Risk of Cancer in Cases of Suspected Lynch Syndrome Without Germline Mutation

Rodríguez–Soler, María; Pérez–Carbonell, Lucía; Guarinós, Carla; Zapater, Pedro; Castillejo, Adela; Barberá, Víctor Manuel; Juárez, Míriam; Bessa, Xavier; Xicola, Rosa M.; Clofent, Juan; Bujanda, Luís; Balaguer, Francesc; Reñé, Josep–Maria; de–Castro, Luisa; Marín-Gabriel, José Carlos; Lanas, Ángel; Cubiella, Joaquín; Nicolás–Pérez, David; Brea‐Fernández, Alejandro; Castellví–Bel, Sergi; Alenda, Cristina; Ruíz-Ponte, Clara; Carracedo, Ángel; Castells, Antoni; Andreu, Montserrat; Llor, Xavier; Soto, José Luís; Payá, Artemio; Jover, Rodrigo

doi:10.1053/j.gastro.2013.01.044

Cited by 195 publications

(237 citation statements)

References 28 publications

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“…These patients need different surveillance and due to the different pattern of inheritance a different risk annotation for family members. 32 We suggest to perform MUTYH genetic testing in these unresolved MSI-H cases with additional adenomas either in the two fragments harbouring the common mutations or in the course of nextgeneration sequencing cancer kits including the MMR genes, APC and MUTYH besides others. 18 We reported for the first time a MAP patient initially suspected of LS, in which two MAP-specific somatic MSH2 mutations explained the IHC loss of MSH2/MSH6 in his MSI-H tumour.…”

Section: Discussionmentioning

confidence: 99%

Biallelic MUTYH mutations can mimic Lynch syndrome

et al. 2014

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The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in B10-15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 'unresolved' patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2-MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2-MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway.

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Section: Discussionmentioning

confidence: 99%

Biallelic MUTYH mutations can mimic Lynch syndrome

et al. 2014

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“…However, it is probable that some LLS patients could actually have Lynch syndrome, as some tumours may be due to constitutional mutations in DNA MMR genes that are not detectable by standard testing. Indeed extended analysis by NGS has demonstrated that in some instances this is the case (Rodriguez-Soler et al, 2013). An alternative cause is somatic mutations in an allele of a DNA MMR gene coupled with loss of heterozygosity (LOH) of the other allele (Geurts-Giele et al, 2014;Mensenkamp et al, 2014).…”

Section: "Lynch-like Syndrome" and Novel Aetiologies Of Msi Colorectamentioning

confidence: 99%

“…There is a significant group of patients (≤35%) whose tumours have an abnormal MMR status by IHC or display MSI on molecular assays, and who have a Lynch syndrome-consistent family history, but in whom genetic testing cannot find an inherited mutation in an MMR gene, and in whom sporadic MLH1 promoter hypermethylation is not demonstrable (Geurts-Giele et al, 2014). "Lynch-like syndrome" (LLS) is a recently proposed term for such cases, and it is thought that it may account for as many as 70% of tumours in which Lynch syndrome is clinically suspected, but genetic testing fails to identify a constitutional MMR gene mutation (Rodriguez-Soler et al, 2013). There are numerous possible reasons for LLS.…”

Section: "Lynch-like Syndrome" and Novel Aetiologies Of Msi Colorectamentioning

confidence: 99%

“…This is best exemplified by the case of EPCAM deletions described above. Analysis of suspected LLS cancers among probands and families demonstrate heterogeneity in risks, with the risk of CRC and extracolonic malignancies in families with LLS being lower than that of families with Lynch syndrome but higher than that of families with sporadic CRC (Rodriguez-Soler et al, 2013). This coupled with the heterogeneous aetiology of LLS means until more information regarding cancer risks and rates of neoplastic progression become available, intensive surveillance for cancer similar to Lynch syndrome guidelines is recommended (Carethers and Stoffel, 2015).…”

Section: "Lynch-like Syndrome" and Novel Aetiologies Of Msi Colorectamentioning

confidence: 99%

“…An alternative cause is somatic mutations in an allele of a DNA MMR gene coupled with loss of heterozygosity (LOH) of the other allele (Geurts-Giele et al, 2014;Mensenkamp et al, 2014). However, up to 50% of LLS CRC exhibits biallelic somatic inactivation of DNA MMR genes within the tumor (Geurts-Giele et al, 2014;Haraldsdottir et al, 2014;Kang et al, 2015;Rodriguez-Soler et al, 2013;Sourrouille et al, 2013). It has now been demonstrated that many of these are due to constitutional mutations and epimutations in other genes, including POLD1 and POLE (Haraldsdottir et al, 2014;Palles et al, 2013), MUTYH (Castillejo et al, 2014;Syngal et al, 2015), FAN1 (Segui et al, 2015), NTHL1 (Weren et al, 2015), PIK3CA (Cohen et al, 2016), BRCA1/2, 2 PTEN, STK11 (Yurgelun et al, 2015) and other cancer susceptibility genes (SMAD4, BMPR1A, KLLN, AKT1, AXIN2, BUB1 and BUB3) (Hansen et al, 2017) with some resultant tumours sometimes acquiring two somatic mutations in the same MMR gene, and consequently dMMR and/or MSI (Frayling and Arends, 2015;Short et al, 2015).…”

Section: "Lynch-like Syndrome" and Novel Aetiologies Of Msi Colorectamentioning

confidence: 99%

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The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

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Sheahan

Creavin

et al. 2017

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Mismatch Repair Genes

Kansikas

Nyström

Peltomäki

2017

Encyclopedia of Life Sciences

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The mismatch repair (MMR) system is necessary for the maintenance of genomic stability. The primary role of MMR is to correct errors such as base/base mismatches and small insertions/deletions that arise during DNA (deoxyribonucleic acid) synthesis. Loss of functional MMR results in increased rates of point mutations and microsatellite instability. Post‐replicative MMR is strand‐specific and serves mutation avoidance. Outside replication, discrimination between old and newly synthesised DNA strands is no longer necessary, and the MMR system can be mutagenic. Such non‐canonical actions of MMR are required, for example, for the generation of immunoglobulin diversity. The anti‐mutator and mutator activities of MMR play important roles in human diseases. Notably, germline mutations in MMR genes cause predisposition to Lynch syndrome, whereas epigenetic inactivation of the MMR gene MLH1 underlies 15% of sporadic colorectal and other cancers. Key Concepts Post‐replicative mismatch repair can counteract or promote mutations. DNA mismatch repair genes are conserved in evolution. DNA mismatch repair genes comply with Knudson's two‐hit paradigm for tumour suppressor genes. Deficient DNA mismatch repair is responsible for microsatellite instability in tumours. Inherited defects in DNA mismatch repair underlie Lynch syndrome, a dominant predisposition to colorectal, endometrial and other cancers.

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Risk of Cancer in Cases of Suspected Lynch Syndrome Without Germline Mutation

Cited by 195 publications

References 28 publications

Biallelic MUTYH mutations can mimic Lynch syndrome

Biallelic MUTYH mutations can mimic Lynch syndrome

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Mismatch Repair Genes

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