Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability

Plaschke, Jens; Preußler, Mark; Ziegler, Andreas; Schackert, Hans K.

doi:10.1007/s00384-011-1408-0

Cited by 20 publications

(17 citation statements)

References 45 publications

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“…56 In humans, MutSα efficiently binds single-base substitutions and small (single-base) insertion/deletion mispairs, whereas MutSβ has a stronger affinity for larger base insertion/deletion loops (IDL) with up to ten unpaired nucleotides. 57; 58 Thus, loss of MutSβ due to MSH3 inactivation in human cells not only results in MSI at loci containing dinucleotide repeats; it also results in MSI at certain loci with tetranucleotide repeats, termed EMAST. 57; 59 It is known that di- and tetranucleotide repeats are affected in the majority of CRC with MSI-L. 58 MMR-deficiency can also result from an imbalance in the relative levels of MSH3 or MSH6.…”

Section: Discussionmentioning

confidence: 99%

“…57; 58 Thus, loss of MutSβ due to MSH3 inactivation in human cells not only results in MSI at loci containing dinucleotide repeats; it also results in MSI at certain loci with tetranucleotide repeats, termed EMAST. 57; 59 It is known that di- and tetranucleotide repeats are affected in the majority of CRC with MSI-L. 58 MMR-deficiency can also result from an imbalance in the relative levels of MSH3 or MSH6. 60 …”

Section: Discussionmentioning

confidence: 99%

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Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Adam

Spier

Zhao

et al. 2016

The American Journal of Human Genetics

206

161

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In around 30% of families with colorectal adenomatous polyposis, no germline mutation in the previously-implicated genes APC, MUTYH, POLE, POLD1, or NTHL1 can be identified, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis was performed. We identified two unrelated individuals with differing compound-heterozygous loss-of-function germline mutations in the mismatch repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1g>a, c.2760delC, c.3001-2a>c) was indicated on RNA and protein level. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST) and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the loss-of-function effect and causal relevance of the mutations. The pedigrees, genotypes, and the frequency of MSH3 mutations in the general population are consistent with an autosomal recessive mode of inheritance. Both index persons had an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing Constitutional Mismatch Repair Deficiency Syndrome (CMMRD). Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study we describe biallelic germline mutations of MSH3 in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Adam

Spier

Zhao

et al. 2016

The American Journal of Human Genetics

206

161

View full text Add to dashboard Cite

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“…With regard to potential mechanisms of CAG expansion it is of interest that MSH3 and MLH3 appear to play relatively minor roles in classical MMR inasmuch as Msh3 and Mlh3 deficiencies result in weak mutator phenotypes and relatively low cancer predisposition phenotypes [42], [72]–[75]. In strong contrast, loss of either of these two proteins has a major impact on CAG/CTG expansion.…”

Section: Discussionmentioning

confidence: 99%

Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches

et al. 2013

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The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease HdhQ111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.HdhQ111) than on a 129 background (129.HdhQ111). Linkage mapping in (B6x129).HdhQ111 F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.HdhQ111 mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. HdhQ111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1–MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2–MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions.

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“…The Cancer Genome Atlas (TCGA) project reported MSH3 variants in 40% of hypermutated tumors of which 3/4 were MSI-H [18–24]. The MSH3 gene, located on chromosome 5q11–q12 [24, 25], encodes the MSH3 protein that has a partially redundant function with MSH6 [25, 26]. Loss of MSH3 has been reported in tumors with the Elevated Microsatellite instability At Selected Tetranucleotides repeats (EMAST) phenotype with instability at tetranucleotide repeats and poor prognosis [27].…”

Section: Introductionmentioning

confidence: 99%

Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer

et al. 2016

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PURPOSENext Generation Sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC), which is on the rise in many parts of the developing World including, Iran. Little is known about its genetic hallmarks in these populations.AIMTo identify variants in 15 CRC-associated genes in patients of Iranian descent.RESULTSThere were 51 validated variants distributed on 12 genes: 22% MSH3 (n = 11/51), 10% MSH6 (n = 5/51), 8% AMER1 (n = 4/51), 20% APC (n = 10/51), 2% BRAF (n = 1/51), 2% KRAS (n = 1/51), 12% PIK3CA (n = 6/51), 8% TGFβR2A (n = 4/51), 2% SMAD4 (n = 1/51), 4% SOX9 (n = 2/51), 6% TCF7L2 (n = 3/51), and 6% TP53 (n = 3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%).MATERIALS AND METHODSCRC specimens from 63 Shirazi patients were used to establish the variant' profile on an Ion Torrent platform by targeted exome sequencing. To rule-out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established.CONCLUSIONThese results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies.

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Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability

Cited by 20 publications

References 45 publications

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches

Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer

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