Clinical and molecular features of young-onset colorectal cancer

Colorectal cancer(CRC) is one of the leading causes of cancer related mortality worldwide. Although young-onset CRC raises the possibility of a hereditary component, hereditary CRC syndromes only explain a minority of young-onset CRC cases. There is evidence to suggest that young-onset CRC have a different molecular profile than late-onset CRC. While the pathogenesis of young-onset CRC is well characterized in individuals with an inherited CRC syndrome, knowledge regarding the molecular features of sporadic young-onset CRC is limited. Understanding the molecular mechanisms of young-onset CRC can help us tailor specific screening and management strategies. While the incidence of late-onset CRC has been decreasing, mainly attributed to an increase in CRC screening, the incidence of young-onset CRC is increasing. Differences in the molecular biology of these tumors and low suspicion of CRC in young symptomatic individuals, may be possible explanations. Currently there is no evidence that supports that screening of average risk individuals less than 50 years of age will translate into early detection or increased survival. However, increasing understanding of the underlying molecular mechanisms of young-onset CRC could help us tailor specific screening and management strategies. The purpose of this review is to evaluate the current knowledge about young-onset CRC, its clinicopathologic features, and the newly recognized molecular alterations involved in tumor progression.     

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 microsatellite stability. Resistance of colorectal cancers with a high frequency of microsatellite instability to 5-fluorouracil-based 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.     

Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients

AIM:To investigate the clinicopathologic characteristics and prognostic implications associated with loss of CDX2 expression in colorectal cancers(CRCs).METHODS:We immunohistochemically evaluated CDX2 expression in 713 CRCs and paired our findings to clinicopathologic and molecular characteristics of each individual.Endpoints included cytokeratin 7 and CK20 expression,microsatellite instability,Cp G island methylator phenotype,and KRAS and BRAF mutation statuses.Univariate and multivariate survival analysis was performed to reveal the prognostic value of CDX2 downregulation.RESULTS:CDX2 expression was lost in 42(5.9%) patients.Moreover,loss of CDX2 expression was associated with proximal location,infiltrative growth,advanced T,N,M and overall stage.On microscopic examination,loss of CDX2 expression was associated with poor differentiation,increased number of tumor-infiltrating lymphocytes,luminal serration and mucin production.Loss of CDX2 expression was also associated with increased CK7 expression,decreased CK20 expression,Cp G island methylator phenotype,microsatellite instability and BRAF mutation.In a univariate survival analysis,patients with loss of CDX2 expression showed worse overall survival(P < 0.001) and progression-free survival(P < 0.001).In a multivariate survival analysis,loss of CDX2 expression was an independent poor prognostic factor of overall survival [hazard ratio(HR) = 1.72,95%CI:1.04-2.85,P = 0.034] and progression-free survival(HR = 1.94,95%CI:1.22-3.07,P = 0.005).CONCLUSION:Loss of CDX2 expression is associated with aggressive clinical behavior and can be used as a prognostic marker in CRCs.     

Approach to early-onset colorectal cancer: Clinicopathological, familial, molecular and immunohistochemical characteristics

AIM:To characterize clinicopathological and familial features of early-onset colorectal cancer(CRC) and compare features of tumors with and without microsatellite instability(MSI).METHODS:Forty-five patients with CRC aged 45 or younger were included in the study.Clinical information,a three-generation family history,and tumor samples were obtained.MSI status was analyzed and mismatch repair genes were examined in the MSI families.Tumors were included in a tissue microarray and an immunohistochemical study w...     

Serrated pathway in colorectal carcinogenesis

Serrated adenocarcinoma is a recently described subset of colorectal cancer(CRC),which account for about10%of all CRCs and follows an alternative pathway in which serrated polyps replace the traditional adenoma as the precursor lesion to CRC.Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps(HPs),sessile serrated adenoma(SSA),traditional serrated adenoma(TSA)and mixed polyps.HPs are the most common serrated polyp followed by SSA and TSA.This distinct histogenesis is believed to have a major influence in prevention strategies,patient prognosis and therapeutic impact.Genetically,serrated polyps exhibited also a distinct pattern,with KRAS and BRAF having an important contribution to its development.Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype.In the present review we will address the current knowledge of serrated polyps,clinical pathological features and will update the most recent findings of its molecular pathways.The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development.     

Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer

Background

The CpG island methylator phenotype (CIMP or CIMP‐high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer. In contrast, a phenotype with less widespread promoter methylation (CIMP‐low) has not been well characterised. O‐6‐methylguanine‐DNA methyltransferase (MGMT) promoter methylation and silencing have been associated with G>A mutations and microsatellite instability‐low (MSI‐low).

Aim

To examine molecular correlates with MGMT methylation/silencing in colorectal cancer.

Methods

Utilising MethyLight technology, we quantified DNA methylation in MGMT and eight other markers (a CIMP‐diagnostic panel; CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) in 920 population‐based colorectal cancers.

