J Med Genet 1999;36:678-682 ( September )

Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer

Loveena Verma^{* a}, Michael F Kane^{* b}, Cecilia Brassett^{* c}, James Schmeits^b, D Gareth R Evans^d, Richard D Kolodner^b, Eamonn R Maher^{a c}

^a Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham B15 2TG, UK, ^b Ludwig Institute for Cancer Research, Department of Medicine and Cancer Center, University of California San Diego Medical School, 9500 Gilman Drive, La Jolla, CA 92093-0660, USA, ^c Cambridge University Department of Pathology, Cambridge CB1 4QP, UK, ^d Department of Medical Genetics, St Mary's Hospital, Manchester, UK

Correspondence to: Professor Maher, Birmingham.

Revised version received 4 May 1999; Accepted for publication 10 June 1999

Germline mutations in the MSH2 and MLH1 mismatch repair genes account for most cases of hereditary non-polyposis colon cancer syndrome (HNPCC). In addition, germline MSH2 and MLH1 mutations have been detected in patients with non-HNPCC early onset colorectal cancer. Germline MSH6 mutations appear to be rare in classical HNPCC families, but their frequency in young colorectal cancer cases has not been studied previously. In a population based study of early onset colorectal cancer (<50 years) investigated for tumour microsatellite instability (MSI), we identified a subgroup of tumours with MSI for mono- but not dinucleotide repeat markers (m-MSI+ group). In contrast to tumours with classical MSI for dinucleotide markers (d-MSI+), the m-MSI+ group cancers were mainly left sided (6/7). As MSH6 mutations in yeast and human cell lines are associated with weak (and preferential mononucleotide) MSI, the complete MSH6 gene coding region was sequenced in blood DNA from the five m-MSI+ cases available for analysis. A germline nonsense mutation was identified in an isolated case of early onset colorectal cancer (age 43 years). These results support previous findings that germline MSH6 mutations may not be associated with classical MSI and suggest a role for germline MSH6 mutations in isolated early onset colorectal cancer.


Keywords: mononucleotide microsatellite instability; germline MSH6 mutation analysis; early onset colorectal cancer

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^* These authors contributed equally to this work

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© 1999 by J Med Genet
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