A robust genomic signature for the detection of colorectal cancer patients with microsatellite instability phenotype and high mutation frequency.

J Pathol. 2012 Aug 27. doi: 10.1002/path.4092.

Tian S, Roepman P, Popovici V, Michaut M, Majewski I, Salazar R, Santos C, Rosenberg R, Nitsche U, Mesker WE, Bruin S, Tejpar S, Delorenzi M, Bernards R, Simon I.

Agendia NV, Amsterdam, The Netherlands; and Agendia Inc., Irvine, CA, USA.



Microsatellite instability (MSI) occurs in 10-20% of colorectal tumours and is associated with good prognosis. Here we describe the development and validation of a genomic signature that identifies colorectal cancer patients with MSI caused by DNA mismatch repair deficiency with high accuracy. Microsatellite status for 276 stage II and III colorectal tumours has been determined. Full-genome expression data was used to identify genes that correlate with MSI status. A subset of these samples (n = 73) had sequencing data for 615 genes available. An MSI gene signature of 64 genes was developed and validated in two independent validation sets: the first consisting of frozen samples from 132 stage II patients; and the second consisting of FFPE samples from the PETACC-3 trial (n = 625). The 64-gene MSI signature identified MSI patients in the first validation set with a sensitivity of 90.3% and an overall accuracy of 84.8%, with an AUC of 0.942 (95% CI, 0.888-0.975). In the second validation, the signature also showed excellent performance, with a sensitivity 94.3% and an overall accuracy of 90.6%, with an AUC of 0.965 (95% CI, 0.943-0.988). Besides correct identification of MSI patients, the gene signature identified a group of MSI-like patients that were MSS by standard assessment but MSI by signature assessment. The MSI-signature could be linked to a deficient MMR phenotype, as both MSI and MSI-like patients showed a high mutation frequency (8.2% and 6.4% of 615 genes assayed, respectively) as compared to patients classified as MSS (1.6% mutation frequency). The MSI signature showed prognostic power in stage II patients (n = 215) with a hazard ratio of 0.252 (p = 0.0145). Patients with an MSI-like phenotype had also an improved survival when compared to MSS patients. The MSI signature was translated to a diagnostic microarray and technically and clinically validated in FFPE and frozen samples. Copyright © 2012 Pathological Society of Great Britain and Ireland.

PMID: 22926706


Supplementary picture:

Iris Simon-1

Clinical relevance summary

It has been known for a long time that MSI colorectal cancer patients have different prognosis and most likely also different responses to therapy than microsatellite stable (MSS) colorectal cancer patients. To date, MSI status is determined by PCR amplification of specific microsatellite repeats. In some clinics, the immunohistochemical analysis of DNA mismatch repair proteins is also used to detect MSI status.

We show here that our gene expression signature identifies MSI tumors with a high degree of specificity and sensitivity. More importantly, we show that tumors that are MSS by conventional diagnostic tests, but are MSI by our gene expression assay, have the same high mutation frequency, frequent BRAF mutations, high TYMS expression and good prognosis as MSI patients, indicating that the tumors that our signature identifies as MSI have all the hallmarks of true MSI tumors. We therefore believe that our gene signature may be clinically relevant to identify MSI colon cancer patients who should receive different treatment.

The signature was developed and independently validated in large sets of samples and showed high reproducibility in technical validation experiments. It has been translated into a diagnostic test and has been validated with both fresh frozen samples and FFPE samples from colorectal cancer patients. This diagnostic tool can improve clinical management of stage 2 and stage 3 colorectal cancer patients.


Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann