A novel MLH1 mutation in a Japanese family with Lynch syndrome associated with small bowel cancer

Akizawa, Yoshika; Yamamoto, Toshiyuki; Tamura, Kazuo; Kanno, Toshiyuki; Takahashi, N.; Ohki, Takeshi; Omori, Teppei; Tokushige, Katsutoshi; Yamamoto, Masakazu; Saito, Kayoko

doi:10.1038/s41439-018-0013-y

Cited by 9 publications

(5 citation statements)

References 19 publications

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“…Based on the InSIGHT five-tier system [38], up till now 1344 MLH1 variants have been registered for LS associated CRCs [39]. According to HGMD database, 1069 different types of mutations in different exons of MLH1 has been reported (Figure 6A,B).…”

Section: Discussionmentioning

confidence: 99%

Combinatorial approach of in silico and in vitro evaluation of MLH1 variant associated with Lynch syndrome like metastatic colorectal cancer

Saleem

Zaib

et al. 2020

Bioscience Reports

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Colorectal cancer (CRC) is the third most developing cancer worldwide and Lynch syndrome (LS) accounts for 3–4% of CRC. Genetic alteration in any of DNA mismatch repair (MMR) gene is the major cause of LS that disrupt the normal upstream and downstream MMR events. Germline mutation of MLH1 in heterozygous state have an increased risk for CRC. Defective MMR pathway mostly results in microsatellite instability (MSI) that occurs in high percentage of CRC associated tumors. Here, we reported a patient with LS like metastatic CRC (mCRC) associated with other related cancers. Whole exome sequencing (WES) of the proband was performed to identify potential causative gene. Genetic screening validated by Sanger sequencing identified a heterozygous missense mutation in exon 12 of MLH1 (c.1151T>A, p.V384D). The clinical significance of identified variant was elucidated on the basis of clinicopathological data, computational predictions and various in vitro functional analysis. In silico predictions classified the variant to be deleterious and evolutionary conserved. In vitro functional studies revealed a significant decrease in protein expression because of stability defect leading to loss of MMR activity. Mutant residue found in MutL transducer domain of MLH1 that localized in the nucleus but translocation was not found to be significantly disturbed. In conclusion, our study give insight into reliability of combinatorial prediction approach of in silico and in vitro expression analysis. Hence, we highlighted the pathogenic correlation of MLH1 variant with LS associated CRC as well as help in earlier diagnosis and surveillance for improved management and genetic counselling.

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Section: Discussionmentioning

confidence: 99%

Combinatorial approach of in silico and in vitro evaluation of MLH1 variant associated with Lynch syndrome like metastatic colorectal cancer

Saleem

Zaib

et al. 2020

Bioscience Reports

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“…In this study, we found a heterozygous missense mutation Furthermore, in the InSiGHT database, more than 1344 MLH1 variants have been registered for LS or other associated disorders [19]. Twelve missense mutations in exon 18 of MLH1 have been classified as class 5 (pathogenic) based on the 5-tier system proposed by InSiGHT [20].…”

Section: Discussionmentioning

confidence: 89%

Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

et al. 2020

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Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRCs) inherited in an autosomal-dominant manner. Here, we reported a multigeneration Chinese family clinically diagnosed with LS according to the Amsterdam II criteria. To identify the underlying causative gene for LS in this family, whole-exome sequencing (WES) was performed. A germline missense variant (c.2054C>T:p.S685F) in exon 18 of MLH1 was successfully identified by WES. Sanger sequencing verified the results of WES and also confirmed the cosegregation of the MLH1 missense variant in all affected members of the family including two unaffected family members. Bioinformatic tools predicted the identified MLH1 variant as deleterious. Immunohistochemistry (IHC) staining showed loss of MLH1 and PMS2 protein expression. In vitro expression analysis also revealed that the identified MLH1 missense variant (c.2054C>T:p.S685F) results in reduced expression of both MLH1 and PMS2 proteins. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, the missense mutation c.2054C>T in MLH1 was classified as a “pathogenic” variant. Two unaffected family members were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years as both were at higher risk of LS. In conclusion, our findings widen the genotypic spectrum of MLH1 mutations responsible for LS. This study increases the phenotypic spectrum of LS which will certainly help the clinicians in diagnosing LS in multigeneration families. This study also puts emphasis on the importance of genetic counselling for the benefit of asymptomatic carriers of MMR gene variants who are at higher risk of LS.

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“…In CRC, the classic model of carcinogenesis is the adenoma carcinoma sequence [117][118][119][120][121]. Based on this scheme, malignant CRC cells have the capacity to accumulate a number of immunogenic mutations and become a potential target for immunotherapy, even though they might remain less immunogenic than melanoma or NSCLC [122].…”

Section: Mutational Burden and Neoantigen Densitymentioning

confidence: 99%

Expanding the Scope of Immunotherapy in Colorectal Cancer: Current Clinical Approaches and Future Directions

Kreidieh

Mukherji

Temraz

et al. 2020

BioMed Research International

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The success of immune checkpoint inhibitors (ICIs) in an increasing range of heavily mutated tumor types such as melanoma has culminated in their exploration in different subsets of patients with metastatic colorectal cancer (mCRC). As a result of their dramatic and durable response rates in patients with chemorefractory, mismatch repair-deficient-microsatellite instability-high (dMMR-MSI-H) mCRC, ICIs have become potential alternatives to classical systemic therapies. The anti-programmed death-1 (PD-1) agents, Pembrolizumab and Nivolumab, have been granted FDA approval for this subset of patients. Unfortunately, however, not all CRC cases with the dMMR-MSI-H phenotype respond well to ICIs, and ongoing studies are currently exploring biomarkers that can predict good response to them. Another challenge lies in developing novel treatment strategies for the subset of patients with the mismatch repair-proficient-microsatellite instability-low (pMMR-MSI-L) phenotype that comprises 95% of all mCRC cases in whom treatment with currently approved ICIs has been largely unsuccessful. Approaches aiming at overcoming the resistance of tumors in this subset of patients are being developed including combining different checkpoint inhibitors with either chemotherapy, anti-angiogenic agents, cancer vaccines, adoptive cell transfer (ACT), or bispecific T-cell (BTC) antibodies. This review describes the rationale behind using immunotherapeutics in CRC. It sheds light on the progress made in the use of immunotherapy in the treatment of patients with dMMR-MSI-H CRC. It also discusses emerging approaches and proposes potential strategies for targeting the immune microenvironment in patients with pMMR-MSI-L CRC tumors in an attempt to complement immune checkpoint inhibition.

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A novel MLH1 mutation in a Japanese family with Lynch syndrome associated with small bowel cancer

Cited by 9 publications

References 19 publications

Combinatorial approach of in silico and in vitro evaluation of MLH1 variant associated with Lynch syndrome like metastatic colorectal cancer

Combinatorial approach of in silico and in vitro evaluation of MLH1 variant associated with Lynch syndrome like metastatic colorectal cancer

Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

Expanding the Scope of Immunotherapy in Colorectal Cancer: Current Clinical Approaches and Future Directions

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