Results

Tumours with both MGMT methylation and loss were correlated positively with MSI‐low (p = 0.02), CIMP‐high (⩾6/8 methylated CIMP markers, p = 0.005), CIMP‐low (1/8–5/8 methylated CIMP markers, p = 0.002, compared to CIMP‐0 with 0/8 methylated markers), KRAS G>A mutation (p = 0.02), and inversely with 18q loss of heterozygosity (p = 0.0002). Tumours were classified into nine MSI/CIMP subtypes. Among the CIMP‐low group, tumours with both MGMT methylation and loss were far more frequent in MSI‐low tumours (67%, 12/18) than MSI‐high tumours (5.6%, 1/18; p = 0.0003) and microsatellite stable (MSS) tumours (33%, 52/160; p = 0.008). However, no such relationship was observed among the CIMP‐high or CIMP‐0 groups.

Conclusion

The relationship between MGMT methylation/silencing and MSI‐low is limited to only CIMP‐low tumours, supporting the suggestion that CIMP‐low in colorectal cancer may be a different molecular phenotype from CIMP‐high and CIMP‐0. Our data support a molecular difference between MSI‐low and MSS in colorectal cancer, and a possible link between CIMP‐low, MSI‐low, MGMT methylation/loss and KRAS mutation.     

CpG island methylation in gastroenterologic neoplasia: a maturing field

Fifteen years after the first demonstration of epigenetic tumor-suppressor gene inactivation associated with promoter methylation, the field has reached a level of understanding that threatens a re-writing of established biologic concepts. In gastrointestinal malignancies, epigenetic analysis has led to novel hypotheses regarding the etiology of age-associated cancer susceptibility and the interactions between environmental exposures and neoplasia. Methylation profiling has uncovered a distinct pathway to colorectal neoplasia that may arise from a hitherto underestimated precursor lesion, the proximal hyperplastic polyp-serrated adenoma pathway. Epigenetic information has shown promise in clarifying susceptibility to cancer and defining poor prognosis groups in gastrointestinal cancers. Finally, the field has engendered renewed interest in therapeutic targeting of epigenetic regulatory molecules, and several such drugs are currently in clinical trials. It is likely that epigenetic pathways will be integrated in the routine management of gastrointestinal malignancies over the next decade.     

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 a...     

CpG岛甲基子表型阳性的散发性大肠癌的临床病理特征

目的 探讨CpG岛甲基子表型阳性的散发性大肠癌的临床病理特征.方法 采用甲基化特异性PCR方法对71例散发性大肠癌患者行p14、hMLH1、p16、MGMT和MINT1共5个基因启动子甲基化检测,分析CpG岛甲基子表型阳性的散发性大肠癌的临床病理特征.结果 71例散发性大肠癌患者中共检出CpG岛甲基子表型阳性者15例,阳性率为21.1%.CpG岛甲基子表型阳性的散发性大肠癌中右半结肠癌（40.0%比12.5%,P＜0.05）、低分化癌（46.7%比14.3%,P＜0.05）、淋巴结转移（86.7%比48.2%,x2=7.112,P＜0.05）、Dukes C期或D期（86.7%比50.0%,x2=6.519,P＜0.05）所占比例均显著高于CpG岛甲基子表型阴性者.结论 CpG岛甲基子表型阳性的散发性大肠癌具有右半结肠癌多发、低分化多见、常有淋巴结转移和分期较晚的特点.     

遗传性非息肉病性结直肠癌的微卫星不稳定研究

目的　探讨国人北方人群HNPCC的微卫星不稳定 (microsatelliteinstability ,MSI)发生情况及其意义。方法　 44例患者来源于 3 0个HNPCC (hereditarynonpolyposiscolorectalcancer)家系 ,这些家系主要分布于北方 5省市。所有患者均符合BGl 3 (Bethes dal 3 )HNPCC诊断标准。以荧光标记法检测 44例患者的石蜡包埋组织微卫星稳定性。结果　 44例患者中高度微卫星不稳定 (highfrequencymicrosatelliteinstability ,MSI H)为 81.81( 3 6/ 44 ) ,低度微卫星不稳定 (lowfrequencymicrosatelliteinstability ,MSI L)为 6.82 ( 3 / 44 ) ,微卫星稳定 (microsatellitestable ,MSS)为 11.3 ( 5 / 44 ) ;所选择的 5个微卫星位点中Bat2 5和Bat2 62个位点MSI H的表达率较高 ,分别为 10 0 %和 97.2 2 %。符合AmsterdamⅡ和符合BGl 3标准的HNPCC患者的MSI H表达率分别为 85 .2 9%和 81,81% ,仅符合BGl 3标准 ,而不符合AmsterdamII的 10个患者中 ,7个发现MSI H。结论　HNPCC肿瘤的MSI H发生率高 ,MSI检测方法简便、易行 ,可作为错配修复基因种系突变初筛方法 ,Bethesdal 3标准可更多地收集到可疑的HNPCC患者     

Early-onset colorectal cancer: A review of current knowledge

Colorectal cancer(CRC) is one of the most prevalent malignancies worldwide. Although most prevalent among older people, its incidence above 50 years old has been decreasing globally in the last decades, probably as a result of better screening. Paradoxically, its incidence in patients below 50 years old [early-onset CRC(EO-CRC)] has been increasing, for reasons not yet fully understood. EOCRC’s increasing incidence is genre independent but shows racial disparities and has been described to occur...     

