumours from POLE carriers. Somatic mutations were screened using semiconductor sequencing. We detected three index patients (0.25%) with a POLE p.(Leu424Val) variant. In one patient, the variant was found to be de-novo. Tumours from three patients from two families were microsatellite instable, and immunohistochemistry showed MSH6/MSH2 deficiency suggestive of Lynch syndrome. Somatic mutations but no germline MSH6 and MSH2 variants were subsequently found, and one tumour displayed a hypermutator phenotype. None of the 1188 patients carried the POLD1 p.(Ser478Asn) variant. POLE germline variant carriers are also associated with a microsatellite instable CRC. POLE DNA analysis now seems warranted in microsatellite instable CRC, especially in the absence of a causative DNA mismatch repair gene germline variant. INTRODUCTIONFaithful DNA replication and the repair of errors are both essential for the maintenance of genomic stability and suppression of carcinogenesis. 1 Duplication of genomes with high accuracy is achieved through three mechanisms: the high selectivity of DNA polymerases; exonucleolytic proofreading; and post replication mismatch repair. 2 The DNA polymerases ε (POLε) and δ (POLδ) are required for the efficient genome replication in the eukaryotic replication fork. 3 Their major component proteins, encoded by POLE and POLD1, respectively, possess an intrinsic 3′-5′ proofreading domain that removes incorrectly inserted nucleotides during DNA synthesis. [4][5][6][7][8][9] Studies in the yeast have shown that mutations in the proofreading domains of POLε or POLδ increase spontaneous mutation rates. 8,9 In addition, somatic mutations in the proofreading domains of POLD1 and POLE have been identified in microsatellite instable (MSI) and hypermutated subgroups of colorectal cancers (CRCs). [10][11][12] Recently, Palles et al reported that heterozygous germline variants in the proofreading domain of the DNA polymerases POLE and POLD1 predispose, with a high penetrance, to multiple colorectal adenomas, early onset CRC (OMIM #114500) and endometrial cancer (OMIM #608089). These variants were found by whole-genome sequencing and linkage analysis in three large families with a dominant pattern of CRC and multiple adenomas. 13 Subsequent screening of 3805 CRC patients revealed that these variants are relatively rare: POLE

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Somatic Mutations in MLH1 and MSH2 Are a Frequent Cause of Mismatch-Repair Deficiency in Lynch Syndrome-Like Tumors

Cited by 296 publications

References 32 publications

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Colorectal cancer carcinogenesis: a review of mechanisms

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

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