Phenotype Comparison of <i>MLH1</i> and <i>MSH2</i> Mutation Carriers in a Cohort of 1,914 Individuals Undergoing Clinical Genetic Testing in the United States

Kastrinos, Fay; Stoffel, Elena M.; Balmañà, Judith; Steyerberg, Ewout W.; Mercado, Rowena; Syngal, Sapna

doi:10.1158/1055-9965.epi-08-0301

Cited by 69 publications

(46 citation statements)

References 22 publications

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“…The manifestation of Lynch syndrome reflects the specific mutation and genetic background of the patient. Compared with patients with an MLH1 mutation, for example, those with an MSH2 mutation have a higher risk of a noncolorectal malignancy and those with an MSH6 mutation have a higher risk of endometrial cancer (35,36). Patients with an MLH1 mutation, in turn, are more likely to develop colorectal cancer at a young age in the presence of specific risk alleles (37).…”

Section: Pathogenesis Of Msi In Colorectal Cancersmentioning

confidence: 99%

Microsatellite Instability as a Biomarker for PD-1 Blockade

Dudley

Lin

et al. 2016

Clinical Cancer Research

744

541

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Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti-PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade. MSI usually arises from either germline mutations in components of the mismatch repair (MMR) machinery (MSH2, MSH6, MLH1, PMS2) in patients with Lynch syndrome or somatic hypermethylation of the MLH1 promoter. The result is a cancer with a 10-to 100-fold increase in mutations, associated in the colon with poor differentiation, an intense lymphocytic infiltrate, and a superior prognosis. Diagnostic approaches have evolved since the early 1990s, from relying exclusively on clinical criteria to incorporating pathologic features, PCR-based MSI testing, and immunohistochemistry for loss of MMR component expression. Tumor types can be grouped into categories based on the frequency of MSI, from colorectal (20%) and endometrial (22%-33%) to cervical (8%) and esophageal (7%) to skin and breast cancers (0%-2%). If initial results are validated, MSI testing could have an expanded role as a tool in the armamentarium of precision medicine.

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Section: Pathogenesis Of Msi In Colorectal Cancersmentioning

confidence: 99%

Microsatellite Instability as a Biomarker for PD-1 Blockade

Dudley

Lin

et al. 2016

Clinical Cancer Research

744

541

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“…Interestingly, different MMR gene deficiencies lead to distinct phenotypic and clinical manifestations. For example, MLH1 mutations are particularly associated with an increased risk of colon cancers, whereas MSH2 mutations have a higher incidence of extracolonic tumors (31,32). Patients carrying heterozygous MSH6 or PMS2 mutations usually display a decreased frequency and a later onset of HNPCC (27).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Therapeutic Targeting of the DNA Mismatch Repair Pathway

Martin

Lord

Ashworth

2010

Clinical Cancer Research

136

112

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The mismatch repair (MMR) pathway is involved in the removal of DNA base mismatches that arise either during DNA replication or are caused by DNA damage. Mutations in four genes involved in MMR, MSH2, MLH1, PMS2 and MSH6, predispose to a range of tumorigenic conditions, including hereditary nonpolyposis colon cancer, also known as Lynch syndrome. Here we discuss the canonical MMR pathway and the burgeoning evidence for noncanonical roles for the MMR genes, and highlight the therapeutic implications of MMR. In particular, we discuss how the DNA repair defect in MMR-deficient cancers could be exploited by the development of novel therapeutic strategies based on synthetic lethal approaches.

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“…The hMLH1 promoter hypermethylation has been observed in ovarian, endometrial, gastric, and colorectal carcinoma (5). The hMSH2 mutations have a higher incidence of extracolonic tumors (6). The defects of both MMR genes are involved in renal carcinogenesis and correlate with the occurrence of microsatellite instability (7).…”

mentioning

confidence: 99%

Ectopic Expression of Human MutS Homologue 2 on Renal Carcinoma Cells Is Induced by Oxidative Stress with Interleukin-18 Promotion via p38 Mitogen-activated Protein Kinase (MAPK) and c-Jun N-terminal Kinase (JNK) Signaling Pathways

Chen

Dai

Kang

et al. 2012

Journal of Biological Chemistry

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Background: Ectopically expressed MutS homologue 2 (hMSH2) is a ligand of ␥␦ T cells. Results: Oxidative stress induces ectopic expression of hMSH2 on renal carcinoma cells with IL-18 promotion via p38 MAPK and JNK pathways, promoting ␥␦ T cell-mediated lysis of renal tumor cells. Conclusion: Ectopically expressed hMSH2 is induced under stressful conditions. Significance: We reveal a mechanism of ectopic hMSH2 expression and its contribution to ␥␦ T cell-mediated immunosurveillance in stress.

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Phenotype Comparison of MLH1 and MSH2 Mutation Carriers in a Cohort of 1,914 Individuals Undergoing Clinical Genetic Testing in the United States

Cited by 69 publications

References 22 publications

Microsatellite Instability as a Biomarker for PD-1 Blockade

Microsatellite Instability as a Biomarker for PD-1 Blockade

Therapeutic Targeting of the DNA Mismatch Repair Pathway

Ectopic Expression of Human MutS Homologue 2 on Renal Carcinoma Cells Is Induced by Oxidative Stress with Interleukin-18 Promotion via p38 Mitogen-activated Protein Kinase (MAPK) and c-Jun N-terminal Kinase (JNK) Signaling Pathways

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