Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation

Gallinger, Steven; Aronson, Melyssa; Shayan, Katayoon; Ratcliffe, Elyanne M.; Gerstle, Justin T.; Parkin, Patricia C.; Rothenmund, Heidi; Croitoru, Marina E.; Baumann, Ewa; Durie, Peter R.; Weksberg, Rosanna; Pollett, Aaron; Riddell, Robert H.; Ngan, Bo; Cutz, Ernest; Lagarde, Alain E.; Chan, Helen S. L.

doi:10.1053/j.gastro.2003.11.008

Cited by 113 publications

(82 citation statements)

References 29 publications

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“…35 More recently, biallelic mutations of MMR genes have been described, often in the setting of consanguinity. [36][37][38][39][40] Affected individuals show early onset colon cancers, hematologic malignancies, and features overlapping neurofibromatosis type I.…”

Section: Genetic Basis For Lsmentioning

confidence: 99%

Microsatellite Instability and Colorectal Cancer

Geiersbach¹,

Samowitz²

2011

Archives of Pathology &Amp; Laboratory Medicine

122

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Context.—About 15% of colorectal cancers are characterized by genomic microsatellite instability, and of these, about 1 in 5 (2%–4% overall) are due to Lynch syndrome, a dominantly inherited condition predisposing the patient to cancers of multiple organ systems, including the gastrointestinal tract. Identification of individuals with Lynch syndrome allows for increased surveillance of the affected individual and of potentially affected family members. Objective.—To review the literature on microsatellite instability in colorectal cancer and current laboratory diagnostic testing strategies for the detection of Lynch syndrome. Data Sources.—This review is based on peer-reviewed literature, published guidelines from professional organizations (Evaluation of Genomic Applications in Practice and Prevention Working Group, National Comprehensive Cancer Network), and information from clinical laboratories performing microsatellite instability testing. Conclusions.—Universal screening for Lynch syndrome in all individuals affected with colorectal cancer has been recommended by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Preliminary screening tests can identify individuals unlikely to be affected by Lynch syndrome, thereby reducing the need for full gene analysis. Immunohistochemistry and polymerase chain reaction–based tests for microsatellite instability have similar clinical sensitivity and specificity, and each method has advantages and limitations. BRAF and MLH1 methylation testing are useful reflex tests for those with a defect in MLH1 identified by immunohistochemistry. Emerging technologies, such as high-throughput sequencing, may substantially affect diagnostic algorithms in the future.

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Section: Genetic Basis For Lsmentioning

confidence: 99%

Microsatellite Instability and Colorectal Cancer

Geiersbach¹,

Samowitz²

2011

Archives of Pathology &Amp; Laboratory Medicine

122

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“…Homozygous and compound heterozygous MMR gene mutations in children had formerly been described as predisposing to leukemia, lymphoma, and brain tumors, and cafe´au lait spots in the absence of gastrointestinal carcinomas. However, Gallinger et al 20 have reported the first known instance of children with homozygous MMR gene deficiency manifesting early-onset gastrointestinal cancers in concert with neurofibromatosis type 1 (NF1) features. All three members of one sibship 'yhad a germline homozygous MLH1 missense mutation (exon 18, codon 687, CGGTGG), whereas both parents were heterozygous for this mutation.'…”

Section: Common Mutationsmentioning

confidence: 99%

“…20 CRC tumors in Lynch syndrome are more often poorly differentiated, with an excess of mucoid and signet-cell features, show a Crohn's-like reaction, and contain a significant excess of infiltrating lymphocytes within the tumor. MSI is found in most CRC tumors in Lynch syndrome; Increased survival from CRC, when controlled for age and stage; Accelerated carcinogenesis and interval CRC; a tiny adenoma may emerge into a carcinoma within 2 -3 years, as opposed to 8 -10 years in the general population; Sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas in the Muir -Torre syndrome variant of Lynch syndrome; The sine qua non, the identification of a germline MMR mutation segregating with syndrome-affected individuals in the family.…”

Section: Cardinal Features Of Lynch Syndromementioning

confidence: 99%

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications

et al. 2006

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“…[10][11][12][13] In recent years, several case reports have been published of children with either compound heterozygosity (CZ) or homozygosity for an MMR gene defect. [14][15][16][17][18][19][20][21][22] These patients had malignancies at a young age. Overviews are given by Menko et al 19 and Bandipalliam.…”

Section: Conclusion Carriage Of Biallelic Mmrmentioning

confidence: 99%

Biallelic germline mutations of mismatch‐repair genes

Poley

Wagner

Hoogmans

et al. 2007

Cancer

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TDP‐43 has been identified as the pathological protein in the majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). TARDBP mutations have so far been uniquely associated with familial and sporadic ALS. We describe clinicopathological and genetic findings in a carrier of the novel K263E TARDBP variation, who developed frontotemporal dementia, supranuclear palsy, and chorea, but no signs of motor neuron disease. Neuropathologic examination revealed neuronal and glial TDP‐43‐immunoreactive deposits, predominantly in subcortical nuclei and brainstem. This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS. © 2009 Movement Disorder Society

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Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation

Cited by 113 publications

References 29 publications

Microsatellite Instability and Colorectal Cancer

Microsatellite Instability and Colorectal Cancer

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications

Biallelic germline mutations of mismatch‐repair genes

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