A prospective analysis of microsatellite instability as a molecular marker in colorectal cancer

BACKGROUND: Microsatellite instability (MSI) may be a molecular marker of colorectal tumor biology. We sought to evaluate the incidence and significance of MSI in an unselected colorectal cancer population. METHODS: Colorectal cancer cases from a community health system were prospectively evaluated for MSI and patient outcomes monitored. RESULTS: Of 240 eligible, 140 underwent testing; 43 (31%) had high-frequency MSI (MSI-H). Those with MSI-H tumors presented with earlier disease stage (P = .014) and lymphocytic infiltration (P < .001). Stage III MSI-H patients trended toward improved disease-free survival (P = .065). MSI-H patients were more likely to have other primary malignancies. CONCLUSIONS: Prevalence of MSI-H in the general colorectal cancer population is higher than previously reported. MSI testing of colorectal cancers is useful as part of a molecular profile to stratify patients for prognosis, treatment, and further study. Patients with MSI-H tumors are more likely to have other primary malignancies, suggesting a role for heightened screening.     

Microsatellite and chromosomal stable colorectal cancers demonstrate poor immunogenicity and early disease recurrence

Objective  Colorectal cancers may demonstrate chromosomal instability (CSI) or microsatellite instability (MSI-H). A third group of microsatellite and chromosome stable (MACS) colorectal cancer has been described more recently. Patients with MSI-H colorectal cancers demonstrate improved outcome and a pronounced inflammatory infiltrate. Enhanced host immune response and increased immunogenicity might explain these observations. This study aims to further characterize colorectal cancer immunogenicity.
Method  Microsatellite stability status was determined in resected tumour samples. Microsatellite stable (MSS) tumour samples were stratified by DNA ploidy status, as determined by flow cytometry into aneuploid MSS (CSI) and diploid MSS (MACS) cancers. Lymphocyte proliferation, quantified by bromodeoxyuridine incorporation assays assessed tumour protein immunogenicity and ELISA assays quantified inflammatory cytokine release. Kaplan–Meier survival curves and multivariate analyses were used to determine prognostic value.
Results  Patients with MSI-H colorectal cancer had improved outcome but those with MACS cancers undergoing curative surgery had significantly poorer disease-free survival ( P  = 0.002). The MACS phenotype was an independent predictor of poor outcome (HR = 2.44, 1.33–4.47, P  = 0.004). Lymphocyte proliferation assays confirmed enhanced immunogenicity of MSI-H proteins and reduced immunogenicity of MACS proteins ( P  < 0.0001). In vitro levels of IFN-γ ( P  = 0.004) and IL-18 ( P  < 0.0001) mirrored these differences in lymphocyte activity.
Conclusions  Stratification of colorectal cancer by MSI and ploidy status may have prognostic value in patients undergoing curative surgery. MSI-H cancers display enhanced immunogenic properties but the immune response to MACS cancers appears to be absent and this may contribute to their poor prognosis.     

Clinicopathological and molecular biological features of colorectal cancer in patients less than 40 years of age

BACKGROUND: The aim of the present study was to identify the clinicopathological and molecular biological characteristics of early-onset colorectal cancers. METHODS: The clinicopathological and molecular biological parameters of 138 consecutive patients with colorectal cancer aged less than 40 years were compared with those of 339 patients aged 60 years or more. RESULTS: The younger patients with colorectal cancer had more mucin-producing (14.5 versus 4.7 per cent; P < 0.001) and poorly differentiated (7.2 versus 3.3 per cent; P = 0.015) tumours, a higher incidence of synchronous (5.8 versus 1.2 per cent; P = 0.007) and metachronous (4.0 versus 0.6 per cent; P = 0.023) colorectal cancers, and more advanced tumour stage (P < 0.001) than older patients. The operative mortality rate was lower (0.7 versus 5.0 per cent; P = 0.026), and cancer-specific survival was similar (in stage I, II and III disease; P > 0.05) or better (in stage IV disease; 95 per cent confidence interval 22.50 to 28.41 versus 12.61 to 17.05 months; P < 0.001). There was a higher percentage of normal p53 expression (61.1 versus 46.8 per cent; P = 0.023) and high-frequency microsatellite instability (MSI-H) (29.4 versus 6.3 per cent; P < 0.001), and a similar family history of cancer (17.5 versus 14.2 per cent; P > 0.05), compared with older patients. CONCLUSION: Young patients with colorectal cancer have several distinct clinicopathological and molecular biological features. The mechanisms underlying the inconsistency between the presence of MSI-H and a family history of cancer in these early-onset colorectal cancers deserve further investigation.     

