Molecular Testing for Microsatellite Instability and DNA Mismatch Repair Defects in Hereditary and Sporadic Colorectal Cancers – Ready for Prime Time?

Abstract

Microsatellite instability (MSI) is a genetic feature of colorectal cancer (CRC) associated with peculiar clinicopathological features and improved prognosis. It is demonstrated in >90% of patients with hereditary non-polyposis colorectal cancer (HNPCC) in which DNA mismatch repair (MMR) defects are the cause of MSI. HNPCC develop at a young age, and patients are at increased risk for additional cancers (e.g. endometrial, stomach, or biliary tract cancer). MSI is found in 15–20% of sporadic CRC, often based on epigenetic silencing (i.e. MLH1). The prognostic and predictive value of MSI is not yet fully elucidated, although improved survival in MSI is suggested. Distinguishing sporadic MSI from HNPCC is at present guided by the combination of familial history, immunohistochemistry, and genotyping of MMR genes (MLH1, MSH2, MSH6, and PMS2). The efficiency and accuracy of MSI testing is evolving, with more knowledge achieved concerning multipopulation polymorphisms, selection of markers (e.g. quasimonomorphic vs. dinucleotides), and more time-efficient panels (e.g. not requiring normal/germline DNA match). The role of distinct genetic features, such as BRAF V600E mutations often found in sporadic MSI but not in HNPCC, may further improve future test algorithms. The present knowledge and controversies pertaining to molecular testing of MSI and MMR defects in CRC are presented.

Biomarkers in precision therapy in colorectal cancer

“…MSI testing in molecular pathology laboratories is becoming increasingly available, but requires expertise and experience in testing and interpretation. Nowadays, immunohistochemistry (IHC) shows high sensitivity and specificity in detecting MSI and could therefore offer a relatively cheap, easy to perform and universally available test for MSI, instead of a more complex polymerase chain reaction (PCR)-based MSI test [44]. Lastly, there are also socio-economic issues to resolve, such as ethical, legal and health care-related issues, before introducing MSI testing in clinical practice.…”

Ultradeep Sequencing of a Human Ultraconserved Region Reveals Somatic and Constitutional Genomic Instability

“…A hallmark of MMR deficiency is microsatellite instability (MSI), which measures the accumulation of insertions and deletions (indels) at repeated regions of the genome. Since more than 90% of HNPCC show MSI [4],[5], this has become a common diagnostic marker of MMR deficiency. Recently, large-scale mutational screenings returned the first estimations of the mutation frequency, which is the number of mutations per genome unit, associated with coding and noncoding sequences of cancer genomes [6]–[9].…”

Multicenter Phase II Trial of Temozolomide in Mycosis Fungoides/Sézary Syndrome: Correlation with O6-Methylguanine-DNA Methyltransferase and Mismatch Repair Proteins

“…Such progressive genetic defects have been extensively shown in hereditary colon carcinoma and correlated with DNA mismatch repair defects (4). Defects in mismatch repair may result in cellular resistance to TMZ, independent of MGMT activity.…”

“…Chromosomal and somatic mutations have been frequently shown in hereditary nonpolyposis colon carcinoma and correlated with mismatch repair gene defects and MSI (4–6). In addition, several reports have identified the loss of mismatch repair function leading to MSI in a number of leukemias and lymphomas (7).…”