Microsatellite instability is inversely associated with type 2 diabetes mellitus in colorectal cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: We conclude that MSS tumors are significantly more common than MSI-H tumors among individuals with T2DM.

Clinicopathological and molecular differences between right-sided and left-sided colorectal cancer in Japanese patients.

BACKGROUND: The aim of this study was to clarify clinicopathological features, frequencies of molecular biomarkers, and prognoses in Japanese colorectal cancer patients and compare them with right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC). METHODS: We consecutively selected 575 colorectal cancer patients who underwent surgical resection from 2008 to 2011. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum. Frequencies of KRAS gene mutation, BRAF gene mutation, microsatellite instability (MSI), l18qLOH and CpG island methylator phenotype (CIMP) were statistically analyzed between groups. RESULTS: Tumors were located in the RCC in 26.3% of patients and in the LCRC in 73.7%. Elderly patients, females and advanced diseases were significantly more frequent in the RCC group than in the LCRC group. However, venous invasion was significantly more frequent in LCRC than in RCC. Between groups, BRAF mutant type, KRAS mutant type, MSI and CIMP+ were significantly more frequent in RCC, whereas 18qLOH was significantly more frequent in LCRC. In overall survival, RCC demonstrated poor prognosis compared with LCRC; however, age, gender, stage, lymphatic invasion, KRAS status and BRAF status rather than tumor location were independent prognostic factors. In addition, the independent prognostic factors in RCC were different from those in LCRC in each stage. However, the consistency between OS and DFS was not observed in this study, excluding lymphatic invasion in LCRC. CONCLUSION: Comparing RCC with LCRC, RCC is different from LCRC in clinicopathological features, molecular biomarkers and prognostic factors in Japanese colorectal cancer patients. Since the proportions of molecular biomarkers of CRC in this study are different from Western CRCs, further studies are required to clarify the clinicopathological differences between Japanese CRCs and Western CRCs.

Tumor development in Japanese patients with Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) patients have a high risk of developing various tumors. This study aimed to clarify the characteristics of tumors developing in LS patients. METHODS: This is a retrospective review of 55 LS patients treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital. RESULTS: The median age at the diagnosis of the first malignant tumor and first LS-related tumor was 44 (range, 19-65) and 44 (range, 24-66) years, respectively. Of the 55 LS patients with developing malignant tumors, 45 (93.8%) developed an LS-related tumor as the first malignant tumor. Colorectal cancer (CRC) developed in 47 patients (85.4%), followed by endometrial cancer (n = 13, 56.5%) in females and gastric cancer (n = 10, 18.1%). In 6 gastric cancer patients, Helicobacter pylori was detected in resected specimens. Twenty-nine patients (52.7%) developed CRC and extra-colonic tumors; of these, 15 patients (48.3%) had mutations in MLH1, 10 (58.8%) in MSH2, and 4 (57.1%) in MSH6. At the age of 50, the cumulative incidence was 50.9% [95% confidence interval (CI), 36.9-63.3%] for CRC, 17.4% (95% CI, 5.2-35.6%) for endometrial cancer, and 5.5% (95% CI, 1.4-13.8%) for gastric cancer. Eight gastric cancer, one breast cancer patient, five bladder cancer patients, and one prostate cancer patient demonstrated loss of expression of the mismatch repair (MMR) protein; patients with thyroid cancer, spindle cell sarcoma, and giant cell tumors did not demonstrate this. CONCLUSION: Gastric cancer incidence was high in Japanese patients with LS and associated with H. pylori infection. MMR protein deficiency caused the development of malignant tumors in LS patients.

Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer.

BACKGROUND: The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients. METHODS: Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis. Of the latter subgroup, 21 (75%) harbored MMR germline mutations. RESULTS: The following were more frequent with sporadic MSI than with Lynch syndrome associated cancers: poor differentiation (50.0 vs. 7.1%, P = 0.0002), especially solid type (30.6 vs. 3.6%, P = 0.0061); medullary morphology (19.4 and 0%, P = 0.015), Crohn-like lymphoid reaction (50.0 vs. 25.0%, P = 0.042), and PD-L1 expression (25.0 vs. 3.6%, P = 0.034). However, the groups did not differ in terms of the mean invasive front and intratumoral CD8-positive cell densities. In a logistic regression analysis, PD-L1 expression correlated with poor differentiation (odds ratio: 7.65, 95% confidence interval: 1.55-37.7, P = 0.012), but not with the difference between sporadic MSI cancer and Lynch-syndrome-associated cancer (odds ratio: 4.74, 95% confidence interval: 0.50-45.0, P = 0.176). CONCLUSIONS: Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.

Colorectal Cancer with BRAF D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis.

OBJECTIVE: BRAF D594G mutations in colorectal cancer patients are not clearly understood. We retrospectively investigated the clinicopathological features of colorectal cancers with BRAF D594G mutations. METHODS: We selected 908 colorectal cancer patients who underwent surgical resection from January 2008 to January 2013, and assessed BRAF, KRAS, microsatellite instability, and CpG island methylator phenotype (CIMP). RESULTS: We detected BRAF D594G in 7 patients and BRAF V600E in 45 patients. The clinicopathological features of cancers with BRAF D594G mutation were similar to those with BRAF wild-type, but differed from those with BRAF V600E mutations. Regarding microsatellite instability status, 44.4% of cases with BRAF V600E mutations exhibited high microsatellite instability, compared to 14.3% of those with BRAF D594G mutations and 4.4% of those with BRAF wild-type. There were no CIMP-positive tumors in cancers with BRAF D594G mutations, whereas 67.8% of tumors with BRAF V600E mutations were CIMP-positive. In stage IV cancers, the survival rates of patients at 2 years were 8.5, 50.0, and 68.2% in the BRAF V600E mutation, BRAF D594G mutation, and BRAF wild-type groups, respectively. CONCLUSION: Colorectal cancers with BRAF D594G mutations exhibit similar clinicopathological features, microsatellite instability status, and prognosis as those with BRAF wild-type.

Underexpression of miR-126 and miR-20b in hereditary and nonhereditary colorectal tumors.

OBJECTIVES: The aim of the study was to determine the significance of miR-126 and miR-20b in colorectal carcinogenesis. METHODS: We analyzed the expressions of miR-126 and miR-20b in 136 colorectal tumors from 39 microsatellite stable (MSS) tumors, 23 high microsatellite instability (MSI-H) tumors, 16 Lynch syndrome, and 58 familial adenomatous polyposis (FAP) tumors including adenoma, intramucosal carcinoma, and invasive carcinoma. RESULTS: All four kinds of tumors showed underexpression of both miR-126 and miR-20b. The frequency of miR-126 downregulation was 100.0% in FAP adenomas, 85.7% in FAP intramucosal carcinomas, 78.9% in invasive carcinomas, 81.3% in Lynch syndrome tumors, 68.4% in MSS tumors, and 65.4% in MSI-H tumors. The frequency of miR-20b downregulation was 64.0% in FAP adenomas, 50.0% in FAP intramucosal carcinomas, 73.3% in invasive carcinomas, 62.5% in Lynch syndrome tumors, 79.5% in MSS tumors, and 91.3% in MSI-H tumors. The current study demonstrated underexpression of miR-126 and miR-20b in various types of colorectal cancer. These findings support the hypothesis that angiogenesis results from underexpressions of miR-126 and miR-20b and occurs as an early event in colorectal carcinogenesis. CONCLUSIONS: Underexpression of miR-126 and miR-20b was observed in various types of colorectal cancer, and occurs as an early event of colorectal carcinogenesis in FAP tumors.