Abstract: A method of diagnosing an MSI cancer in a patient including extracting and sequencing DNA from a tumoral sample and if available from a normal sample and operate an analyse of MNRs. The method is based on the demonstration that the FDA-approved NGS-based diagnostic test for identifying MSI in mCRC and nmCRC gave inaccurate results when compared with the gold standard reference methods. Consequently, whole exome sequencing (WES) data from all samples was further analyzed to improve detection of the MSI genomic signal in CRC and other primary tumor types. This allowed identification of weaknesses and limits of MSISensor and the design and validation of a newly optimized algorithm, namely MSICare. The high accuracy of MSICare for the detection of MSI in CRC and non-CRC tumors should allow it to become a future reference test for assessing MSI in pan-cancer.

Abstract: The invention relates to method for treating cancer. Through whole exome sequencing, the inventors analyzed 47 MSI CRC and results were confirmed in a series of 53 MSI CRC. Negatively selected coding alterations in MSI CRC were further investigated for their functional role in CRC cell lines and survival impact in a cohort of 164 MSI CRC patients. Five coding negatively selected, MSI-related mutational events were demonstrated to have deleterious effects on tumor expansion, while they were associated with worse prognosis inpatients. The inventors investigated the functional consequences of the silencing of WNK1, HMGXB4, GART, and/or PRRC2C using siRNA and/or shRNA in CRC cell lines in vitro and in vivo using xenograft models. Their inactivation in CRC cells led to deleterious effects on apoptosis, proliferation and/or cell migration. The deleterious effects were greatly enhanced when several of the targets were concomitantly silenced.