Functional Significance and Clinical Phenotype of Nontruncating Mismatch Repair Variants of MLH1

Raevaara, Tiina E.; Korhonen, Mari; Lohi, Hannes; Hampel, Heather; Lynch, Elly; Lönnqvist, Karin E.; Holinski‐Feder, Elke; Sutter, Christian; McKinnon, Wendy; Duraisamy, Sekhar; Gerdes, Anne-Marie; Peltomäki, Païvi; Kohonen-Ccorish, Maija; Mangold, Elisabeth; Macrae, Finlay; Greenblatt, Marc S.; Chapelle, Albert de la; Nyström, Minna

doi:10.1053/j.gastro.2005.06.005

Cited by 124 publications

(165 citation statements)

References 38 publications

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“…Guerrette et al 43 45 Bianchi et al, 29 and Kosinski et al 46 found normal MLH1-PMS2 in vitro binding activity in their studies. Raevaara et al 45 also performed other in vitro MLH1 protein functional studies, including protein expression and stability, subcellular localization, protein-protein interaction, and repair efficiency. MLH1 K618A was found to be normal by all parameters.…”

Section: Functional Studiesmentioning

confidence: 86%

“…The first three studies (Guerrette et al, 43 Kondo et al, 44 and Belvederesi et al 28 ) show that the K618A variant has substantially lower ability to bind PMS2, but that it still binds a nontrivial fraction of the available PMS2. The studies by Raevaara et al 45 and Kosinski et al, 46 however, showed no difference between K618A and wild-type MLH1 constructs with respect to PMS2 binding. The Raevaara group used a method quite different from those of the other four studies, one that may not be able to distinguish between normal and reduced binding.…”

Section: In Silico Analysismentioning

confidence: 89%

“…Although K618 is often described as being in the PMS2 binding domain (eg, Figure 2 in Chao et al 2008 52 ), this more detailed model shows that position 618 is not directly involved in PMS2 binding. 46 Raevaara et al 45 used a somewhat different experimental design. They coexpressed mutant MLH1 and wild-type PMS2 from baculovirus constructs in Sf9 cells.…”

Section: In Silico Analysismentioning

confidence: 99%

“…Raevaara et al 45 performed several in vitro studies, including protein expression and stability, subcellular localization, protein-protein interaction, and repair efficiency. They found that K618A MLH1 did not perform differently compared with wild-type protein in any of the assays.…”

Section: In Silico Analysismentioning

confidence: 99%

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The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

Medeiros

Lindor

Couch

et al. 2012

The Journal of Molecular Diagnostics

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Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG¡GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR ‫؍‬ 2.1, 95% CI ‫؍‬ 1.3 to 3.5; P ‫؍‬ 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was overrepresented in 1742 cases (allele frequency of 0.83) (OR ‫؍‬ 2.0, 95% CI ‫؍‬ 1.2 to 3.2; P ‫؍‬ 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.

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Section: Functional Studiesmentioning

confidence: 86%

Section: In Silico Analysismentioning

confidence: 89%

Section: In Silico Analysismentioning

confidence: 99%

Section: In Silico Analysismentioning

confidence: 99%

See 2 more Smart Citations

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

Medeiros

Lindor

Couch

et al. 2012

The Journal of Molecular Diagnostics

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“…Mut1 is an in-frame deletion (3.5 kb genomic deletion affecting codons 578-632 of exon 16 and flanking intron sequences), Mut2 is a frameshift mutation (g>a at 454-1 splice acceptor of exon 6) and Mut3 is a missense mutation (T>G at nucleotide 320 in exon 4, I107R). Mut1 and Mut2 together account for a majority of Finnish HNPCC kindreds meeting the international diagnostic criteria (Nystrom-Lahti et al, 1995), and the pathogenicity of the missense mutation (Mut3) has been verified by functional tests (Raevaara et al, 2005). The appropriate institutional review boards of the Helsinki University Central Hospital approved this study.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

et al. 2007

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Mutations in the DNA mismatch repair gene MLH1 are a major cause of hereditary nonpolyposis colorectal cancer (HNPCC). No mutant phenotype is observed before the wild-type (wt) allele is somatically inactivated in target tissue. We addressed the mechanisms of MLH1 inactivation in 25 colorectal (CRC) and 32 endometrial cancers (ECs) from MLH1 mutation carriers (Mut1, in-frame genomic deletion; Mut2, out-of-frame splice site mutation; Mut3, missense mutation). By a quantitative method, matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF), utilizing four intragenic single nucleotide polymorphisms and mutations, loss of heterozygosity (LOH) was present in 31/57 (54.4%) of tumors. The wt allele displayed LOH more often than the mutant allele (23/57 vs 8/57, P ¼ 0.006). For Mut1, LOH was more frequent in CRC than EC (10/11 vs 1/13, Po0.0001), whereas Mut2 and Mut3 displayed opposite LOH pattern. Moreover, although wt LOH predominated in CRC irrespective of the predisposing mutation, LOH often affected the mutant allele in EC from Mut2 and Mut3 carriers (6/19, 31.6%). MLH1 promoter methylation, which reflected a more widespread hypermethylation tendency, occurred in 4/55 (7.3%) of tumors and was inversely associated with LOH. In conclusion, the patterns of somatic events (LOH and promoter methylation) differ depending on the tissue and germline mutation, which may in part explain the differential tumor susceptibility of different organs in HNPCC. MALDI-TOF provides a novel approach for the detection and quantification of LOH.

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Analysis of telomere dynamics in peripheral blood cells from patients with Lynch syndrome

Bozzao

Lastella

Leòn

et al. 2011

Cancer

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BACKGROUND:In patients with Lynch syndrome, germline mutations in DNA mismatch repair (MMR) genes cause a high risk of developing a broad spectrum of cancers. To date, the management of patients with Lynch syndrome has represented a major challenge because of large variations in age at cancer onset. Several factors, including genetic anticipation, have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Telomere shortening is a common event in tumorigenesis and also has been observed in different familial cancers. In this study, the authors investigated the possibility of a relation between telomere length and cancer onset in patients with Lynch syndrome. METHODS: The mean telomere length was measured using quantitative polymerase chain reaction in peripheral blood samples from a control group of 50 individuals, from 31 unaffected mutation carriers, and from 43 affected patients, and the results were correlated with both gene mutation and cancer occurrence. In affected patients, telomere attrition was correlated with age at cancer onset. In all patients, a t test was used to assess the linearity of the regression. RESULTS: A significant correlation between telomere length and age was observed in both affected and unaffected mutation carriers (P ¼ .0016 and P ¼ .004, respectively) and in mutS homolog 2 (MSH2) mutation carriers (P ¼ .0002) but not in mutL homolog 1 (MLH1) mutation carriers. Telomere attrition was correlated significantly with age at onset in MSH2 carriers (P ¼ .004), whereas an opposite trend toward longer telomeres in patients with delayed onset was observed in MLH1 carriers. CONCLUSIONS: The current data suggested that telomere dynamics differ between MLH1 and MSH2 mutation carriers. It is possible that subtle, gene-specific mechanisms can be linked to cancer onset and anticipation in patients with Lynch syndrome. Cancer 2011;117:4325-

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Functional Significance and Clinical Phenotype of Nontruncating Mismatch Repair Variants of MLH1

Cited by 124 publications

References 38 publications

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

Analysis of telomere dynamics in peripheral blood cells from patients with Lynch syndrome

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