Microsatellite instability in gastrointestinal tract tumours

Although a number of studies have documented microsatellite instability (MSI) in gastrointestinal tumours, the clinical significance is uncertain. In this study the MSI status and clinicopathological features were examined in gastric and colorectal tumours. Eighty-four gastrointestinal tumours were examined for MSI. Normal and tumour DNA isolated from the same patients were analysed at five different microsatellite loci. Clinical features of these patients were also collated and compared with MSI status. High level MSI (MSI-H) (as defined by instability in 2 or more microsatellites) was detected in 6 out of 47 (13%) colon tumours and 6 of 37 (16%) gastric tumours. The frequency of MSI-H between these groups was not statistically significant (P = 0.36). There was no significant correlation with patient age or gender, UICC stage, or degree of differentiation of the tumour. This was true both when analysed as a group, as well as when divided into colon and gastric sites. Our results confirm that a proportion of sporadic tumours from the colon and stomach exhibit an MSI-H phenotype. However, there was no significant relationship between the presence of MSI and any of the clinicopathological characteristics studied.     

The mechanism of microsatellite instability is different in synchronous and metachronous colorectal cancer

MLH1 promoter hypermethylation has been described as the primary mechanism for high-frequency microsatellite instability (MSI-H) in sporadic colorectal cancers (CRCs). The underlying molecular mechanism for microsatellite instability (MSI) in synchronous and metachronous CRCs is not well described. A total of 33 metachronous CRC patients and 77 synchronous CRC patients were identified from 2884 consecutive patients undergoing cancer surgery in an academic center. Evaluable tumors were tested for MSI, immunohistochemistry for MLH1 and MSH2 protein expression, and hypermethylation of the MLH1 promoter. MSI-H tumors were found in 12 (36%) metachronous CRC patients and 29 (38%) synchronous CRC patients. MSI-H metachronous CRC patients were younger at index cancer diagnosis (64 vs. 76 years, P = 0.01) and more often were diagnosed before 50 years of age (4 of 12 vs. 0 of 29, P = 0.005). Loss of MLH1 expression associated with promoter hypermethylation was common in all patients, although more common in MSI-H synchronous patients (50% metachronous vs. 83% synchronous, P = 0.03). Overall, MLH1 promoter hypermethylation was seen in 7 of 17 (41%) metachronous and 44 of 54 (81%) synchronous MSI-H CRCs tested (P = 0.004). Although MSI occurred with equal frequency among patients with synchronous and metachronous CRCs, the underlying mechanism for MSI was different. Observed differences in MLH1 promoter hypermethylation and patient characteristics suggest most MSI-H synchronous CRCs in our population were sporadic in origin. In contrast, more MSI-H metachronous CRCs were associated with patient and tumor characteristics suggestive of underlying hereditary nonpolyposis CRC. Presented as a poster at Digestive Disease Week 2001, Atlanta, Georgia, May 20–23, 2001.     

Clinicopathologic and molecular profiles of microsatellite unstable Barrett Esophagus-associated adenocarcinoma

Microsatellite instability (MSI) has been reported in various tumors, with colon cancer as the prototype. However, little is known about MSI in Barrett esophagus (BE)-associated adenocarcinoma. Thus, the aim of this study was to compare the clinicopathologic and molecular features of BE-associated adenocarcinomas with and without MSI. The study cohort consisted of 76 patients with BE-associated adenocarcinomas (66 male, 10 female), with a mean age of 65.1 years. Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, PMS2, and CD3 and in situ hybridization for Epstein-Barr virus-encoded RNA were performed. MLH1 and PMS2 expression was lost by IHC in 5 cases (6.6%); of these, 5 showed high-level MSI (MSI-H) by polymerase chain reaction assay, and 4 showed hMLH1 promoter methylation. Histologically, tumors with MSI-H were heterogenous and included conventional adenocarcinomas with tumor-infiltrating lymphocytes (n=1), medullary carcinoma (n=2), signet ring cells (n=1), and signet ring cell and mucinous components (n=1). Compared with tumors negative for MSI by IHC, BE-associated adenocarcinomas with MSI-H were associated with older patient age (P=0.0060), lymphovascular invasion (P=0.027), and significantly larger numbers of tumor-infiltrating lymphocytes (P<0.0001). However, there was no statistical difference in overall survival between the 2 groups (P=0.285). In conclusion, MSI-H is uncommon in BE-associated adenocarcinomas, but is associated with clinicopathologic features fairly similar to sporadic microsatellite unstable colorectal cancers. Given the growing evidence that indicates lack of benefits from adjuvant therapy with fluorouracil in the colonic counterpart, it may be important to identify MSI-H in BE-associated adenocarcinomas.     

Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer

Identification of colorectal carcinomas with high levels of DNA microsatellite instability (MSI-H) is important because of the suggested prognostic and therapeutic significance associated with MSI. The role of histology in identifying MSI-H colorectal carcinomas has been suggested by some studies but not confirmed by others. Furthermore, previous studies assumed that hereditary nonpolyposis colorectal cancer (HNPCC)-associated MSI-H tumors and sporadic MSI-H tumors have similar histology. This assumption, however, has been challenged by more recent studies. In this report, we first analyzed the value of various histologic features in predicting MSI-H in a series of 218 colorectal carcinomas containing mixed HNPCC and sporadic cases [77 tumors (35%) were MSI-H by polymerase chain reaction (PCR) method]. Then, we evaluated the various histologic features comparatively in two groups extracted from the 218 cases. Group A was composed of 84 tumors from 82 patients obtained based on a strong family history (HNPCC/HNPCC-like group) (male to female ratio, 42:40; age range, 23-80 years, median, 53.5 years). Thirty-one of the 84 tumors (41.7%) were MSI-H by PCR, and all 31 cases were HNPCC by Amsterdam criteria. Group B was composed of 109 patients with no family history of colorectal cancer or HNPCC-associated cancer, obtained from surgical clinics (sporadic group) (male to female ratio, 65:69; age range, 31-84 years, median, 65 years). Thirty-five of the 109 tumors (32.1%) were MSI-H by PCR. Our results showed that, overall, poor tumor differentiation, medullary type, mucinous type, signet-ring cell component, histologic heterogeneity, and increased tumor-infiltrating lymphocytes (TILs) were features more commonly seen in MSI-H tumors than in non-MSI-H tumors. Comparative analyses showed that the overall TIL count was significantly higher in HNPCC/HNPCC-like group, and mucinous type appeared to be more frequent in HNPCC MSI-H tumors than in sporadic MSI-H tumors. However, there was no significant difference in the odds ratio for predicting MSI-H status for any of the analyzed histologic features between HNPCC/HNPCC-like group and sporadic group, indicating that differences between HNPCC and sporadic MSI-H tumors did not significantly impact on the informative value of histology in predicting MSI in the two different clinical settings. TIL counts followed by histologic heterogeneity provided the greatest sensitivity and specificity in predicting MSI status in both HNPCC/HNPCC-like and sporadic cases. Using a stepwise logistic regression model, a formula was generated that could be used to calculate the probability of a colorectal carcinoma being MSI-H based on morphologic features.     

Clinical significance of microsatellite instability in colorectal cancer

Introduction

Colorectal cancer is a heterogeneous tumor type with regard to molecular pathogenesis and genetic instability. The majority of colorectal cancers display chromosomal instability and follow the classical adenoma-carcinoma sequence of tumor progression. A subset of about 15 % of colorectal cancers, however, displays DNA mismatch repair (MMR) deficiency and the high-level microsatellite instability (MSI-H) phenotype. MSI-H colorectal cancers can occur as sporadic tumors or in the context of hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome.

Clinical relevance

The MSI-H phenotype is a hallmark of Lynch syndrome-associated cancers, which is of diagnostic relevance for the identification of Lynch syndrome mutation carriers. MSI-H colorectal cancers are characterized by a distinct clinical behavior, which results from their particular molecular pathogenesis and gives microsatellite instability testing its clinical significance. The MSI-H phenotype shows association with proximal tumor localization, a dense local lymphocyte infiltration, and a low frequency of distant organ metastasis. Moreover, MSI-H colorectal cancers have a better prognosis than their microsatellite-stable counterparts. A distinct responsiveness of MSI-H colorectal cancer patients towards chemotherapy has been shown in several studies.

Conclusions

The clinical characteristics of MSI-H cancers are closely linked to their molecular pathogenesis, and research on the molecular alteration characteristic of MSI-H cancers may provide the basis for novel diagnostic or therapeutic approaches.     

微卫星不稳定对散发性结直肠癌患者预后的影响

目的 探讨微卫星不稳定(MSI)对散发性结直肠癌预后的影响.方法 收集2004年8月至2006年9月南京中医药大学第三附属医院手术治疗并具有完整随访资料的134例结直肠癌病例,根据MSI检测结果 将其分成MSI组和微卫星稳定(MSS)组.采用单因素和多因素预后分析来评估MSI的预后价值.结果 134例患者中MSI组26例,MSS组108例.两组患者术后复发率分别为7.7%(2/26)和35.2%(38/108),差异有统计学意义(P=0.006);两组患者5年生存率分别为92.3%和63.5%,差异亦有统计学意义(P=0.016).经多因素分析,MSI为结直肠癌患者的独立预后因素(P=0.029).结论 微卫星不稳定是影响散发性结直肠癌患者预后的重要因素.

Abstract：

Objective To investigate the role of microsatellite instability (MSI) in Chinese sporadic coloretal cancer. Methods A total of 146 patients with colorectal cancer were treated surgically from August 2004 to September 2006 in the Third Affiliated Hospital of Nanjing University of Traditional Chinese Medicine. Data were collected prospectively. Univariate and multivariable analyses were performed for parameters such as age, gender, tumor location, differentiation, MSI, tumor type, lymph node metastasis,TNM stage, and survival. Results Follow-up was available in 134 patients including telephone call and office visit. MSI(P=0.029), tumor type (P=0.000), TNM stage (P=0.000) were independently associated with survival on Cox regression model. There were 26 patients with MSI, and the 1-, 3-, and 5-year survival rates were 100% , 92.3% , and 92.3% , respectively. The remaining 108 patients had microsatellite stable tumor, and the 1-, 3-, and 5year survival rates were 96.3% , 72.2% , and 63.5% , respectively. The difference was statistically significant(P=0.016). Conclusion Microsatellite instability is an important factor associated with patient survival in Chinese sporadic colorectal cancer.     

微卫星不稳定性和肝细胞生长因子对结直肠癌患者生存状况的影响

目的探讨微卫星不稳定性(MSI)和肝细胞生长因子(HGF)对结直肠癌患者生存状况的影响。方法选取2012年1月至2014年5月收治的82例结直肠癌患者为研究对象。采用免疫组织化学法检测MSI及HGF表达情况。所有资料采用SPSS 20.0进行分析处理,计量资料采用均数±标准差表示并行t检验,MSI及HGF表达阳性率采用χ2检验,多因素分析采用Cox回归分析,生存分析采用Kaplan-Meier法,MSI与HGF表达的关系采用spearman相关性分析。P0.05作为差异有统计学意义。结果 MSI阳性患者32例,占39.0%;HGF表达阳性58例,占70.7%。MSI与分化程度相关(P0.05),与年龄、性别、肿瘤部位、肿瘤大小、组织学类型、大体类型、淋巴转移无关(P0.05)。HGF表达与上述指标均无关(P0.05)。MSI与HGF表达之间具有明显负相关性(r=-0.6531,P=0.032)。年龄、淋巴转移、MSI和HGF表达阳性是结直肠癌患者总生存期的独立影响因素(P0.05)。结论HGF在结直肠癌中表达较MSI更明显,MSI和HGF表达水平与结直肠癌患者生存期相关。     

Comparison of microsatellite instability and chromosomal instability in predicting survival of patients with T3N0 colorectal cancer

