The changing landscape of Lynch syndrome due to <i>PMS2</i> mutations

Blount, Jessa; Prakash, Aishwarya

doi:10.1111/cge.13205

Cited by 29 publications

(29 citation statements)

References 101 publications

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“…This technology allows clinicians to simultaneously test multiple genes with massive parallel sequencing in a cost‐effective manner. The number of genes in a panel range from two to >100 and the use of gene panels to test for hereditary cancer syndromes became integrated into standard clinical practice starting in 2012 in developed countries, and in some countries from Latin America, e.g. Argentina, Brazil, Uruguay and Peru.…”

Section: Genetic Profile For Hereditary Crc: Lynch Syndromementioning

confidence: 99%

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America

Vaccaro

López-Köstner

Adriana

et al. 2018

Intl Journal of Cancer

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Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.

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Section: Genetic Profile For Hereditary Crc: Lynch Syndromementioning

confidence: 99%

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America

Vaccaro

López-Köstner

Adriana

et al. 2018

Intl Journal of Cancer

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“…However, the availability of experimental evidence such as biochemical, structural, and functional studies to accurately characterize VUSs as pathogenic or benign, is still lacking. This is particularly observed for variants in PMS2 that have not been studied as rigorously as variants in the other MMR genes (Blount & Prakash, ). Approximately 26% of the variants that have been identified in PMS2 remain categorized as VUSs.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

2019

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Lynch syndrome (LS) is an autosomal dominant inherited disorder that is associated with an increased predisposition to certain cancers caused by loss‐of‐function mutations in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The diagnosis of LS is often challenged by the identification of missense mutations where the functional effects are not known. These are termed variants of uncertain significance (VUSs) and account for 20%–30% of noncoding and missense mutations. VUSs cause ambiguity during clinical diagnosis and hinder implementation of appropriate medical management. In the current study, we focus on the functional and biological consequences of two nonsynonymous VUSs in PMS2. These variants, c.620G>A and c.123_131delGTTAGTAGA, result in the alteration of glycine 207 to glutamate (p.Gly207Glu) and the deletion of amino acid residues 42–44 (p.Leu42_Glu44del), respectively. While the PMS2 p.Gly207Glu variant retains in vitro MMR and ATPase activities, PMS2 p.Leu42_Glu44del appears to lack such capabilities. Structural and biophysical characterization using circular dichroism, small‐angle X‐ray scattering, and X‐ray crystallography of the N‐terminal domain of the PMS2 variants indicate that the p.Gly207Glu variant is properly folded similar to the wild‐type enzyme, whereas p.Leu42_Glu44del is disordered and prone to aggregation.

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“…The lowest frequency of pathogenic variants was present in the group of HNPCC patients with MSS tumors (10/35 or 28.5%). As mentioned above, four of these patients had Lynch syndrome due to mutations in the MMR genes (two in MSH6 and two in PMS2), which are known to be associated with a lower degree of MSI that might have been undetected by our assay [25][26][27]. In the other six patients, the variants were present in five DRG, of which four in genes from DNA double-strand break repair pathway (BRIP1 in two patients, BRCA2, FANCM and CHEK2 in one patient each) and one in nucleotide excision repair pathway (ERCC2).…”

Section: P R O O F Introductionmentioning

confidence: 77%

Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

Staninova-Stojovska

Matevska-Geskovska

Panovski

et al. 2019

Balkan Journal of Medical Genetics

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Hereditary factors are assumed to play a role in ~35.0-45.0% of all colorectal cancers (CRCs) with about 5.0-10.0% associated with high penetrant disease-causing mutations in genes correlated to hereditary polyposis (HP) or hereditary non polyposis syndromes (HNPCC). Although inherited germline mutations in mismatch repair (MMR) and the APC genes contribute significantly to CRC, genetic diagnosis cannot yet be obtained in more than 50.0% of familial cases. We present updated data of 107 probands from the Macedonian population with clinically diagnosed HP (n = 41) or HNPCC (n = 66) obtained by next generation sequencing (NGS) with three different gene panels covering the coding, flanking and promoter regions of 114 cancer predisposition genes. Using this approach, we were able to detect deleterious mutations in 65/107 (60.7%) patients, 50.4% of which were in known well-established CRC susceptibility genes and 10.2% in DNA repair genes (DRG). As expected, the highest frequencies of deleterious variants were detected in familial adenomatous polyposis (FAP) and in HNPCC patients with microsatellite instability (MSI) tumors (93.8 and 87.1%, respectively). Variants of unknown significance (VUS) were detected in 24/107 (22.4%) patients, mainly in HNPCC patients with microsatellite stable (MSS) tumors or patients with oligopolyposis. The majority of VUS were also found in DRG genes, indicating the potential role of a doble-strand brake DNA repair pathway deficiency in colorectal cancerogenesis. We could not detect any variant in 18/107 (16.8%) patients, which supports the genetic heterogeneity of hereditary CRC, particularly in HNPCC families with MSS tumors and in families with oligopolyposis.

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The changing landscape of Lynch syndrome due to PMS2 mutations

Cited by 29 publications

References 101 publications

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America

Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

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