基于DWI深度学习特征的预测模型评估子宫内膜癌微卫星不稳定状态的价值

目的探索基于扩散加权成像(DWI)深度学习特征的预测模型在子宫内膜癌微卫星不稳定状态评估中的价值。资料与方法回顾性分析2020年6月—2023年4月于新乡市中心医院行MRI检查的32例微卫星不稳定和55例微卫星稳定子宫内膜癌患者的DWI资料,测量原发病灶的表观扩散系数(ADC),并分别应用多层卷积神经网络和PyRadiomics提取原发病灶的深度学习特征和影像组学特征。使用最小绝对收缩和选择算子及随机森林进行特征筛选和模型建立,采用受试者工作特征曲线下面积(AUC)和净重新分类指数评估模型性能,基于1000次重采样的Bootstrap进行模型内部验证。结果深度学习模型共纳入6个特征,分别为第7、57、77、82、97和108个特征,AUC为0.905(95%CI 0.823~0.957);影像组学模型共纳入6个特征,分别为1个邻域灰度差矩阵、4个灰度区域大小矩阵和1个灰度游程长度矩阵特征,AUC为0.844(95%CI 0.751~0.913);微卫星不稳定组的ADC小于微卫星稳定组(t=-4.123,P<0.001),AUC为0.810(95%CI 0.712~0.886)。与影像组学模型和ADC相比,深度学习模型的风险预测效果得到改善,净重新分类指数分别为0.856和0.486(P<0.01,P=0.024)。在基于Bootstrap的内部验证中深度学习模型也展示出较影像组学模型更高的性能,二者的AUC分别为0.897(95%CI 0.889~0.905)和0.829(95%CI 0.812~0.839)。结论与影像组学模型和ADC相比,基于DWI图像深度学习特征的预测模型能够更好地评估子宫内膜癌患者的微卫星不稳定状态。

微卫星不稳定性检测在大肠癌研究中的应用

大肠癌是常见的消化道恶性肿瘤,发病机制尚不清楚,近年来将微卫星不稳定性检测用于大肠癌的研究,取得一些进展,本文针对微卫星不稳定性检测在大肠癌研究中的应用作一综述,并展望其应用前景。

Microsatellite Alterations on Chromosome 8 of Hepatocellular Carcinoma

Objective: To study the features of microsatellite alterations on chromosome 8 and their asso- ciation with clinicopathological characteristics of hepatocellular carcinoma (HCC). Methods: Ten highly- polymorphic microsatellite markers on chromosome 8 were selected to be detected for loss of heterozygosity (LOH), microsatellite instability (MSI) and allelic imbalance (AI) in 56 HCC using MegaBACE 500 auto- matic DNA analysis system. Results: LOH was found in 37 of 56 HCC (66.1%) on at least 1 locus, and the top three loci were D8S261(53.5%), D8S1721(52.5%) and D8S1771(52.5%). LOH frequency on D8S277 was signi?cantly higher in cases positive for serum HBsAg than in those negative for HBsAg (P <0.01). Similarly, LOH on D8S261, D8S298 and D8S1733 occurred more frequently in patients with negative HB- sAg than those with positive HBsAg (P <0.01). LOH on D8S298 and D8S1771 was more frequent in those tumors larger than 3 cm in size (P <0.05 or P <0.01). LOH frequencies of D8S1721 were signi?cantly higher in the patients with absent or not intact tumor capsule than in those with intact tumor capsule (P <0.05). LOH on D8S298 and D8S1771 was more frequently detected in tumors with intrahepatic metastasis than in those without intrahepatic metastasis (P <0.01). MSI was found in 12.5% (7/56) cases, and AI was found in 19.6% (11/56), no correlation was found between MSI and AI and clinicopathological character- istics of HCC. Conclusion: Frequent microsatellite alterations on chromosome 8 existed in HCC. LOH, which represents tumor suppressor gene pathway, plays a more important role in hepatocarcinogenesis; MSI representing mismatch repair gene pathway ranks next. LOH at a particula locus is associated with the clinicopathological parameters of human HCC.

Study on the Correlation between the Expression of Angiogenic Factor VEGF and Microsatellite Instability in Gastric Adenocarcinoma

Objective: To investigate the correlation between the microsatellite instability (MSI) and the expression of vascular endothelial growth factor (VEGF) in gastric adenocarcinoma. Methods: PCR SSCP method was used to detect MSI of thirty cases with gastric adenocarcinoma at five loci in each patient. Expression of VEGF was examined by the method of immunohistochemistry. Results: The positive of MSI was in 13 patients out of 30 patients (43.4%) in our study. Positive VEGF Immunostaining was detected in 18 patients (60.0%). VEGF was decreased in microsatellite instability high (MSI H) gastric adenocarcinoma. Conclusion: MSI H and microsatellite stable (MSS) gastric adenocarcinoma may follow a different pathway of angiogenesis. The low frequency of VEGF expression among MSI H cancer may partially explain why these cancers are less aggressive.

Nuclear and mitochondrial DNA microsatellite instability in hepatocellular carcinoma in Chinese

AIM：To study the nuclear microsatellite instability (nMSI) at BAT26 and mitochondral microsalellite instability (mtMSI) in the occurrence and development of hepatocellular carcinoma and the relationship between nMSI and mtMSI.METHODS: nMSI was observed with PCR and mtMSI with PCR-SSCP in 52 cases of hepatocellular carcinoma.RESULTS:mtMSI was detected in 11 out of the 52 cases of hepatocellular carcinoma (21.2%). Among the 11 cases of hepatocellular carcinoma with mtMSI, 7 occured in one locus and 4 in 2 loci. The frequency of mtMSI in the 52 cases of hepatocellular carcinoma showed no correlation to sex, age,infection of hepatitis B, liver cirrhosis as well as positive AFP of the patients (P>0.05). In addition, nMSI was detected in 3 out of 52 cases of hepatocellular carcinoma (5.8%) and there was no correlation of the incidence of mtMSI to that of nMSI (P>0.05).CONCLUSION:mtMSI may be involved in the coccurrence and development of hepatocellular carcinoma and it is independent of nMSI.

Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer

There is an increasing understanding of the roles that microsatellite instability （MSI） plays in Lynch syndrome （by mutations） and sporadic （by mainly epigenetic changes） gastrointestinal （GI） and other cancers. Defi- cient DNA mismatch repair （MMR） results in the strong mutator phenotype known as MSI, which is the hall- mark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syn- drome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and en-dometrial cancers and in lower frequencies in a minor- ity of other cancers where it is often associated with the hypermethylation of the IVlLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of m/R-IEE has been shown to downregulate expression of MLH1, IVlSH2, and MSH6. Thus, a subset of MSI-positive （MSI＋） cancers without known MMR defects may result from m/R-1E5 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular func- tions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epi- genetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI＋ GI cancers. Thus, a subset of MSI＋ colorectal cancers （CRCs） has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic dif- ferences exist between MSI＋ and MSI- cancers. Mo- lecular signatures of miRNA expression apparently have the potential to distinguish between MSI＋ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.

Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis.

Genetic changes of p53,K-ras,and microsatellite instability in gallbladder carcinoma in high-incidence areas of Japan and Hungary

AIM： To disclose geographic differences in genetic changes involved in gallbladder carcinogenesis between two distinct high-incidence areas of Japan and Hungary. METHODS： We examined 42 cases of gallbladder carcinoma： 22 Japanese and 20 Hungarian cases, p53 mutations at exons 5 to 8 and K-ras mutations at codon 12 were tested by direct sequencing. Microsatellite instability was determined from fluorescent dye-labeled PCR amplifications of flve-microsatellite markers （BAT-25, BAT-26, D2S123, DSS346, and D17S250）. RESULTS： Mutations of p53 were detected in 11 of 22 Japanese cases and 6 of 18 Hungarian cases （11/22 vs 6/18, P = 0.348）. Transition at CpG sites was found in none of 11 Japanese cases and 2 of 6 Hungarian cases; the difference was marginally significant （0/11 vs 2/6,P = 0.110）. K-ras mutations were detected in only one of the Hungarian cases. Eight of 19 （42.1%） ]apanese cases were MSI-high （presence of novel peaks in more than one of the five loci analyzed）, whereas only 1 of 15 （6.7%） Hungarian cases was MSI-high （P = 0.047）. CONCLUSION： It appears that the p53 mutations and MSI differ in patients with gallbladder carcinoma between two distinct high-incidence areas. Geographic variation might exist in the process of gallbladder carcinogenesis.

Genomic and genetic alterations influence the progression of gastric cancer

Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer.In this review, we summarize the sometimes contradictory findings regarding those markers which influence the progression of gastric adenocarcinoma.

Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer

Colorectal cancer （CRC） is caused by a series of genetic or epigenetic changes, and in the last decade there has been an increased awareness that there are multiple forms of colorectal cancer that develop through different pathways. Microsatellite instability is involved in the genesis of about 15% of sporadic colorectal cancers and most of hereditary nonpolyposis cancers. Tumors with a high frequency of microsatellite instability tend to be diploid, to possess a mucinous histology, and to have a surrounding lymphoid reaction. They are more prevalent in the proximal colon and have a fast pass from polyp to cancer. Nevertheless, they are associated with longer survival than stage-matched tumors with microsateUite stability. Resistance of colorectal cancers with a high frequency of microsatellite instability to 5-fluorouracilbased chemotherapy is well established. Silencing the MLH1 gene expression by its promoter methylation stops the formation of MLH1 protein, and prevents the normal activation of the DNA repair gene. This is an important cause for genomic instability and cell proliferation to the point of colorectal cancer formation. Better knowledge of this process will have a huge impact on colorectal cancer management, prevention, treatment and prognosis.

KRAS mutation testing in metastatic colorectal cancer

The KRAS oncogene is mutated in approximately 35%-45% of colorectal cancers, and KRAS mutational status testing has been highlighted in recent years. The most frequent mutations in this gene, point substitutions in codons 12 and 13, were validated as negative predictors of response to anti-epidermal growth factor receptor antibodies. Therefore, determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers. Currently, a variety of detection methods have been established to analyze the mutation status in the key regions of the KRAS gene; however, several challenges remain related to standardized and uniform testing, including the selection of tumor samples, tumor sample processing and optimal testing methods. Moreover, new testing strategies, in combination with the mutation analysis of BRAF , PIK3CA and loss of PTEN proposed by many researchers and pathologists, should be promoted. In addition, we recommend that microsatellite instability, a prognostic factor, be added to the abovementioned concomitant analysis. This review provides an overview of KRAS biology and the recent advances in KRAS mutation testing. This review also addresses other aspects of status testing for determining the appropriate treatment and offers insight into the potential drawbacks of mutational testing.

Telomerase activity in colorectal cancer,prognostic factor and implications in the microsatellite instability pathway

AIM： To determine whether the telomerase activity is related to the Microsatellite instability （MSI） genetic pathway and whether it means a difference in the survival.METHODS： The population consisted of 97 colorectal cancer patients. MSI determination was performed in accordance with the NCI criteria using PCR and Genescan. Telomerase activity was determined by the TRAP-assay, an ELISA procedure based on the amplification of telomeric repeat sequences.RESULTS： 6.2% showed high MSI （MSI-H）, 10.3% showed low MSI （MSI-L） and 83.5% did not show this alteration （MSS）. Positive telomerase activity was detected in 92.8% of the patients. 83.3% of MSI-H tumors showed positive telomerase against 93.8% of MSS tumors. In the overall survival analysis the absence of telomerase activity conferred a better prognosis.CONCLUSION： Previous works have shown that tumors which develop via the MSI pathway present a better prognosis. No link between telomerase activity and MSl status is observed, although sample sizes are small. Patients with telomerase negative tumors had better overall survival than patients with telomerase positive tumors.

