BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum

BACKGROUND AND AIMS: Mutations in BRAF have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). METHODS: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as "sessile serrated adenoma" (SSA). All tumours were screened for BRAF activating mutations. RESULTS: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001). CONCLUSIONS: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this "serrated" pathway.     

Clinicopathologic features and prognostic analysis of MSI-high colon cancer

Purpose

The objectives of the study were to estimate the incidence and clarify the clinicopathologic feature of sporadic microsatellite instability (MSI)-high (MSI-H) colon cancer. Furthermore, the role of MSI in colon cancer prognosis was also investigated.

Methods

Microsatellite status was identified by genotyping. The clinicopathologic differences between two groups (MSI-H vs. MSI-L/S) and the prognostic value of MSI were analyzed.

Results

From 1993 to 2006, 709 sporadic colon cancer patients were enrolled. MSI-H colon cancers showed significant association with poorly differentiated (28.3% vs. 7.2%, p?=?0.001), proximally located (76.7% vs. 34.5%, p?=?0.001), more high mucin-containing tumor (10.0% vs. 5.1%, p?=?0.001) and female predominance (56.7% vs. 30.2%, p?=?0.001). In multivariate analysis, MSI-H is an independent factor for better overall survival (HR, 0.459; 95% CI, 0.241–0.872, p?=?0.017).

Conclusions

Based on the hospital-based study, MSI-H colon cancers demonstrated distinguished clinicopathologic features from MSI-L/S colon cancers. MSI-H is an independent favorable prognostic factor for overall survival in colon cancer.     

Proximal colon cancer in patients aged 51–60 years of age should be tested for microsatellites instability. A comment on the Revised Bethesda Guidelines

PURPOSE: The Bethesda guidelines suggest to perform microsatellite instability (MSI) test in early onset rectal cancer and not in patients >50 years with proximal colon cancer. The aim of the study was to evaluate whether the risk of high MSI (MSI-H) is greater in proximal colon cancer of patients 51-60 years old than in early-onset rectal cancer. METHODS: Consecutive colorectal cancer (CRC) patients were evaluated. Tumor location, cancer family history, MSI status and histology were recorded. Mutations in MLH1/MSH2 were investigated in MSI-H tumors. Patients were subdivided into groups: group A, proximal colon cancer patients 51-60 years old and groups B, C and D, patients 相似文献   

Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer

Colon cancer has been viewed as the result of progressive accumulation of genetic and epigenetic abnormalities. However, this view does not fully reflect the molecular heterogeneity of the disease. We have analyzed both genetic (mutations of BRAF, KRAS, and p53 and microsatellite instability) and epigenetic alterations (DNA methylation of 27 CpG island promoter regions) in 97 primary colorectal cancer patients. Two clustering analyses on the basis of either epigenetic profiling or a combination of genetic and epigenetic profiling were performed to identify subclasses with distinct molecular signatures. Unsupervised hierarchical clustering of the DNA methylation data identified three distinct groups of colon cancers named CpG island methylator phenotype (CIMP) 1, CIMP2, and CIMP negative. Genetically, these three groups correspond to very distinct profiles. CIMP1 are characterized by MSI (80%) and BRAF mutations (53%) and rare KRAS and p53 mutations (16% and 11%, respectively). CIMP2 is associated with 92% KRAS mutations and rare MSI, BRAF, or p53 mutations (0, 4, and 31% respectively). CIMP-negative cases have a high rate of p53 mutations (71%) and lower rates of MSI (12%) or mutations of BRAF (2%) or KRAS (33%). Clustering based on both genetic and epigenetic parameters also identifies three distinct (and homogeneous) groups that largely overlap with the previous classification. The three groups are independent of age, gender, or stage, but CIMP1 and 2 are more common in proximal tumors. Together, our integrated genetic and epigenetic analysis reveals that colon cancers correspond to three molecularly distinct subclasses of disease.     

