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Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer

¹ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
² Department of Gastroenterology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
³ Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
⁴ Departments of Human Genetics and Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
⁵ Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
⁶ Department of Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Correspondence to:
Correspondence to:
J H Kleibeuker
Department of Gastroenterology, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands;j.h.kleibeuker{at}int.umcg.nl

Background: Patients with early-onset colorectal cancer (CRC) or those with multiple tumours associated with hereditary non-polyposis colorectal cancer (HNPCC) raise suspicion of the presence of germline DNA mismatch repair (MMR) gene mutations.

Aim: To analyse the value of family history, microsatellite instability (MSI) analysis and MMR protein staining in the tumour to predict the presence of an MMR gene mutation in such patients.

Methods: In 281 patients diagnosed with CRC before the age of 50 years or with CRC and at least one additional HNPCC-associated cancer, germline mutation analysis in MLH1, MSH2 and MSH6 was carried out with denaturing gradient gel electrophoresis and multiplex ligation-dependent probe amplification. MSI analysis with five consensus markers and MMR protein staining for MLH1, MSH2 and MSH6 were carried out in the tumours.

Results: 25 pathogenic mutations (8 in MLH1, 9 in MSH2 and 8 in MSH6) were found. MSI analysis missed three and immunohistochemistry (IHC) missed two mutation carriers. Sensitivities of family history, MSI analysis and IHC for the presence of a mutation were 76%, 82% and 88%, specificities were 64%, 70% and 84%, and positive predictive values were 19%, 23% and 38%, respectively. Multivariate analysis showed the highest odds ratio for IHC (38.3, 95% confidence interval 9.0 to 184). Prevalence of pathogenic germline MMR gene mutations in patients with CRC before the age of 50 years was 6% and in those with 2 HNPCC-associated tumours was 22%. In the second group, no mutation carriers were found among the 29 patients who were diagnosed with their first tumour after the age of 60 years.

Conclusion: Family history, MSI analysis and IHC are indicative parameters to select patients with CRC for MMR gene mutation analysis. The data show that IHC is the best single selection criterion.

Abbreviations: ACI, Amsterdam criteria I; ACII, Amsterdam criteria II; CRC, colorectal cancer; HNPCC, hereditary non-polyposis colorectal cancer; IHC, immunohistochemistry; MMR, mismatch repair; MSI, microsatellite instability

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