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Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome Vrije Universiteit Brussel

Heleen M van der Klift, Arjen R Mensenkamp, Mark Drost, Elsa C Bik, Yvonne J Vos, Bert E J W Redeker, Yvonne Tiersma, José B M Zonneveld, Encarna Gómez García

Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined ...

Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2 Vrije Universiteit Brussel

Sanne W Ten Broeke, Tom C van Bavel, Anne M L Jansen, Encarnca Gómez-García, Frederik Jan Hes, Liselot P van Hest, Tom G W Letteboer, Maran J W Olderode-Berends, Dina Ruano, Liesbeth Spruijt, et al.

BACKGROUND & AIMS: Germline variants in mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in older patients than CRCs with ...

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers Vrije Universiteit Brussel

Manon Suerink, Heleen M van der Klift, Sanne W Ten Broeke, Olaf M Dekkers, Inge Bernstein, Gabriel Capellá Munar, Encarna Gomez Garcia, Nicoline Hoogerbrugge, Tom G W Letteboer, Fred H Menko, et al.

PURPOSE: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype.

METHODS: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression ...

Lynch syndrome caused by germline PMS2 mutations Vrije Universiteit Brussel

Sanne W Ten Broeke, Richard M Brohet, Carli Mj Tops, Heleen M van der Klift, Mary E Velthuizen, Inge Bernstein, Gabriel Capellá Munar, Encarna Gomez Garcia, Nicoline Hoogerbrugge, Tom G W Letteboer, et al.

PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers.

METHODS: Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To ...

Insertion of an SVA element, a nonautonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome Vrije Universiteit Brussel

Heleen M van der Klift, Carli Mj Tops, Frederik Jan Hes, Peter Devilee, Juul T Wijnen

Heterozygous germline mutations in the mismatch repair gene PMS2 predispose carriers for Lynch syndrome, an autosomal dominant predisposition to cancer. Here, we present a LINE-1-mediated retrotranspositional insertion in PMS2 as a novel mutation type for Lynch syndrome. This insertion, detected with Southern blot analysis in the genomic DNA of the patient, is characterized as a 2.2 kb long 5' truncated SVA_F element. The insertion is not ...