No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

Steinke, Verena; Rahner, Nils; Morak, Monika; Keller, Gisela; Schackert, Hans K.; Görgens, Heike; Schmiegel, Wolff; Royer‐Pokora, Brigitte; Dietmaier, Wolfgang; Kloor, Matthias; Engel, Christoph; Propping, Peter; Aretz, Stefan

doi:10.1038/ejhg.2008.26

Cited by 18 publications

(18 citation statements)

References 28 publications

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“…This finding is consistent with other studies: Steinke et al [19] found that the frequency of monoallelic MUTYH mutations in MSH6 mutation carriers with colorectal cancer (2/64, 3.1 %) was not significantly higher than that of controls (9/577, 1.6 %, p = 0.30); Ashton et al [22] found that the frequency of MUTYH mutations in MLH1 and MSH2 mutation carriers (2/209, 1 %) was not higher than that of controls (4/296, 1.35 %; p = 0.69); van Puijenbroek et al [21] found no evidence of a combined effect of heterozygous MSH6 and MUTYH mutations, except perhaps for urothelial tumors; and Gorgens et al [23] found only one monoallelic MUTYH mutation of c.1187G>A p.(Gly396Asp) in 50 individuals with suspected HNPCC compared with no MUTYH mutation in 116 controls. Further, Stormorken et al [20] reported that frequency of monoallelic MUTYH mutations in individuals with HNPCC, HNPCC-like or dominantly inherited late-onset colorectal cancer (2/96, 2 %) was not more than expected by chance, and concluded that monoallelic MUTYH mutations may not increase risk of cancer in these individuals.…”

Section: Discussionsupporting

confidence: 94%

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Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene

et al. 2015

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The base excision repair protein, MUTYH, functionally interacts with the DNA mismatch repair (MMR) system. As genetic testing moves from testing one gene at a time, to gene panel and whole exome next generation sequencing approaches, understanding the risk associated with co-existence of germline mutations in these genes will be important for clinical interpretation and management. From the Colon Cancer Family Registry, we identified 10 carriers who had both a MUTYH mutation (6 with c.1187G>A p.(Gly396Asp), 3 with c.821G>A p.(Arg274Gln), and 1 with c.536A>G p.(Tyr179Cys)) and a MMR gene mutation (3 in MLH1, 6 in MSH2, and 1 in PMS2), 375 carriers of a single (monoallelic) MUTYH mutation alone, and 469 carriers of a MMR gene mutation alone. Of the 10 carriers of both gene mutations, 8 were diagnosed with colorectal cancer. Using a weighted cohort analysis, we estimated that risk of colorectal cancer for carriers of both a MUTYH and a MMR gene mutation was substantially higher than that for carriers of a MUTYH mutation alone [hazard ratio (HR) 21.5, 95 % confidence interval (CI) 9.19–50.1; p < 0.001], but not different from that for carriers of a MMR gene mutation alone (HR 1.94, 95 % CI 0.63–5.99; p = 0.25). Within the limited power of this study, there was no evidence that a monoallelic MUTYH gene mutation confers additional risk of colorectal cancer for carriers of a MMR gene mutation alone. Our finding suggests MUTYH mutation testing in MMR gene mutation carriers is not clinically informative.

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Section: Discussionsupporting

confidence: 94%

“…[17, 18] Other studies, however, have observed no such associations. [19-23] In this study, we aimed to estimate the risk of colorectal cancer for carriers of both a MUTYH mutation and a MMR gene mutation compared with carriers of monoallelic MUTYH mutation alone and carriers of a MMR gene mutation alone.…”

Section: Introductionmentioning

confidence: 99%

Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene

et al. 2015

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“…Niessen et al [10], found a significantly higher frequency of monoallelic MUTYH mutations in MSH6 missense mutation carriers (20%) than in Caucasian controls (1.5%, P = 0.001) and Dutch colorectal and endometrial cancer patients without MSH6 gene mutation (0.7%, P = 0.002). In contrast, Steinke et al [11] failed to find this association when they examined the MSH6 mutation carriers of the German HNPCC Consortium for MUTYH mutations.…”

Section: Discussionmentioning

confidence: 81%

“…One study has previously reported a significantly higher frequency of monoallelic MUTYH mutations in CRC patients carrying missense MSH6 mutations [10], whereas another has failed to find such correlation [11]. A third study showed that MSH6/MUTYH heterozygote mutation carriers display a predominant Lynch syndrome molecular tumor phenotype, and that abrogation of both MSH6 and MUTYH repair genes might be mutually exclusive in humans [12].…”

Section: Introductionmentioning

confidence: 96%

Association of MUTYH and MSH6 germline mutations in colorectal cancer patients

et al. 2009

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Colorectal cancer (CRC) risk associated with germline monoallelic MUTYH mutations remains controversial, although a slightly increased risk for this disease has been suggested. MUTYH and MSH6 proteins act in cooperation during the DNA repair process. Based on this interaction, it was hypothesized that the combination of heterozygote germline mutations in both genes could result in an increased CRC risk. To further clarify the interaction between MUTYH and MSH6, we analyzed the prevalence of MSH6 mutations in a cohort of CRC patients and controls previously tested for MUTYH mutations: CRC patients with and without a monoallelic MUTYH mutation (group I, n = 26; group II, n = 50, respectively), and healthy carriers with a monoallelic MUTYH mutation (group III, n = 21). In group I, we found three patients (11.5%) with MSH6 mutations, a missense mutation (p.R635G), a change in the 3'UTR region (c.*4098A > C) and a nonsense mutation (p.Q982X). In group II and III, no mutations were detected. In CRC patients, MSH6 mutations were more frequently found in MUTYH mutation carriers than in noncarriers (11.5% vs. 0%, P = 0.037). CRC patients carrying monoallelic MUTYH mutations harbor more frequently concomitant MSH6 mutations than patients without them, thus suggesting that both genes could act cooperatively and confer together an increased CRC risk.

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“…Liu et al [14] described an index subject from a LS family with two heterozygous variants (c.546-2A>G and c.1852_1853AA>GC); only the former segregated with LS in the family. Similarly, Steinke et al [15], described the co-occurrence of the p.Lys618Ala (c.1852_1853AA>GC) variant with the MSH6 p.Arg1068X (c.3202C>T) deleterious variant.…”

Section: Discussionmentioning

confidence: 99%

Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome

et al. 2011

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BackgroundLynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS.MethodsThe following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers.ResultsTwenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients.ConclusionsThe p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.

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No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

Cited by 18 publications

References 28 publications

Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene

Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene

Association of MUTYH and MSH6 germline mutations in colorectal cancer patients

Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome

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