BACKGROUND: At least 2 apparently independent mechanisms, microsatellite instability (MSI) and chromosomal instability, are implicated in colorectal tumorigenesis. Their respective roles in predicting clinical outcomes of patients with T3N0 colorectal cancer remain unknown. METHODS: Eighty-eight patients with a sporadic T3N0 colon or rectal adenocarcinoma were followed up for a median of 67 months. For chromosomal instability analysis, Ki-ras mutations were determined by single-strand polymerase chain reaction, and p53 protein staining was studied by immunohistochemistry. For MSI analysis, DNA was amplified by polymerase chain reaction at 7 microsatellite targets (BAT25, BAT26, D17S250, D2S123, D5S346, transforming growth factor receptor II, and BAX). RESULTS: Overall 5-year survival rate was 72%. p53 protein nuclear staining was detected in 39 patients (44%), and MSI was detected in 21 patients (24%). MSI correlated with proximal location (P <.001) and mucinous content (P <.001). In a multivariate analysis, p53 protein expression carried a significant risk of death (relative risk = 4.0, 95% CI = 1.6 to 10.1, P =.004). By comparison, MSI was not a statistically significant prognostic factor for survival in this group (relative risk = 2.2, 95% CI = 0.6 to 7.3, P =.21). CONCLUSIONS: p53 protein overexpression provides better prognostic discrimination than MSI in predicting survival of patients with T3N0 colorectal cancer. Although MSI is associated with specific clinicopathologic parameters, it did not predict overall survival in this group. Assessment of p53 protein expression by immunocytochemistry provides a simple means to identify a subset of T3N0 patients with a 4-times increased risk for death.     

人T细胞因子4外显子3～9突变在微卫星不稳定性直肠癌中的意义

目的 探讨人T细胞因子4(hTCF-4)外显子3～9突变在微卫星不稳定散发性直肠癌中的意义.方法 对102例散发性直肠癌患者进行微卫星标记遗传筛选.11例证实为高频率微卫星不稳定.对这11例以及来源于不同样本的微卫星稳定和正常组织病例各5例进行hTCF-4基因外显子3～9编码区测序分析.结果 研究揭示几个新的突变和序列变异体.在外显子4,一个为导致氨基酸由Q131T改变为S132I的一个四位连续变化(391insA、392G＞A、393A＞G and 395delC),另一个为核苷酸缺失(395delC),这些改变分别存在于不同的高频率微卫星不稳定病例(5/10,50%和4/10,40%),而对照组缺乏.结论 这些突变与高频率微卫星不稳定性散发性直肠癌患者高度相关.     

微卫星不稳定性检测在遗传性非息肉病性结直肠癌家系遴选中的作用

目的 探讨微卫星不稳定性(MSI)检测在遗传性非息肉病性结直肠癌(HNPCC)家系遴选中敏感性、特异性及临床应用的价值。方法 对12例符合Amsterdam标准的HNPCC患和16例散发性结直肠癌患的肿瘤标本进行微卫星不稳定性检测。结果 若将高微卫星不稳定性(MSI-H)及低微卫星不稳定性(MSI-L)的结直肠癌患作为HNPCC家系的诊断标准,其敏感性为100％,特异性为75％,正确率为81％;若仅将MSI-H的结直肠癌患作为HNPCC家系的诊断标准,其敏感性为100％,特异性为94％,正确率为95％。结论 微卫星不稳定性检测遴选HNPCC家系敏感性和特异性较高,而且两简单、经济,适合在临床广泛应用。     

Clinicopathological significance of PTEN loss and the phosphoinositide 3-kinase/Akt pathway in sporadic colorectal neoplasms: is PTEN loss predictor of local recurrence?

