Research Article: Microsatellite instability is inversely associated with type 2 diabetes mellitus in colorectal cancer

Date Published: April 19, 2019

Publisher: Public Library of Science

Author(s): Yujiro Nakayama, Takeru Iijima, Rika Wakaume, Keiichi Takahashi, Hiroshi Matsumoto, Daisuke Nakano, Michiko Miyaki, Tatsuro Yamaguchi, Bente A. Talseth-Palmer.


Microsatellite instability (MSI) is a clonal change in the number of repeated DNA nucleotide units in microsatellites. High-frequency MSI (MSI-H) colorectal cancers (CRCs) are known to have different clinicopathological features compared with microsatellite stable (MSS) CRCs. In addition, previous studies have shown that type2 diabetes mellitus (T2DM) is a risk factor for malignant tumors including CRCs. The aim of this study was to investigate the relationship between T2DM and MSI-H colorectal cancer.

The study design is a single center, cross-sectional study. Data from a series of 936 patients with CRCs were collected and MSI status was assessed.

In total, 29 (3.1%) and 907 (96.9%) tumors were classified as having MSI-H and low-frequency microsatellite instability or being MSS (MSS), respectively. Of the 936 patients, 275 (29.6%) were associated with T2DM. One (3.4%) of the 29 MSI-H patients and 274 (30.2%) of the 907 MSS patients had T2DM. Thus, the incidence of T2DM was significantly less frequent in MSI-H compared with MSS patients (Fisher’s exact test: p = 0.0007).

We conclude that MSS tumors are significantly more common than MSI-H tumors among individuals with T2DM.

Partial Text

Colorectal cancer (CRC) is one of the most common solid tumors, and details associated with its carcinogenesis have been intensively studied. Some colorectal cancers are microsatellite stable (MSS). The typical development of MSS tumors proceeds stepwise by the inactivation of increasing numbers of tumor suppressor genes, including the APC and p53 genes, through mutation as well as loss of heterozygosity (LOH) and the activation of oncogenes such as KRAS [1, 2].

Total of 936 CRC patients were enrolled during study period in this study. All patients underwent surgical resection of the primary tumor and the diagnosis of adenocarcinoma was made pathologically. None received neo-adjuvant chemotherapy or radiotherapy. The clinical and pathological characteristics of the patients are shown in Table 1. Of the 936 colorectal cancers, 29 (3.1%) and 907 (96.9%) tumors were classified as MSI-H and MSS, respectively. Significant differences between MSI-H and MSS cancers were observed with respect to sex (p = 0.022), age (p = 0.007), tumor location (p < 0.0001) and histology (p < 0.0001); whereas, there were no significant differences with respect to UICC classification (p = 0.57). One hundred seventy-five (18.7%) patients had T2DM and no patient had type 1 diabetes mellitus. The incidence of T2DM was significantly less frequent in MSI-H than MSS patients (p = 0.0007). However, there was no significant difference in BMI between MSI-H and MSS patients (p = 0.65). Of the 936 CRC patients, 277 (29.6%) had KRAS mutation and 49 (5.2%) had BRAF mutation. None of the 29 MSI-H patients were a KRAS mutation, whereas 277 (30.5%) of the 907 MSS patients had a KRAS mutation, and frequency of KRAS mutation was significantly different between MSI-H and MSS (p < 0.0001). Inversely, frequency of BRAF mutation was significantly high in MSI-H patients than in MSS patients (p < 0.0001). According to logistic regression analysis, age, tumor location, histology and T2DM status were independent factors in MSI-H tumor (Table 2). Our study findings indicated that T2DM is significantly less common among MSI-H patients compared with MSS patients. This is the first report to indicate that T2DM may be associated with MSS CRC. There have been no previous reports of a relationship between T2DM and MSI status in CRC, even though it is well known that the incidence of malignant tumors is increased in patients with T2DM [7, 21].   Source: