Medline ® Abstracts for References 29,30
of 'Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis'
A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome.
Clendenning M, Senter L, Hampel H, Robinson KL, Sun S, Buchanan D, Walsh MD, Nilbert M, Green J, Potter J, Lindblom A, de la Chapelle A
J Med Genet. 2008;45(6):340. Epub 2008 Jan 4.
BACKGROUND: When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (<2% of all identified mutations), yet the immunohistochemical analysis of tumour samples indicates that approximately 5% of Lynch syndrome cases are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences.
METHODS: Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis.
RESULTS: We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n = 61). These individuals all display the rare allele (population frequency<0.05) at a single nucleotide polymorphism (SNP) in exon 11, and have been shown to possess a short common haplotype, allowing us to calculate that themutation arose around 1625 years ago (65 generations; 95% confidence interval 22 to 120).
CONCLUSION: Ancestral analysis indicates that this mutation is enriched in individuals with British and Swedish ancestry. We estimate that there are>10 000 carriers of this mutation in the USA alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands' families, would suggest that this is a prevalent mutation with reduced penetrance.
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients.
Ligtenberg MJ, Kuiper RP, Geurts van Kessel A, Hoogerbrugge N
Fam Cancer. 2013;12(2):169.
Lynch syndrome, one of the most common cancer susceptibility syndromes, is caused by germline mutations of genes affecting the mismatch repair proteins MLH1, MSH2, MSH6 or PMS2. Most of these mutations disrupt the open reading frame of the genes involved and, as such, lead to constitutive inactivation of the mutated allele. In a subset of Lynch syndrome patients MSH2 was found to be specifically inactivated in cell lineages exhibiting EPCAM expression. These patients carry deletions of the 3' end of the EPCAM gene, including its polyadenylation signal. Due to concomitant transcriptional read-through of EPCAM, the promoter of MSH2 15 kb further downstream becomes inactivated through hypermethylation. As these 3' EPCAM deletions occur in the germline, this MSH2 promoter methylation ('epimutation') is heritable. Worldwide, numerous EPCAM 3' end deletions that differ in size and location have been detected. The risk of colorectal cancer in carriers of such EPCAM deletions is comparable to that of MSH2 mutation carriers, and is in accordance with a high expression of EPCAM in colorectal cancer stem cells. The risk of endometrial cancer in the entire group of EPCAM deletion carriers is significantly lower than that in MSH2 mutation carriers, but the actual risk appears to be dependent on the size and location of the EPCAM deletion. These observations may have important implications for the surveillance of EPCAM deletion carriers and, thus, calls for an in-depth assessment of clinically relevant genotype-phenotype correlations and its underlying molecular mechanism(s).
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. firstname.lastname@example.org