The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer

BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP) is one of the mechanisms involved in colorectal carcinogenesis (CRC). Although CIMP is probably the cause of high-frequency microsatellite instability (MSI-H) sporadic CRCs, its role in microsatellite stable (MSS) tumors is debated. The majority of MSS CRCs demonstrate chromosomal instability (CIN) with frequent loss of heterozygosity (LOH) at key tumor suppressor genes. We hypothesized that the majority of sporadic CRCs without CIN would be associated with CIMP. METHODS: We tested 126 sporadic CRCs for MSI and LOH and categorized tumors into MSI, LOH, or MSI-/LOH- subgroups. Methylation status was evaluated using 6 CIMP-related markers (MINT1, MINT2, MINT31, p16(INK4alpha), p14(ARF), and hMLH1) and 6 tumor suppressor genes (PTEN, TIMP3, RUNX3, HIC1, APC, and RARbeta2). BRAF V600E mutation analysis was performed using allele-specific polymerase chain reaction and DNA sequencing. RESULTS: We observed frequent methylation at all 12 loci in all CRCs. BRAF V600E mutations correlated with the MSI (P < .0001) and MSI-/LOH- (P = .03) subgroups. MSI and MSI-/LOH- tumors exhibited more promoter methylation than CRCs with LOH (P < .0001). We also found an inverse correlation between the frequencies of methylation and LOH (rho = -0.36; P < .0001). CONCLUSIONS: The associations between methylation frequencies at CIMP-related markers and MSI or MSI-/LOH- sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP.     

Location-related differences in sporadic microsatellite unstable colorectal cancer

BackgroundMicrosatellite unstable CRC is associated with female gender, large tumours, and poor differentiation. However, there are few reports about the characteristics and differences of sporadic microsatellite unstable CRC based on tumour location.AimsSite-specific heterogeneity of sporadic microsatellite unstable colorectal cancer (CRC) based on location was elucidated.MethodsWe enrolled 164 CRC patients with high-frequency microsatellite instability (MSI-H) from the prospective database of 2686 consecutive CRC patients who underwent surgical resection. We analysed microsatellite instability (MSI) and expression of mismatch repair (MMR) proteins (MLH1, MSH2, and MSH6).ResultsAmong the 164 MSI-H CRC, 105 (64.0%) were located in the proximal colon and 59 (36.0%) were located in the distal colon. The proximal MSI-H CRC was predominantly in female (p = 0.014), had a more aggressive differentiation (p = 0.001), was of advanced stage (p = 0.035), and had a frequent loss of MLH1 expression (p = 0.005) compared to the distal MSI-H CRC.ConclusionThere were different clinicopathologic characteristics and MMR protein expression between proximal and distal MSI-H CRC. These findings suggest that the underlying carcinogenic pathway or molecular background differs according to location, despite being microsatellite unstable CRC.     

Association between fasting serum glucose levels and incidence of colorectal cancer in Korean men: The Korean Cancer Prevention Study-II

Introduction

The incidence of colorectal cancer (CRC) is steadily increasing worldwide. Numerous studies have demonstrated that diabetes mellitus is related to an increased risk of CRC; however, the association between impaired fasting glucose and CRC is unclear. Therefore, we evaluated the correlation between fasting serum glucose (FSG) levels and the incidence of CRC, which can be used to develop novel methods for preventing CRC.

Methods

A total of 175,677 individuals from the Korean Metabolic Syndrome Research Initiative study were enrolled between 2004 and 2011. The incidence of CRC was assessed during a mean follow-up of 4.7 years. Hazard ratios (HR) for CRC according to FSG levels were calculated with the Cox proportional hazard model adjusted for age, sex, body mass index, smoking status, alcohol consumption, and regular exercise.

Results

The risk of developing CRC in subjects with high FSG was significant (HR, 1.45; 95% confidence interval [CI], 1.10–1.90), and the risk was higher in men (HR, 1.51; 95% CI, 1.12–2.05). The HR of rectal cancer, but not colon cancer, was significantly higher both in the total population and in men in the high FSG group.

Conclusions

The incidence of CRC positively correlated with FSG levels in men. Rectal cancer incidence was especially correlated with high FSG in the site-specific analysis. Therefore, serum glucose levels maybe a potential marker of colorectal cancer. Early detection and intervention for controlling elevated glucose levels may be indicated as a way to prevent carcinogenesis.     

Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer

BACKGROUND & AIMS: The concept of a CpG island methylator phenotype (CIMP), especially in microsatellite stable colon cancer, is not accepted universally. We therefore evaluated a large population-based sample of individuals with colon cancer and used univariate and multivariate analyses of CIMP with clinicopathologic variables and tumor mutations to determine the biologic relevance of this phenotype. METHODS: A total of 864 tumors from individuals with colon cancer from Utah and Northern California were evaluated by methylation-specific polymerase chain reaction of CpG islands in hMLH1, methylated in tumors (MINT) 1, MINT 2, MINT 31, and CDKN2A (p16). CIMP high was defined as methylation at 2 or more of these loci. The BRAF V600E mutation was determined by sequencing. Microsatellite instability had been determined previously. RESULTS: In a multivariate analysis of microsatellite stable tumors, CIMP high was related significantly to the V600E BRAF mutation (odds ratio, 39.52; 95% confidence interval, 11.44-136.56), KRAS2 mutations (odds ratio, 2.22; 95% confidence interval, 1.48-3.34), older age (P trend = .03), and increased stage (P trend = .03), and these tumors were less likely to be located in the distal colon (odds ratio, .42; 95% confidence interval, .27-.65). CIMP-high unstable tumors also were more likely to have the V600E BRAF mutation, be located proximally, and occur in older individuals (in univariate analyses). However, CIMP-high unstable tumors were significantly more likely than their stable counterparts to be KRAS2 wild type, TP53 wild type, poorly differentiated, proximally located, occur at lower stages, and have the BRAF V600E mutation (64.1% vs 17.6%). CONCLUSIONS: The evaluation of a large, population-based sample strongly supports the biologic relevance of CIMP in colon cancer. However, the presence or absence of microsatellite instability has a major effect on the expression of this phenotype.     

Association of Adenoma Detection Rate and Adenoma Characteristics With Colorectal Cancer Mortality After Screening Colonoscopy

Background & AimsThe adenoma detection rate (ADR) and characteristics of previously resected adenomas are associated with colorectal cancer (CRC) incidence and mortality. However, the combined effect of both factors on CRC mortality is unknown.Patients and methodsUsing data of the Austrian quality assurance program for screening colonoscopy, we evaluated the combined effect of ADR and lesion characteristics on subsequent risk for CRC mortality. We analyzed mortality rates for individuals with low-risk adenomas (1–2 adenomas <10 mm), individuals with high-risk adenomas (advanced adenomas or ≥3 adenomas), and after negative colonoscopy (negative colonoscopy or small hyperplastic polyps) performed by endoscopists with an ADR <25% compared with ≥25%. Cox regression was used to determine the association of combined risk groups with CRC mortality, adjusted for age and sex.ResultsWe evaluated 259,885 colonoscopies performed by 361 endoscopists. A total of 165 CRC-related deaths occurred during the follow-up period, up to 12.2 years. In all risk groups, CRC mortality was higher when colonoscopy was performed by an endoscopist with an ADR <25%. Compared with negative colonoscopy with an ADR ≥25%, CRC mortality was similar for individuals with low-risk adenomas irrespective of ADR (for ADR ≥25%: adjusted hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.59–2.49; for ADR <25%: adjusted HR, 1.25; 95% CI, 0.64–2.43) and after negative colonoscopy with ADR <25% (adjusted HR, 1.27; 95% CI, 0.81–2.00). Individuals with high-risk adenomas were at significantly higher risk for CRC death if colonoscopy was performed by an endoscopist with an ADR <25% (adjusted HR, 2.25; 95% CI, 1.18–4.31) but not if performed by an endoscopist with an ADR ≥25% (adjusted HR, 1.35; 95% CI, 0.61–3.02).ConclusionsOur study adds important evidence for mandatory assessment and monitoring of performance quality in screening colonoscopy. High-quality colonoscopy was associated with a lower risk for CRC death, and the impact of ADR was strongest for individuals with high-risk adenomas.     

Better survival of right-sided than left-sided stage II colon cancer: a propensity scores matching analysis based on SEER database

Background/AimsMost studies have found that right-sided colon cancer (RCC) has worse prognosis than left-sided colon cancer (LCC), especially in stage III, but the reported prognosis of stage II colon cancer is variable. This study aimed to evaluate the impact of tumor location on survival outcomes in stage II colon cancer.Materials and MethodsPatients with stage II colon cancer were identified in the Surveillance, Epidemiology, and End Results database from 2004 to 2009. The effect of tumor location on overall survival and cancer-specific survival was analyzed using Cox proportional hazards regression models and propensity score matching.ResultsOf 16,519 patients, 69.6% had RCC and30.4% had LCC. In unadjusted analyses, RCC had a 13% increased overall mortality risk (hazards ratio [HR], 1.13; 95% confidence interval [CI], 1.07–1.19; p<0.001) but an18% reduction in cancer-specific mortality risk compared with LCC (HR, 0.82; 95% CI, 0.76–0.89; p<0.001). After propensity scores matching analyses, RCC had a 21% reduced overall mortality risk (HR, 0.79; 95% CI, 0.72–0.87; p<0.001) and a 49% reduction in cancer-specific mortality risk compared with LCC (HR, 0.51; 95% CI, 0.44–0.60; p<0.001).ConclusionWhen adjusted for multiple clinicopathological features, stage II RCC showed better prognosis than stage II LCC.     

Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer

AIM: To investigate the prognostic role of KRAS and BRAF mutations after adjustment for microsatellite instability(MSI) status in Japanese colorectal cancer(CRC) population.METHODS: We assessed KRAS and BRAF mutations and MSI status in 813 Japanese patients with curatively resected, stage Ⅰ-Ⅲ CRC and examined associations of these mutations with disease-free survival(DFS) and overall survival(OS) using uni- and multivariate Cox proportional hazards models.RESULTS: KRAS and BRAF mutations were detected in 312(38%) of 812 and 40(5%) of 811 tumors, respectively. KRAS mutations occurred more frequently in females than in males(P = 0.02), while the presence of BRAF mutations was significantly associated with the female gender(P = 0.006), proximal tumor location(P 0.001), mucinous or poorly differentiated histology(P 0.001), and MSI-high tumors(P 0.001). After adjusting for relevant variables, including MSI status, KRAS mutations were associated with poorer DFS(HR = 1.35; 95%CI: 1.03-1.75) and OS(HR = 1.46; 95%CI: 1.09-1.97). BRAF mutations were poor prognostic factors for DFS(HR = 2.20; 95%CI: 1.19-4.06) and OS(HR = 2.30; 95%CI: 1.15-4.71). Neither the BRAF by MSI interaction test nor the KRAS by MSI interaction test yielded statistically significant results for DFS and OS.CONCLUSION: KRAS and BRAF mutations are associated with inferior survival, independent of MSI status, inJapanese patients with curatively resected CRC.     

Increased Risk of Cancer after Cholecystectomy: A Nationwide Cohort Study in Korea including 123,295 Patients

Background/AimsContradictory findings on the association between cholecystectomy and cancer have been reported. We aimed to investigate the risk of all types of cancers or site-specific cancers in patients who underwent cholecystectomy using a nationwide dataset.MethodsSubjects who underwent cholecystectomy from January 1, 2007, to December 31, 2014, who were older than 20 years and who underwent an initial baseline health check-up within 2 years were enrolled. Those who were diagnosed with any type of cancer before the enrollment or within 1 year after enrollment were excluded. Ultimately, patients (n=123,295) who underwent cholecystectomy and age/sex matched population (n=123,295) were identified from the database of the Korean National Health Insurance Service. The hazard ratio (HR) and 95% confidence interval (CI) for cancer were estimated, and Cox regression analysis was performed.ResultsThe incidence of cancer in the cholecystectomy group was 9.56 per 1,000 person-years and that in the control group was 7.95 per 1,000 person-years. Patients who underwent cholecystectomy showed an increased risk of total cancer (adjusted HR, 1.19; 95% CI, 1.15 to 1.24; p<0.001), particularly leukemia and malignancies of the colon, liver, pancreas, biliary tract, thyroid, pharynx, and oral cavity. In the subgroup analysis according to sex, the risk of developing cancers in the pancreas, biliary tract, thyroid, lungs and stomach was higher in men than in women.ConclusionsPhysicians should pay more attention to the possibility of the occurrence of secondary cancers among patients who undergo cholecystectomy.     

Efficacy of Surgery and Adjuvant Therapy in Older Patients With Colorectal Cancer: A STROBE-compliant article

The present study aimed to assess the efficacy of surgery and adjuvant therapy in older patients (age ≥70 years) with colorectal cancer (CRC). Older CRC patients are under-represented in available clinical trials, and therefore their outcomes after receiving surgery and adjuvant therapy are unclear. From two prospective Swedish databases, we assessed a cohort of 1021 patients who underwent curative surgery for stage I, II, or III primary CRC, with or without adjuvant chemotherapy/radiotherapy. Of the patients with colon cancer (n = 467), 182 (39%) were aged <70 years, 162 (35%) aged 70 to 80 years, and 123 (26%) were aged ≥80 years. Of rectal cancer patients (n = 554), 264 (48%) were aged <70 years, 234 (42%) aged 70 to 80 years, and 56 (10%) aged ≥80 years. Older patients with either colon or rectal cancer had higher comorbidity than did younger patients. Older patients with colon cancer had equivalent postoperative morbidity and 30-day mortality to younger patients. Rectal cancer patients aged ≥80 years had a higher 30-day mortality than younger patients (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.6–4.55; P = 0.03). For either colon or rectal cancer, adjuvant chemotherapy compromised the 5-year overall survival (OS) of older patients with stage II disease and had no effect on those with stage III disease. Receiving adjuvant chemotherapy was a poor factor of OS for older patients with either colon (HR 1.88, 95% CI: 1.20–4.35, P = 0.03) or rectal cancer (HR 1.72, 95% CI: 1.05–2.26, P = 0.004). Preoperative short-course radiotherapy improved both OS and local control for older patients with stage III rectal cancer and had no effect on those with stage II disease. Radiotherapy was a favorable factor for the OS of the older patients with rectal cancer (HR 0.42, 95% CI: 0.21–3.57, P = 0.01). In conclusion, Older CRC patients had equal safety of surgery as younger patients, except rectal cancer patients aged ≥80 years that had a higher mortality. Adjuvant 5FU-based chemotherapy did not benefit older CRC patient, while neoadjuvant radiotherapy improved the prognosis of older patients with stage III rectal cancer.     

Vitamin D and estrogen receptor gene polymorphisms and the risk of colorectal cancer in Bulgaria

Background and aims Different epidemiological studies report the protective effect on colorectal cancer (CRC) exerted by vitamin D₃ intake, estrogen replacement therapy, and increase of the risk of microsatellite instability (MSI) in CRC by withdrawal of estrogens. The aim of our study was to search for association between CRC and polymorphisms in estrogen receptor-α (ER-α) and Vitamin D receptor (VDR) genes. Materials and methods We analyzed the PvuII and XbaI polymorphisms from the ER-α gene and the BsmI polymorphism of the VDR gene in 140 patients with CRC (subsequently divided according to their MSI status) and 94 controls. Results We have demonstrated that the presence of the PvuII pp genotype increased the risk of developing MSI(+) tumors about three times compared to MSI(−) tumors [odds ratio (OR)=3.09, 95% confidence interval (CI) 0.88–10.91]. The effect of the XbaI xx genotype was similar (OR=2.08, 95% CI 0.49–8.81). Our results for the VDR BsmI polymorphism showed an increased risk for CRC in bb carriers (OR=1.8, 95% CI 0.81–4.05). Conclusion We conclude that PvuII and XbaI polymorphisms in the ER-α gene were associated with the risk of developing MSI in CRC patients. The BsmI polymorphism in the VDR gene was linked to the risk of developing CRC.     

Dinucleotide microsatellite repeats are essential for the diagnosis of microsatellite instability in colorectal cancer in Asian patients

AIM: The molecular diagnosis of microsatellite instability (MSI) in colorectal cancer (CRC) is based on the analysis of five microsatellite markers. Among them, the two mononu-cleotide microsatellite repeats are considered more informative for this analysis than the three dinucleotide ones. The aim of this study is to establish the most relevant markers for MSI analysis in colorectal cancers from Asian patients. METHODS: The MSI analysis of 143 CRC cases in a routine molecular diagnostic laboratory was reviewed. Analysis by fluorescence-based PCR of the five recommended microsatellites was performed, followed by data interpretation according to internationally accepted guidelines. The results were analyzed to address (1) the rate of success in the analysis of histopathological samples not specifically prepared for molecular analysis; (2) the relative importance of individual markers in the diagnosis of high-MSI (H-MSI). RESULTS: MSI analysis was unsuccessful in 34 cases (24%), but for tissues archived in recent years the unsuccessful rate was 5%. We found the D2S123 marker the most vulnerable to inadequate tissue preservation, failing to amplify in 58 instances. Approximately 30% (32/109) of the cases were H-MSI, while 7/109 (6%) were low-MSI. A detailed analysis of the H-MSI cases revealed that the dinucleotide repeats (and D5S346 in particular) were more relevant than the mononucleotide repeats in assigning the correct MSI status. CONCLUSION: The analysis of dinucleotide repeats is essential for the establishment of MSI status in Asian CRC patients.     

