Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability

Ma, A.-H.; Xia, Liang; Littman, Susan J.; Swinler, Sandra E.; Lader, G.; Polinkovsky, Alexander; Olechnowicz, Joseph; Kasturi, Lakshmi; Lutterbaugh, James; Modrich, Paul; Veigl, Martina L.; Markowitz, Sanford D.; Sedwick, W. David

doi:10.1038/sj.onc.1203568

Cited by 27 publications

(12 citation statements)

References 31 publications

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“…A possible contribution of PMS2 inactivation to the development of sporadic colon cancers was shown in vitro by Ma et al (32). In this study, somatic mutations of both alleles resulted in PMS2 gene inactivation in a Vaco481 colon cancer.…”

Section: Discussionmentioning

confidence: 72%

“…The overall contribution of loss of PMS2 expression (either by mutation or other mechanisms including methylation or chromosomal loss) to MSI colon cancers has been suggested but remains undefined (32). In this report, we describe the frequency of altered PMS2 protein expression within a rare subset of patients: those with MSI-H colorectal tumors and intact protein expression of MLH1, MSH2, and MSH6.…”

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confidence: 92%

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Isolated Loss of PMS2 Expression in Colorectal Cancers: Frequency, Patient Age, and Familial Aggregation

Gill

Lindor

Burgart³

et al. 2005

Clinical Cancer Research

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Purpose: Most colorectal cancers that have high levels of microsatellite instability (MSI-H) show loss of immunohistochemical expression of proteins that participate in the DNA mismatch repair process, most often involving MLH1 and MSH2. Less commonly, a third DNA mismatch repair protein, MSH6, may also be lost as the primary event. Rarely, tumors with MSI-H show normal expression of these three proteins.The genetic deficiency leading to the MSI-H phenotype in such cases is unknown. PMS2 is another member of the DNA mismatch repair complex. Its expression is generally lost in tumors with MLH1 loss of expression. Rarely, there is selective loss of PMS2 expression. We sought to describe the frequency and clinical correlates of selective loss of expression of PMS2 with the MSI-H tumor phenotype. Experimental Design: Two thousand seven hundred nineteen colorectal cancers from both clinic-and research-based ascertainment were studied. Tumor MSI testing and immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 were conducted. Medical records were abstracted for age at diagnosis, gender, colorectal cancer site, and family history. Results: Five hundred thirty-five of the 2,719 tumors were MSI-H. Of these, 93% showed loss of expression of MLH1, MSH2, and/or MSH6. Thirty-eight showed normal expression for these proteins. PMS2 immunohistochemical staining was successful in 32 of 38 of these tumors. Of the 32, 23 showed selective loss of expression of PMS2. This was associated with young age of diagnosis and right-sided location but not with a striking family history of cancer. Conclusions: Overall, 97% of the MSI-H tumors showed loss of expression for one or more of these four mismatch repair proteins. Selective loss of expression of PMS2 was present in 72% of cases in which colorectal cancers had an MSI-H phenotype but no alteration of expression of MLH1, MSH2, and MSH6. The underlying mechanism involved cannot be determined from this study but could involve point mutations in other DNA mismatch repair genes with retention of immunohistochemical expression, somatic inactivation of PMS2, or germ line mutation of PMS2.Tumor DNA microsatellite instability (MSI) is a consequence of defects in DNA mismatch repair. A high level of microsatellite instability (MSI-H) is recognized in a subset of patients diagnosed with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) by pedigree, and in 10% to 15% of all colorectal cancers in most unselected series (1 -3). Both somatic and germ line mutations have been identified in several putative genes from the mutS (MSH2, MSH3, and MSH6) and mutL (MLH1, MLH3, PMS1, and PMS2) gene families in colon cancer with defective mismatch repair (4 -7).

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Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 92%

Isolated Loss of PMS2 Expression in Colorectal Cancers: Frequency, Patient Age, and Familial Aggregation

Gill

Lindor

Burgart³

et al. 2005

Clinical Cancer Research

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“…Heterogeneous losses for multiple MMR markers were detected in the hypermutant/MSI+ tumors and while the interpretation of variable staining for these proteins is still the subject of debate , it reflects the heterogeneity observed at the genomic level. Notably, while no genomic alterations of the MMR complex were detected in D1P, loss of MLH1 protein expression is often the result of promoter hypermethylation , and PMS2 stability appears to depend directly on the presence of MLH1 .…”

Section: Discussionmentioning

confidence: 97%

Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma

Grande

Delaidelli

El-Naggar

et al. 2019

The Journal of Pathology

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Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations. Sequencing of 13 osteosarcoma patients including 13 primary, 10 metastatic, and 3 locally recurring tumors revealed a highly heterogeneous mutational landscape, including cases of hypermutation and microsatellite instability positivity, but with virtually no recurrent alterations except for mutations involving the tumor suppressor genes RB1 and TP53. At the germline level, we detected alterations in multiple cancer related genes in the majority of the cohort, including those potentially disrupting DNA damage response pathways. Metastases retained only a minimal number of short variants from their corresponding primary tumors, while copy number alterations showed higher conservation. One recurrently amplified gene, KDR, was highly expressed in advanced cases and associated with poor prognosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…HT-29 is a mismatch repair proficient colon cancer cell line (22). Vaco432 is a mismatch repair deficient (dMMR) colon cancer cell line due to MLH1 promoter methylation and silencing (23). The four cell lines used (HT-29, Vaco432, A375, and SKMel-28) do not have any mutations in the KRAS , NRAS , or HRAS genes.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition

et al. 2017

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BRAF V600E colorectal cancers (CRC) are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that CRC progression specimens invariably harbored lesions in elements of the RAS-RAF-MEK-ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in CRC patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in CRC than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant CRC.

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Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability

Cited by 27 publications

References 31 publications

Isolated Loss of PMS2 Expression in Colorectal Cancers: Frequency, Patient Age, and Familial Aggregation

Isolated Loss of PMS2 Expression in Colorectal Cancers: Frequency, Patient Age, and Familial Aggregation

Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma

Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition

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