Colorectal cancer： Pathways,pathology and practice： From the editor

This review explores the chief genetic and epigenetic events that promote pathological progression in colorectal carcinogenesis. This article discusses the molecular and pathological basis for classifying colorectal neoplasia into suppressor, mutator and methylator pathways. These differing mechanisms of genomic instability are associated with specific cancer characteristics, and may provide the opportunity for more effective prevention and surveillance strategies in the future. This is the first review in a series of five topics outlining important and developing aspects of colorectal cancer.     

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.     

Perspectives for tailored chemoprevention and treatment of colorectal cancer in Lynch syndrome

Lynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair (MMR) genes. The resulting loss of MMR gene function induces a strong mutator phenotype and predisposition to colorectal cancer (CRC). LS mutation carriers undergo regular colonoscopic surveillance and have extensive colonic resection in case of cancer because of the chance of metachronous tumors. Given the high risk and early onset of CRC, LS mutation carriers are good candidates for chemoprevention. Furthermore, evidence increases indicating that the response of MMR-deficient tumors to standard chemotherapy and radiotherapy differs from that of MMR-proficient tumors. Efforts should thus be directed at designing tailored strategies concerning both chemoprevention and medical cancer treatment for LS individuals. This review provides guidance for future studies in this field based on results from clinical and preclinical research.     

Frequency of hereditary nonpolyposis colorectal cancer in southern Alberta

The frequency of hereditary nonpolyposis colorectal cancer was evaluated in a group of colorectal cancer patients under age 50 diagnosed in southern Alberta between 1973 and 1987. Families were identified as positive for this syndrome if three-first-degree relatives in the kindred had colorectal cancer. Of the 390 patients with adenocarcinoma, 318 patients participated. The frequency of hereditary nonpolyposis colorectal cancer was 3.1% (12 families) in this group (Ci₉₅ 1.6–5.3%). Clinical characteristics reported on from the index patients include tumor location, Dukes stage at presentation, frequency of synchronous and metachronous tumors, frequency of second primaries, and survival. The 5- and 10-year actuarial survival was 86% and 69%, respectively.This work was supported by grants from Alberta Cancer Board and Foothills Hospital Foundation.Presented in part at the annual American Gastroenterological Association meeting (1990).     

Molecular pathways in colorectal cancer

Colorectal cancer (CRC) is the second most common newly diagnosed cancer and accounts for the second highest number of cancer related deaths in Australia, the third worldwide and of increasing importance in Asia. It arises through cumulative effects of inherited genetic predispositions and environmental factors. Genomic instability is an integral part in the transformation of normal colonic or rectal mucosa into carcinoma. Three molecular pathways have been identified: these are the chromosomal instability (CIN), the microsatellite instability (MSI), and the CpG Island Methylator Phenotype (CIMP) pathways. These pathways are not mutually exclusive, with some tumors exhibiting features of multiple pathways. Germline mutations are responsible for hereditary CRC syndromes (accounting for less than 5% of all CRC) while a stepwise accumulation of genetic and epigenetic alterations results in sporadic CRC. This review aims to discuss the genetic basis of hereditary CRC and the different pathways involved in the process of colorectal carcinogenesis.     

Clinical and molecular analysis of hereditary non-polyposis colorectal cancer in Chinese colorectal cancer patients

AIM:To analyze the frequency of hereditary non-polyposis colorectal cancer(HNPCC)in Chinese colorectal cancer(CRC)patients,and to discuss the value of microsatellite instability(MSI)and/or immunohistochemistry(IHC)for MSH2/MLH1 protein analysis as pre-screening tests in China.METHODS:The Amsterdam criteriaⅠandⅡ(clinical diagnosis)and/or germline hMLH1/hMSH2 mutations(genetic diagnosis)were used to classify HNPCC families.Genetic tests,including microsatellite instability,immunohistochemistry for MSH2/MLH1 proteins and hMSH2/hMLH1 genes,were performed in each proband.RESULTS:From July 2000 to June 2004,1988 patients with colorectal cancer were analysed and 114 CRC patients(5.7%)from 48 families were categorized as having HNPCC,including 76 from 26 families diagnosed clinically and 38 from the other 22 families diagnosed genetically.The sensitivity and specificity of high MSI and IHC for predicting mutations were 100% and 54%,and 79% and 77%,respectively.CONCLUSION:The frequency of HNPCC is approximately 10% among all Chinese CRC cases.The MSI and IHC detections for hMSH2/hMLH1 proteins are reliable pre-screening tests for hMLH1/hMSH2 germline mutations in families suspected of having HNPCC.     

Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.