Microsatellite instability in patients with multiple primary cancers of the gastrointestinal tract

BACKGROUND: Little is known about the genetic alterations in multiple primary cancers of the gastrointestinal tract. Microsatellite instability (MSI) is frequently observed in hereditary non-polyposis colorectal cancer (HNPCC), and multiple primary cancers is a feature of this syndrome. AIMS: To identify MSI incidence, target gene mutation, and mismatch repair (MMR) protein status in patients with multiple primary cancers of the gastrointestinal tract. SUBJECTS: Fifty seven cancers from 22 Japanese patients with multiple primary cancers of the stomach, duodenum, colon, and rectum. METHODS: MSI was examined at 5-7 microsatellite loci. Mutation analysis for TGFbetaRII, IGFIIR, and BAX was performed in cancers with MSI. MMR protein status was examined by immunohistochemical analysis using a monoclonal antibody against hMSH2 and hMLH1. RESULTS: MSI was observed in 16 of 22 patients (73%) and in 29 of 57 lesions (51%). High frequency MSI (MSI-H) was found often in patients with multiple cancers in the same organ (p = 0.042), especially in multiple gastric cancer patients (p = 0.038). In contrast, patients with multiple cancers in different organs had a tendency to show low frequency MSI (MSI-L) or microsatellite stable (MSS) phenotype. Both target gene mutation and decreased expression of MMR protein were found only in seven lesions of three patients with MSI at more than four microsatellite loci. CONCLUSIONS: These results suggest that genetic instability may play an important role in the development of multiple gastrointestinal cancers but there may be different genetic alterations between multiple gastrointestinal cancers of the same and different organs.     

Prognostic significance of microsatellite instability in sporadic colorectal cancer

Background and aims Colorectal cancers exhibiting microsatellite instability (MSI) appear to have unique biological behavior. The influence of MSI on the prognosis of sporadic colorectal cancers is controversial and requires further investigation. The aim of this study was to analyze the association between MSI status and clinicopathological features and prognosis in sporadic colorectal cancer patients.Patients and methods Of the 322 consecutive colorectal cancer patients operated upon at the Seoul National University Hospital between January and December 1998, we examined the clinicopathological features and prognosis of 248 patients with sporadic primary colorectal cancer. The MSI status of these 248 patients has been reported in a previous study. Of the 248 patients, 23 (9.3%) had MSI+ tumors. The patients clinicopathological parameters were obtained from their medical records, and follow-up and survival data were obtained from medical records and phone calls.Results MSI+ sporadic colorectal cancers were found predominantly in the proximal colon (p<0.001) and were associated with poor differentiation (p=0.030), a lower preoperative serum carcinoembryonic antigen (CEA) level (p=0.012), and less frequent systemic metastasis (p=0.034) than MSI– tumors. Low tumor grade (p=0.022), low tumor T-stage (p=0.002), no lymph node metastasis (p<0.001), no systemic metastasis (p<0.001), adjuvant chemotherapy (p<0.001) and MSI+ status (p=0.038) were independent favorable prognostic factors for survival in sporadic colorectal cancer patients.Conclusion MSI status was an independent favorable prognostic factor for survival in sporadic primary colorectal cancer patients.     

Impact of Visceral Fat on Survival and Metastasis of Stage III Colorectal Cancer

Background/AimsPrevious studies have investigated the relationship between visceral obesity and the risk of colorectal tumors. Visceral obesity may affect the outcome of colorectal cancer (CRC), including survival and metastasis. We investigated the associations between visceral adipose tissue and oncologic outcomes in stage III CRC.MethodsFour hundred seventy-two patients with stage III CRC were identified. Subcutaneous and visceral adipose tissue areas were measured volumetrically via computed tomography for each patient at different levels of the lumbar spine. After adjusting for age, sex, and other clinical factors, the effects of visceral adipose tissue area on mortality and recurrence were assessed using Cox proportional hazard regression.ResultsIn univariate and multivariate analyses, a higher visceral adipose tissue to total adipose tissue (VT) ratio (hazard ratio [HR], 1.041; 95% CI, 1.008 to 1.075; p=0.015) and higher visceral adipose tissue to subcutaneous adipose tissue (VS) ratio (HR, 1.016; 95% CI, 1.005 to 1.028; p=0.006) were both associated with poor CRC-specific survival. Interestingly, in the evaluation of each site of recurrence, a higher VT ratio (HR, 1.069; 95% CI, 1.010 to 1.131; p=0.020) and higher VS ratio (HR, 1.024; 95% CI, 1.003 to 1.045; p=0.023) were both related to a higher risk of peritoneal seeding and tumor recurrence. The VT ratio at the L3–L4 level was significantly associated with a higher risk of peritoneal seeding and tumor recurrence (HR, 4.969; 95% CI, 1.303 to 18.949; p=0.019), while other levels showed no such relationship.ConclusionsVisceral obesity is closely related to increased risks of CRC-specific mortality and peritoneal seeding metastasis in stage III CRC patients.