BACKGROUND: PTEN is a tumor-suppressor gene located on chromosome 10. Deficient PTEN expression leads to activation of the phosphoinositide 3-kinase (PI3K)/Akt (pAkt) signaling pathway, which may contribute to multiple human cancers. The relation between PTEN expression and Akt activation is still unclear in colorectal cancers and adenomatous polyps. Moreover, PTEN and pAkt expression in relation to demographic, tumoral, and outcome variables remains to be elucidated. METHODS: PTEN and pAkt expression were evaluated in 76 primary colorectal cancers and 25 adenomatous colorectal polyp tissues using immunohistochemical staining on paraffin-embedded sections. PTEN and pAkt expression were compared with clinicopathologic features of colorectal cancers. The relationship between PTEN and pAkt expression was also investigated. RESULTS: In colorectal cancers, pAkt expression was found to be significantly higher than polyps (P = .007). On the other hand, PTEN expression was significantly lower in polyps (P <.0001). In colorectal cancer patients, PTEN expression showed a negative correlation with young age, female sex, and left-sided (distal) tumors. On multivariate analysis, low PTEN expression (PTEN loss) was noted as an independent parameter for local recurrence (P = .024). There was significant association between pAkt expression and stage (P = .008), and preoperative serum carcinoembryonic antigen (CEA) levels (P = .017) in colorectal cancers. A negative correlation between PTEN and pAkt expression was found in colon cancer patients (P = .010), whereas no significiant association was found in adenomatous polyps (P = .403). No correlation of PTEN expression or pAkt expression was observed in Kaplan-Meier survival statistics and multivariate analyses for disease-free and overall survival. CONCLUSIONS: The current study suggests that the PTEN loss-PI3K/pAkt pathway may play an important role in sporadic colon carcinogenesis and that reduced PTEN expression may predict relapse in colorectal cancer patients.     

Microsatellite Instability as a Prognostic Factor in Resected Colorectal Cancer Liver Metastases

Background: Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are currently recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Untreated CRC hepatic metastases are incurable and are associated with a median survival of 4 to 12 months. Conversely, surgical resection in selected patients results in a 20% to 50% cure rate. The aim of this study was to investigate the prognostic importance of MSI-H in patients undergoing resection of hepatic CRC metastases.Methods: DNA was extracted from paraffin-embedded, resected metastatic CRC liver lesions and corresponding normal liver parenchyma from 190 patients. MSI-H status was determined by polymerase chain reaction–based evaluation of the noncoding mononucleotide repeats BAT-25 and BAT-26.Results: MSI was detected in tumors from 5 (2.7%) of the 190 CRC patients. All MSI-H tumors were in patients with node-positive CRC primary tumors. The median survival after hepatic resection of MSI-H and non–MSI-H tumors was 67 and 61 months, respectively (P = .9).Conclusions: These data suggest that MSI-H is not a common feature in resected CRC liver metastases and do not suggest a role for MSI in stratifying good versus poor prognosis in these patients.the Annual Meeting of the Society of Surgical Oncology, Los Angeles, California, March 5–9, 2003.     

Clinical significance of mutator phenotype and chromosome 17p and 18q allelic loss in gastric cancer

BACKGROUND: Tumour stage is the only reliable prognostic factor for gastric cancer. The molecular anomalies involved in this process have the potential to serve as additional prognostic markers. METHODS: Forty-four gastric cancers, treated by surgery alone, have been analysed for chromosome 17p and 18q allelic loss and for the presence of microsatellite instability (MSI), using microsatellite markers and DNA from paraffin-embedded tumours. RESULTS: Eight cancers showed a MSI-positive (MSI+) phenotype. Among the 36 MSI-negative cancers, chromosome 17p and 18q allelic losses were found in 22 of 34 and 19 of 33 informative cases respectively. Multivariate survival analysis indicated MSI status to be an independent prognostic factor along with the tumour stage. MSI+ cancers were associated with longer patient survival, whereas MSI-negative cancers had a significantly poorer prognosis (P = 0.007), with a median actuarial survival of 24 months. CONCLUSION: MSI status is an independent prognostic factor among gastric cancers at the same stage. Chromosome 17p and 18q status added no additional prognostic information to that of tumour stage. The combined use of tumour stage and MSI status may help in deciding whether patients with advanced gastric cancer require additional therapy other than surgery alone.     

