Guidelines on Genetic Evaluation and Management of Lynch Syndrome

Giardiello, Francis M.; Allen, John I.; Axilbund, Jennifer E.; Boland, C. Richard; Burke, Carol A.; Burt, Randall W.; Church, James M.; Dominitz, Jason A.; Johnson, David A.; Kaltenbach, Tonya; Levin, Theodore R.; Lieberman, David A.; Robertson, Douglas J.; Syngal, Sapna; Rex, Douglas K.

doi:10.1097/dcr.000000000000000

Cited by 89 publications

(22 citation statements)

References 96 publications

(143 reference statements)

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“…PMS2 mutations are associated with LS, a condition that increases the risk for developing CRC, uterine, ovarian, hepatobiliary, urinary tract, brain, skin, and other gastrointestinal malignancies ( 49 , 92 – 95 ). The exact cancer risks conferred by PMS2 mutations are unclear, but they are thought to be lower than other MMR gene mutations ( 96 ).…”

Section: Resultsmentioning

confidence: 99%

Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management

et al. 2015

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BackgroundMultigene panels can be a cost- and time-effective alternative to sequentially testing multiple genes, especially with a mixed family cancer phenotype. However, moving beyond our single-gene testing paradigm has unveiled many new challenges to the clinician. The purpose of this article is to familiarize the reader with some of the challenges, as well as potential opportunities, of expanded hereditary cancer panel testing.MethodsWe include results from 348 commercial multigene panel tests ordered from January 1, 2014, through October 1, 2014, by clinicians associated with the City of Hope’s Clinical Cancer Genetics Community of Practice. We also discuss specific challenging cases that arose during this period involving abnormalities in the genes: CDH1, TP53, PMS2, PALB2, CHEK2, NBN, and RAD51C.ResultsIf historically high risk genes only were included in the panels (BRCA1, BRCA2, MSH6, PMS2, TP53, APC, CDH1), the results would have been positive only 6.2% of the time, instead of 17%. Results returned with variants of uncertain significance (VUS) 42% of the time.ConclusionThese figures and cases stress the importance of adequate pre-test counseling in anticipation of higher percentages of positive, VUS, unexpected, and ambiguous test results. Test result ambiguity can be limited by the use of phenotype-specific panels; if found, multiple resources (the literature, reference laboratory, colleagues, national experts, and research efforts) can be accessed to better clarify counseling and management for the patient and family. For pathogenic variants in low and moderate risk genes, empiric risk modeling based on the patient’s personal and family history of cancer may supersede gene-specific risk. Commercial laboratory and patient contributions to public databases and research efforts will be needed to better classify variants and reduce clinical ambiguity of multigene panels.

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Section: Resultsmentioning

confidence: 99%

Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management

et al. 2015

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“…Therefore, they have been considered to be insufficient as independent screening tools. To increase the accuracy of screening for Lynch syndrome, microsatellite instability (MSI) and immunohistochemistry (IHC) are used in cases with colorectal cancer, and when losses of MLH1 and PMS2 proteins are detected using IHC, universal screening, including BRAF testing and analysis for MLH1 promoter methylation, is recommended [ 5 , 6 ]. Similarly, in endometrial cancer, MSI and IHC are useful in screening for Lynch syndrome [ 7 – 10 ], and the mutation site can be estimated using IHC.…”

Section: Introductionmentioning

confidence: 99%

Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review

et al. 2018

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BackgroundLynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer.Case presentationHere we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome.ConclusionsBoth MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

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“…The Revised Bethesda Guidelines recommend MSI analysis and/or IHC analysis of tumor tissue to select patients for definitive DNA sequence analysis [ 12 ]. Our study identified three putative LS patients from Mexico, initially suspected based upon family history and screened by IHC and confirmed with DNA analyses.…”

Section: Discussionmentioning

confidence: 99%

Novel Mutations inMLH1andMSH2Genes in Mexican Patients with Lynch Syndrome

Moreno-Ortiz

Ayala-Madrigal

Corona‐Rivera

et al. 2016

Gastroenterology Research and Practice

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Background. Lynch Syndrome (LS) is characterized by germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. This syndrome is inherited in an autosomal dominant pattern and is characterized by early onset colorectal cancer (CRC) and extracolonic tumors. The aim of this study was to identify mutations in MMR genes in three Mexican patients with LS. Methods. Immunohistochemical analysis was performed as a prescreening method to identify absent protein expression. PCR, Denaturing High Performance Liquid Chromatography (dHPLC), and Sanger sequencing complemented the analysis. Results. Two samples showed the absence of nuclear staining for MLH1 and one sample showed loss of nuclear staining for MSH2. The mutations found in MLH1 gene were c.2103+1G>C in intron 18 and compound heterozygous mutants c.1852_1854delAAG (p.K618del) and c.1852_1853delinsGC (p.K618A) in exon 16. In the MSH2 gene, we identified mutation c.638dupT (p.L213fs) in exon 3. Conclusions. This is the first report of mutations in MMR genes in Mexican patients with LS and these appear to be novel.

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Guidelines on Genetic Evaluation and Management of Lynch Syndrome

Cited by 89 publications

References 96 publications

Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management

Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management

Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review

Novel Mutations inMLH1andMSH2Genes in Mexican Patients with Lynch Syndrome

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