Endoscopic and clinicopathologic characteristics of early gastric cancer with high microsatellite instability

AIM： To investigate endoscopic and clinicopathologic characteristics of early gastric cancer （EGC） according to microsatellite instability phenotype. METHODS： Data were retrospectively collected from a single tertiary referral center. Of 981 EGC patients surgically treated between December 2003 and October 2007, 73 consecutive EGC patients with two or more microsatellite instability （MSI） mutation [high MSI （MSI-H）] and 146 consecutive EGC patients with one or no MSI mutation （non-MSI-H） were selected. The endoscopic and clinicopathologic features were compared between the MSI-H and non-MSI-H EGC groups.RESULTS： In terms of endoscopic characteristics, MSI-H EGCs more frequently presented with elevated pattern （OR 4.38, 95% Cl： 2.40-8.01, P 〈 0.001）, moderate- to-severe atrophy in the surrounding mucosa （OR 1.91, 95% CI： 1.05-3.47, P = 0.033）, antral location （OR 3.99, 95% CI： 2.12-7.52, P 〈 0.001） and synchronous le- sions, compared to non-MSI-H EGCs （OR 2.65, 95% CI： 1.16-6.07, P = 0.021）. Other significant clinicopatholog- ic characteristics of MSI-H EGC included predominance of female sex （OR 2.77, 95% CI： 1.53-4.99, P 〈 0.001）, older age （〉 70 years） （OR 3.30, 95% CI： 1.57-6.92, P = 0.002）, better histologic differentiation （OR 2.35, 95% Cl： 1.27-4.34, P = 0.007）, intestinal type by Lau- ren classification （OR 2.34, 95% CI： 1.15-4.76, P = 0.019）, absence of a signet ring cell component （OR 2.44, 95% CI： 1.02-5.86, P = 0.046）, presence of mu- cinous component （OR 5.06, 95% Cl： 1.27-20.17, P = 0.022）, moderate-to-severe lymphoid stromal reaction （OR 3.95, 95% CI： 1.59-9.80, P = 0.003）, and co-exist- ing underlying adenoma （OR 2.66, 95% CI： 1.43-4.95, P = 0.002）. CONCLUSION： MSI-H EGC is associated with unique endoscopic and clinicopathologic characteristics includ- ing frequent presentation in protruded type, co-exist- ing underlying adenoma, and synchronous lesions.

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

AIM: To study the characteristics of mismatch repair gene mutation of Chinese hereditary non-polyposis colorectal cancer (HNPCC) and hMLH1 gene promoter methylation, and to improve the screening strategy and explore the pertinent test methods. METHODS: A systematic analysis of 30 probands from HNPCC families in the north of China was performed by immunohistochemistry, microsatellite instability (MSI), gene mutation and methylation detection. RESULTS: High frequency microsatellite instability occurred in 25 probands (83.3%) of HNPCC family. Loss of hMLH1 and hMSH2 protein expression accounted for 88% of all microsatellite instability. Pathogenic muta-tion occurred in 14 samples and 3 novel mutational sites were discovered. Deletion of exons 1-6, 1-7 and 8 of hMSH2 was detected in 3 samples and no large fragment deletion was found in hMLH1. Of the 30 probands, hMLH1 gene promoter methylation occurred in 3 probands. The rate of gene micromutation detection combined with large fragment deletion detection was 46.7%-56.7%. The rate of the two methods in combination with methylation detection was 63.3%. CONCLUSION: Scientific and rational detection strategy can improve the detection rate of HNPCC. Based on traditional molecular genetics and combined with epigenetics, multiple detection methods can accurately diagnose HNPCC.

Simplified microsatellite instability detection protocol provides equivalent sensitivity to robust detection strategies in Lynch syndrome patients

