Unfavorable pathological characteristics in familial colorectal cancer with low-level microsatellite instability

Abstract

A high degree of microsatellite instability (MSI) in colorectal cancer (CRC) is a hallmark of hereditary nonpolyposis colorectal cancer (HNPCC), caused by germline defects in the mismatch repair (MMR) genes. A low degree of instability (less than 30% of the microsatellites) is seen in a subset of tumors. To clarify the significance of this low degree of MSI phenotype, we studied the differences between patients with colorectal tumors with high-level, low-level and no MSI. Colorectal tumors with no (n ¼ 68) and low-level (n ¼ 18) MSI of patients clinically suspected of HNPCC were compared to colorectal tumors with high-level MSI (n ¼ 12) of patients that carry a pathogenic germline mutation in a MMR gene. Compared to tumors with no MSI, tumors with low-level MSI were classified more frequently as stage T3 or T4 (100% vs 68% respectively), and showed less immune response (P ¼ 0.02). No significant differences in familial CRC risk were found by comparing pedigrees of these two groups of tumors. Compared to the group of tumors with high-level MSI, the group of tumors with low-level MSI had a less suspicious family history, a higher percentage of lymph node metastasis (56 vs 17%), and less immune response. Thus, with respect to genetic risks, familial CRC can be divided into two groups: Tumors with high-level MSI and tumors with low-level or no MSI. However, tumors with low-level MSI show unfavorable pathological characteristics compared to tumors with no and tumors with high-level MSI. These differences suggest a distinct underlying biology of CRC with low-level MSI.

MSI‐L/EMAST is a predictive biomarker for metastasis in colorectal cancer patients

“…However, the reported prevalence varies according to ethnicity, number of markers, and the panels that were used for the MSI (Azzoni et al, 2011;Kets et al, 2006;Y. H. Kim et al, 2009;Mojarad et al, 2016;Rudzki et al, 2003), our results confirmed that tumors classified as MSI-L are a distinct molecular group with different clinicopathological features, however, other studies did not support the discrimination of MSI-L from MSS tumors in clinicopathological features (Kambara et al, 2001;S.…”

Genetic Instability Caused by Loss of MutS Homologue 3 in Human Colorectal Cancer

“…Families of late onset CRC with MSI-L or MSS exist (34). Therefore, it would be interesting to determine whether these families carry MSH3 germline mutations.…”

“…MSH3-deficiency is also associated with progression of disease (28, 35). MSI-L CRCs have poor clinical outcomes (34, 36, 37, 38), raising the possibility that MSH3-deficiency might contribute to metastasis in CRC. Certain genes containing di-, tri- or tetranucleotide repeats in their 5′ promoter, coding, and/or 3′ untranslated regions could be mutational targets of MSH3-deficiency, whose mutation might contribute to initiation or progression of tumors (38, 39).…”

Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients

“…This particular study focused on patients with stage I and II CRC. Several studies have examined MSI-high colorectal carcinomas and characterized both the number and phenotype of the tumor infiltrating cells [30, 31, 41, 43, 47–49, 101, 102]. Studies by Smyrk et al described an increased level of tumor infiltrating lymphocytes (TILs) in CRCs with high levels of microsatellite instability.…”