Microsatellite Instability in Gastrointestinal Tract Cancers: A Brief Update

Microsatellite instability (MSI) was initially reported in colorectal cancer and, particularly, in hereditary nonpolyposis colorectal cancer (HNPCC). Since mutations in the genes functioning in DNA mismatch repair (MMR) were found in HNPCC kindred, this phenotype has been connected to a deficiency in MMR. The MSI⁺ phenotype is associated with various human malignancies. As MSI⁺ tumors appear to form a unique clinicopathological and molecular entity that is clearly distinct from that of classical colorectal tumors, which are accompanied by chromosomal instability (CIN), an exclusive pathway of tumorigenesis has been proposed in colorectal cancer. However, this scheme, comprising two mutually exclusive pathways, is now being reexamined, in light of a series of evidence accumulating in the literature, which relates to (a) distinction between high-level MSI (MSI-H) and low-level MSI (MSI-L), (b) heterogeneity in MSI-H, particularly in the sporadic and hereditary settings, (c) molecular mechanisms underlying the MSI⁺ phenotypes, and (d) relationships between the MSI⁺ and CIN phenotypes. Several molecular mechanisms may underlie repeat instability in eukaryotic cells. The relationship between MSI and defective MMR may be more complicated than has been suspected. The role of MMR deficiency in tumorigenesis in the digestive tract appears to be diverse and is not simple, even in the colorectum.     

Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers

BACKGROUND: The assessment of microsatellite instability (MSI) is not included yet in the routine evaluation of patients with gastric cancer, as controversial data exist regarding its prognostic value. METHODS: We determined the clinical significance of MSI in 510 sporadic gastric cancers, using the mononucleotide markers BAT25 and BAT26. The results were compared with the immunohistochemical expression of the mismatch repair proteins Mlh1 and Msh2. RESULTS: MSI was present in 83 (16%) cancers and correlated with better survival (P < .001). Multivariate analysis showed that the MSI phenotype was an independent factor (P = .005) and added prognostic information to TNM stage, location, and age. The relative risk of death for MSI cancer patients was 0.6 (95% confidence interval [CI], 0.4-0.8). Moreover, when grouped according to stage, only stage II cancers showed a significant effect of MSI status on survival (P = .011; hazard ratio = 0.3; 95% CI, 0.1-0.8). MSI also correlated with older age (P = .002), female gender (P < .001), intestinal histotype (P = .011), lower T stage (P = .018), and less lymph node involvement (P < .001). Finally, comparison of the results of immunohistochemical expression of the mismatch repair proteins Mlh1 and Msh2 with microsatellite analysis showed concordant results in 95% of neoplasms, with a sensitivity of 82% and specificity of 98%. CONCLUSIONS: Microsatellite analysis of gastric cancer has clinical utility in determination of prognosis, but should be determined in only stage II neoplasms in a routine clinical setting. Immunohistochemistry may be considered sufficient, although microsatellite analysis is preferable.     

散发性结直肠癌CpG岛甲基子表型和基因组遗传学不稳定性的关系

目的探讨散发性结直肠癌CpG岛甲基子表型和基因组不稳定性的关系。方法对采用甲基化特异性PCR的方法对71例散发性结直肠癌组织进行P14^ARF、hMLH1、P16^INK4a、MGMT和MINT1共5个基因启动子甲基化的检测,确定CpG岛甲基子表型;选择BAT25和BAT26两个位点进行微卫星不稳定检测和流式细胞术检测分析倍体类型;分析散发性结直肠癌中CpG岛甲基子表型和微卫星不稳定、染色体不稳定的关系。结果全组结直肠癌组织中CpG岛甲基子表型的阳性率为21.1%（15/71）;微卫星不稳定的阳性率为9.9%（7/71）;异倍体的阳性率为73.5%（50/68）。CpG岛甲基子表型阳性者,微卫星不稳定的阳性率高于阴性者（20.0%vs7.1%）,但差异无统计学意义（P=0.158）。hMLH1基因启动子甲基化阳性者微卫星不稳定的比例为57.1%,高于阴性者的4.7%（P=0.001）。CpG岛甲基子表型阳性者二倍体的比例高于阴性者（61.5%vs.18.2%,P=0.003）。结论CpG岛甲基子表型阳性的散发性结直肠癌具有显著的二倍体倾向,多基因同时甲基化和染色体不稳定可能是两种相互独立的基础性发病机制。