Objective:Germline mutations in mismatch repair(MMR)genes cause Lynch syndrome(LS).LS is an inherited disease,and an important consequence of MMR deficiency is microsatellite instability(MSI)phenotype.MSI phenotype influences the efficacy of5 fluorouracil(5-FU)chemotherapy.Reproducible,cost effective,and easy to perform laboratory tests are required to include MSI detection in routine laboratory practice.Evaluation of CAT25 as monomorphic short tandem repeat sequence enables CAT25 to be an efficient screening tool among hereditary nonpolyposis colorectal cancer(HNPCC)patients compared with other methods used currently.Methods:Based on Amsterdam II criteria,31 patients in 31 families were shortlisted from a total number of 1,659 colorectal cancer patients.MSI status was examined in these patients using CAT25 and a commercially available Promega MSI five-markerbased detection system as well as immunohistochemical(IHC)staining of four important MMR proteins.Patients were scored as high microsatellite instable(MSI-H),low(MSI-L),or stable(MSS).MSI status determined by CAT25 single mononucleotide marker was compared with that of five mononucleotide markers,Promega commercial kit,and IHC method.Results:MMR protein deficiency was observed on 7/31 probands using IHC methodology and 6/31 categorized as MSI-H using commercial kit or CAT25 single marker.The sensitivity and specificity of the CAT25 single marker were the same as those detected by five-marker Promega commercial kit in our patients.Conclusions:Based on our results,the performance of the CAT25 single mononucleotide marker for MSI status determination in our HNPCC patients is the same as that of the five-marker-based commercial kit.

Checkpoint with forkhead-associated and ring finger promoter hypermethylation correlates with microsatellite instability in gastric cancer

AIM:To examine the methylation status of the promoter region of the checkpoint with forkhead-associated and ring fi nger(CHFR) and microsatellite mutator status in 59 primary gastric cancers.METHODS:We investigated the promoter methylation of CHFR in 59 cases of gastric cancer using methylation-specifi c PCR.Five microsatellite loci were analyzed using high-intensity microsatellite analysis reported previously, and p53 gene mutations were investigated by direct sequencing.RESULTS:Twenty cases(33.9%) showed promoter methylation and no relation was observed with the clinicopathological factors.We found that the promoter methylation of CHFR was frequently accompanied with microsatellite instability(MIN).Seven of 20(35.0%) cases showed MIN in hypermethylation of the CHFR tumor, while three of 39(7.7%) cases showed MIN in the non-methylated CHFR tumor(P < 0.01).However, we failed to fi nd any relationship between CHFR methylation and p53 mutation status.CONCLUSION:The coordinated loss of both the mitotic check point function and mismatch repair system suggests the potential to overcome the cell cycle check point, which may lead to an accumulation of mutations.However, the p53 mutation was not related to hypermethylation of the CHFR promoter and MIN, which indicates that an abnormality in p53 occurs as an independent process from the mismatch repair deficiency in carcinogenesis.

Colorectal cancer carcinogenesis:a review of mechanisms

Colorectal cancer(CRC) is the second most common cancer in women and the third most common in men globally. CRC arises from one or a combination of chromosomal instability, Cp G island methylator phenotype, and microsatellite instability. Genetic instability is usually caused by aneuploidy and loss of heterozygosity. Mutations in the tumor suppressor or cell cycle genes may also lead to cellular transformation. Similarly, epigenetic and/or genetic alterations resulting in impaired cellular pathways, such as DNA repair mechanism, may lead to microsatellite instability and mutator phenotype. Non-coding RNAs, more importantly micro RNAs and long non-coding RNAs have also been implicated at various CRC stages. Understanding the specific mechanisms of tumorigenesis and the underlying genetic and epigenetic traits is critical in comprehending the disease phenotype. This paper reviews these mechanisms along with the roles of various non-coding RNAs in CRCs.

Identification of patients at-risk for Lynch syndrome in a hospital-based colorectal surgery clinic

AIM:To determine the prevalence of a family history suggestive of Lynch syndrome (LS) among patients with colorectal cancer (CRC) followed in a coloproctology outpatient clinic in Southern Brazil.METHODS:A consecutive sample of patients with CRC were interviewed regarding personal and family histories of cancer.Clinical data and pathology features of the tumor were obtained from chart review.RESULTS:Of the 212 CRC patients recruited,61 (29%) reported a family history of CRC,45 (21.2%) were diagnosed under age 50 years and 11 (5.2%) had more than one primary CRC.Family histories consistent with Amsterdam and revised Bethesda criteria for LS were identified in 22 (10.4%) and 100 (47.2%) patients,respectively.Twenty percent of the colorectal tumors had features of the high microsatellite instability phenotype,which was associated with younger age at CRC diagnosis and with Bethesda criteria (P < 0.001).Only 5.3% of the patients above age 50 years had been previously submitted for CRC screening and only 4% of patients with suspected LS were referred for genetic risk assessment.CONCLUSION:A significant proportion of patients with CRC were at high risk for LS.Education and training of health care professionals are essential to ensure proper management.

