Loss of MSH3 Protein Expression Is Frequent in MLH1-Deficient Colorectal Cancer and Is Associated with Disease Progression

Plaschke, Jens; Krüger, Stefan; Jeske, Birgit; Theissig, F; Kreuz, Friedmar R.; Pistorius, Steffen; Saeger, H. D.; Iaccarino, Ingram; Marra, Giancarlo; Schackert, Hans K.

doi:10.1158/0008-5472.can-03-2807

Cited by 52 publications

(57 citation statements)

References 34 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results are also in agreement with the inverse relationship between clinicopathologic staging and accumulation of frameshift mutations observed in a large series of sporadic microsatelliteunstable cancers (42). In contrast, others (43) found an association between MSH3 loss and advanced tumor stage in a small group of MLH1-deficient CRCs, but the high rate of loss of heterozygosity suggests that that series was somehow enriched with tumors with overlapping patterns of microsatellite and chromosomal instability.…”

Section: Discussionsupporting

confidence: 91%

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

Laghi

Bianchi

Delconte

et al. 2012

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Patients with colorectal cancers (CRC) and high microsatellite instability (MSI) have a better outcome than their chromosome-unstable counterpart. Given the heterogeneity of microsatellite-unstable CRCs, we wanted to see whether any MSI-associated molecular features are specifically associated with prognosis.Experimental Design: One hundred and nine MSI-high CRCs were typed for primary mismatch repair (MMR) defect and for secondary loss of MMR proteins. Frameshifts at seven target genes, mutations in the RAS pathway, and methylation at MLH1/CDKN2A promoters were also searched. The interplay of molecular findings with clinicopathologic features and patient survival was analyzed.Results: Of 84 MLH1-deficient CRCs, 31 (36.9%) had MSH3 and 11 (13.1%) had MSH6 loss (P < 0.001), biallelic frameshift mutations at mononucleotide repeats accounting for most (78%) MSH3 losses. As compared with MSH3-retaining cancers, MLH1-deficient tumors with MSH3 loss showed a higher number of mutated target genes (3.94 AE 1.56 vs. 2.79 AE 1.75; P ¼ 0.001), absence of nodal involvement at pathology [N0; OR, 0.11; 95% confidence interval (CI), 0.04-0.43, P < 0.001], and better disease-free survival (P ¼ 0.06). No prognostic value was observed for KRAS status and for MLH1/CDKN2A promoter methylation. The association between MSH3 loss and N0 was confirmed in an independent cohort of 71 MLH1-deficient CRCs (OR, 0.23; 95% CI, 0.06-0.83, P ¼ 0.02).Conclusions: MLH1-deficient CRCs not expressing MSH3 have a more severe MSI, a lower rate of nodal involvement, and a better postsurgical outcome.

show abstract

Section: Discussionsupporting

confidence: 91%

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

Laghi

Bianchi

Delconte

et al. 2012

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…PMS2L3 has a similar function to that of PMS2 in MutL␣, which is to play a role in maintaining genome integrity via MMR and DNA damage-induced apoptosis [26]. Loss of MSH3 protein expression has been related to tumor progression in colorectal cancer [27]. Our finding that the MSH3 genetic variants contributed to shorter OS in patients with locally advanced or metastatic pancreatic cancer suggests that MSH3 deficiency may contribute to rapid tumor progression, possibly through accumulation of larger IDLs in patients with late-stage disease.…”

Section: Discussionmentioning

confidence: 99%

DNA Mismatch Repair Gene Polymorphisms Affect Survival in Pancreatic Cancer

Dong

Hess

et al. 2011

The Oncologist

View full text Add to dashboard Cite

Purpose. DNA mismatch repair (MMR) maintains genomic stability and mediates cellular response to DNA damage. We aim to demonstrate whether MMR genetic variants affect overall survival (OS) in pancreatic cancer.Materials and Methods. Using the Sequenom method in genomic DNA, we retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 MMR genes from 706 patients with pancreatic adenocarcinoma seen at The University of Texas MD Anderson Cancer Center. Association between genotype and OS was evaluated using multivariable Cox proportional hazard regression models.Results. At a false discovery rate of 1% (p < .0015), 15 SNPs of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, TP73, and TREX1 in patients with localized disease (n ‫؍‬ 333) and 6 SNPs of MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease (n ‫؍‬ 373) were significantly associated with OS. In multivariable Cox proportional hazard regression models, SNPs of EXO1, MSH2, MSH3, PMS2L3, and TP73 in patients with localized disease, MSH2, MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease, and EXO1, MGMT, MSH2, MSH3, MSH6, PMS2L3, and TP73 in all patients remained significant predictors for OS (p < .0015) after adjusting for all clinical predictors and all SNPs with p < .0015 in singlelocus analysis. Sixteen haplotypes of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, RECQL, TP73, and TREX1 significantly correlated with OS in all patients (p < .001).Conclusion. MMR gene variants may have potential value as prognostic markers for OS in pancreatic cancer patients. The Oncologist 2011;16:61-70

show abstract

“…Further analysis revealed that MSH3 mutations gained strongly in signifi cance ( P = 7.43 × 10 −6 ) and activity effect (GI 50 ratio, 5.3) when restricted to protein structure-damaging microdeletions in the two longest mononucleotide/trinucleotide repeat sequences of the MSH3 coding sequence ( Fig. 1A and B (24)(25)(26)(27). Concordantly, we detected such mutations in our cancer cell line panel; 10 of 67 cell lines displayed microdeletions in the two longest mononucleotide/trinucleotide repeat sequences ( Fig.…”

Section: Activity Profi Le Of Ku60648 In a Large Panel Of Genomicallymentioning

confidence: 99%

A Functional Cancer Genomics Screen Identifies a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC

et al. 2014

View full text Add to dashboard Cite

Here, we use a large-scale cell line-based approach to identify cancer cell-specifi c mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profi led the mutational landscape across 1,319 cancerassociated genes of 67 distinct cell lines and identifi ed numerous genes involved in homologous recombination-mediated DNA repair, including BRCA1 , BRCA2 , ATM , PAXIP , and RAD50 , as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3 , which have been reported to occur recurrently in numerous human cancer entities, emerged as the most signifi cant predictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3 -mutant cell lines in vitro and displayed remarkable single-agent effi cacy against MSH3 -mutant tumors in vivo . Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects. SIGNIFICANCE:We associate mutations in the MSH3 gene, which are frequently detected in microsatellite-instable colon cancer (∼40%), with a therapeutic response to specifi c DNA-PKcs inhibitors. Because potent DNA-PKcs inhibitors are currently entering early clinical trials, we offer a novel opportunity to genetically stratify patients who may benefi t from a DNA-PKcs-inhibitory therapy. Cancer Discov; 4(5);[592][593][594][595][596][597][598][599][600][601][602][603][604][605]

show abstract

Loss of MSH3 Protein Expression Is Frequent in MLH1-Deficient Colorectal Cancer and Is Associated with Disease Progression

Abstract: ABSTRACT

Cited by 52 publications

References 34 publications

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

DNA Mismatch Repair Gene Polymorphisms Affect Survival in Pancreatic Cancer

A Functional Cancer Genomics Screen Identifies a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC

Contact Info

Product

Resources

About