MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer.

Cancer Res 2002 Feb;62(3):848-53

Laboratoire de Génétique Moléculaire, CHU de Rouen et Institut National de la Santé et de la Recherche Médicale EMI 9906, Faculté de Médecine et de Pharmacie, IFRMP, 22 Boulevard de Gambetta, 76183 Rouen, France.

To estimate the relative frequency of mismatch repair genes, rearrangements in hereditary nonpolyposis colorectal cancer (HNPCC) families without detectable mutations in MSH2 or MLH1, we have analyzed by multiplex PCR of short fluorescent fragments MSH2, MLH1, and MSH6 in 61 families, either fulfilling Amsterdam criteria or including cases of multiple primary cancers belonging to the HNPCC spectrum. We detected 13 different genomic rearrangements of MSH2 in 14 families (23%), whereas we found no rearrangement of MLH1 and MSH6. Analysis of 31 other families, partially meeting Amsterdam criteria, revealed no additional rearrangement of MSH2. All of the MSH2 rearrangements, except one, corresponded to genomic deletions involving one or several exons. In 8 of 13 families with a MSH2 genomic deletion, the MSH2 promoter was also deleted, and the 5' breakpoint was located either within or upstream the MSH2 gene. This study demonstrates the heterogeneity of MSH2 exonic and promoter rearrangements and shows that, in HNPCC families without detectable MSH2 or MLH1 point mutation, one must consider the presence of MSH2 genomic rearrangements before the involvement of other mismatch repair genes. The simplicity and rapidity of their detection, using fluorescent multiplex PCR, led us to recommend to begin the molecular analysis in HNPCC by screening for MSH2 rearrangements.

Download full-text PDF

Source
February 2002
6 Reads

Publication Analysis

Top Keywords

msh2
13
msh2 mlh1
12
mlh1 msh6
12
mismatch repair
8
repair genes
8
colorectal cancer
8
hereditary nonpolyposis
8
nonpolyposis colorectal
8
families detectable
8
msh2 genomic
8
genomic rearrangements
8
amsterdam criteria
8
msh2 rearrangements
8
multiplex pcr
8
rearrangements hereditary
8
hnpcc families
8
exonic promoter
8
promoter rearrangements
8
rearrangements
7
families
6

Similar Publications