Expression of Cyclooxygenase-2 and Its Relationship with Mismatch Repair and Microsatellite Instability in Hereditary Nonpolyposis Colorectal Cancer

Objective To investigate cyclooxygenase-2 (COX-2) expression and its relationship with mismatch repair (MMR) protein expression and microsatellite instability (MSI) in hereditary nonpolyposis colorectal cancer (HNPCC). Methods A total of 28 cases of colorectal adenoma and 14 cases of colorectal carcinoma were collected between July 2003 and July 2007 from 33 HNPCC families. Sporadic colorectal adenoma (n=32) and carcinoma patients (n=24) served as controls. With samples of tumor tissues and normal colonic mucosa collected from the patients, the protein expressions of COX-2 and MMR (hMLH1, hMSH2, and hMSH6) were examined with immunohistochemical assay. Frequency of MSI in five standard MSI loci BAT25, BAT26, D2S123, D5S346, and D17S250 were analyzed by means of polymerase chain reaction. Results The rate of COX-2 high-expression was 53.6% (15/28) and 42.9% (6/14) in HNPCC adenoma and carcinoma; 62.5% (20/32) and 91.7% (22/24) in sporadic adenoma and carcinoma, respectively. That rate was lower in HNPCC carcinoma than in sporadic carcinoma (P<0.05). MMR-deletion rate and percentage of high-frequency MSI (MSI-H) in HNPCC carcinoma were higher than those in sporadic colorectal carcinoma [both 71.4% (10/14) vs. 12.5% (3/24), both P<0.01]. Among the 10 MMR-deficient HNPCC carcinoma patients, COX-2 low-expression was observed in 8 cases (80.0%), while COX-2 high-expression was observed in all of the 4 MMR-positive HNPCC carcinoma cases (P<0.05). In comparison to MMR positive HNPCC carcinoma, HNPCC adenoma, and sporadic carcinoma, COX-2 expression was significantly lower in corresponding MMR-deficient cases (all P<0.05). The rates of COX-2 low-expression in HNPCC adenoma, HNPCC carcinoma, and sporadic carcinoma with MSI-H were significantly higher than those in the cases with microsatellite stability (all P<0.05). Conclusion COX-2 is expressed at a low level in HNPCC carcinoma, different from the high COX-2 expression in sporadic carcinoma.

Clinicopathological Features of Non-familial Colorectal Cancer with High-frequency Microsatellite Instability

Objective To explore the clinicopathological features of non-familial colorectal cancer with high-frequency microsatellite instability (MSI-H). Methods One hundred and fifty patients with colorectal cancer who had no family history were enrolled in this study from June 2006 to June 2008. Five standard microsatellite loci including BAT25, BAT26, D2S123, D5S346, and D17S250 were amplified with immunofluorescent polymerase chain reaction. The patient information including age, sex, and tumor location was recorded. Pathological features including differentiation, mucinous differentiation, histological heterogeneity, and Crohn's-like reaction were observed under light microscope. The presence of tumor-infiltrating lymphocytes (TLs, CD4+ and CD8+) was detected by means of immunohistochemistry. A regression equation was obtained by stepwise logistic regression analysis to evaluate the relationship between MSI-H phenotype in colorectal cancer ands pathological features. Results MSI-H phenotype occurred in 13.33% of the 150 patients with non-familial colorectal cancer. Poor differentiation, histological heterogeneity, Crohn's-like reaction, and presence of TLs were found to be independent factors to identify MSI-H non-familial colorectal cancer. Logistic regression equation showed an overall sensitivity of 70.0%, specificity of 99.2%, and accuracy of 95.3% in identifying MSI-H non-familial colorectal cancer. Conclusion MSI-H non-familial colorectal cancer manifests specific pathological features, which may be relied upon for effective identification of that disease.