Hereditary non-polyposis colorectal cancer: The rise and fall of a confusing term

The term Hereditary Non-Polyposis Colorectal Cancer （HNPCC） is a poor descriptor of the syndrome described by Lynch. Over the last decade, the term has been applied to heterogeneous groups of families meeting limited clinical criteria, for example the Amsterdam criteria. It is now apparent that not all Amsterdam criteria-positive families have the Lynch syndrome. The term HNPCC has also been applied to clinical scenarios in which CRCs with DNA microsateUite instability are diagnosed but in which there is no vertical transmission of an altered DNA mismatch repair （MMR） gene. A term that has multiple, mutually incompatible meanings is highly problematic, particularly when it may influence the management of an individual family. The Lynch syndrome is best understood as a hereditary predisposition to malignancy that is explained by a germline mutation in a DNA MMR gene. The diagnosis does not depend in an absolute sense on any particular family pedigree structure or age of onset of malignancy. Families with a strong family history of colorectal cancer that do not have Lynch syndrome have been grouped as ‘Familial Colorectal Cancer Type-X＇. The first step in characterizing these cancer families is to distinguish them from Lynch syndrome. The term HNPCC no longer serves any useful purpose and should be phased out.

Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families:Implications for genetic testing

AIM: To analyze the prevalence of germline MLH1 and MSH2 gene mutations and evaluate the clinical characteristics of Hungarian hereditary non-polyposis colorectal cancer (HNPCC) families. METHODS: Thirty-six kindreds were tested for mutations using conformation sensitive gel electrophoreses, direct sequencing and also screening for genomic rearrangements applying multiplex ligation-dependent probe amplifi cation (MLPA). RESULTS: Eighteen germline mutations (50%) were identifi ed, 9 in MLH1 and 9 in MSH2. Sixteen of these sequence alterations were considered pathogenic, the remaining two were non-conservative missense alterations occurring at highly conserved functional motifs. The majority of the defi nite pathogenic mutations (81%, 13/16) were found in families fulfilling the stringent Amsterdam Ⅰ/Ⅱ criteria, including three rearrangements revealed by MLPA (two in MSH2 and one in MLH1). However, in three out of sixteen HNPCC-suspected families (19%), a disease-causing alteration could be revealed. Furthermore, nine mutations described here are novel, and none of the sequence changes were found in more than one family.CONCLUSION: Our study describes for the f irst time the prevalence and spectrum of germline mismatch repair gene mutations in Hungarian HNPCC and suspected-HNPCC families. The results presented here suggest that clinical selection criteria should be relaxed and detection of genomic rearrangements should be included in genetic screening in this population.

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 criteria Ⅰ and Ⅱ （clinical diagnosis） and/or germline hMLHI/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 prescreening tests for hMLHI/hMSH2 germline mutations in families suspected of having HNPCC.

Risk of colon cancer in hereditary non-polyposis colorectal cancer patients as predicted by fuzzy modeling:Influence of smoking

AIM： To investigate whether a fuzzy logic model could predict colorectal cancer （CRC） risk engendered by smoking in hereditary non-polyposis colorectal cancer （HNPCC） patients. METHODS： Three hundred and forty HNPCC mismatch repair （MMR） mutation carriers from the Creighton University Hereditary Cancer Institute Registry were selected for modeling. Age-dependent curves were generated to elucidate the joint effects between gene mutation （hMLH1 or hMSH2）, gender, and smoking status on the probability of developing CRC. RESULTS： Smoking significantly increased CRC risk in male hMSH2 mutation carriers （P 〈 0.05）. hMLH1 mutations augmented CRC risk relative to hMSH2 mutation carriers for males （P 〈 0.05）. Males had a significantly higher risk of CRC than females for hMLH1 non smokers （P 〈 0.05）, hMLH1 smokers （P 〈 0.1） and hMSH2 smokers （P 〈 0.1）. Smoking promoted CRC in a dose-dependent manner in hMSH2 in males （P 〈 0.05）. Females with hMSH2 mutations and both sexes with the hMLH1 groups only demonstrated a smoking effect after an extensive smoking history （P 〈 0.05）. CONCLUSION： CRC promotion by smoking in HNPCC patients is dependent on gene mutation, gender and age. These data demonstrate that fuzzy modeling may enable formulation of clinical risk scores, thereby allowing individualization of CRC prevention strategies.

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.

MLH1 promoter germline-methylation in selected probands of Chinese hereditary non-polyposis colorectal cancer families

AIM： To detect the MLH1 gene promoter germline- methylation in probands of Chinese hereditary non- polyposis colorectal cancer （HNPCC）, and to evaluate the role of methylation in MLH1 gene promoter and molecular genetics in screening for HNPCC.METHODS： The promoter germline methylation of MLH1 gene was detected by methylation-specific PCR （MSP） in 18 probands from unrelated HNPCC families with high microsatellite-instability （MSI-H） phenotype but without germline mutations in MSH2, MLH1 and MSH6 genes. At the same time, 6 kindreds were col- lected with microsatellite-stability （MSS） phenotype but without germline mutations in MSH2, MIH1 and MSH6 genes as controls. The results of MSP were confirmed by clone sequencing. To ensure the reliability of the results, family H65 with nonsense germline mutation at c.2228C 〉 A in MSH2 gene was used as the negative control and the cell line sw48 was used as the known positive control along with water as the blank control. Immunochemical staining of MIH1 protein was performed with Envision two-step method in those patients with aberrant methylation to judge whether the status of MLH1 gene methylation affects the expression of MLH1 protein.RESULTS： Five probands with MIH1 gene promoter methylation were detected in 18 Chinese HNPCC families with MSI-H phenotype but without germline mutations in MSH2, MLH1 and MSH6 genes. Two of the five probands from families H10 and H29 displayed exhaustive-methylation, fulfilling the Japanese criteria （JC） and the Amsterdam criteria （AC）, respectively. The other 3 probands presented part-methylation fulfilling the AC. Of the 13 probands with unmethylation phenotype, 8 fulfilled the JC and the Bethesda guidelines （BG）, 5 fulfilled the AC. The rate of aberrant methylation in MLH1 gene in the AC group （22.2%, 4/18） was higher than that in the JC/BG groups （5.6%, 1/18） in all HNPCC families with MSI-H phenotype but without germline mutations in PISH2, PIIH1 and MSH6 genes. However, no proband with methylation in MLH1 gene was found in the families with MSS phenotype and without germline mutations in MSH2, MLH1 and MSH6 genes. No expression of MLH1 protein was found in tumor tissues from two patients with exhaustive-methylation phenotype, whereas positive expression of MLH1 protein was observed in tumor tissues from patients with partial methylation phenotype （excluding family H42 without tumor tissue）, indicating that exhaustive-methylation of MLH1 gene can cause defective expression of MLH1 protein.CONCLUSION： Methylation phenotype of MLH1 gene is correlated with microsatellite phenotype of MMR genes, especially with MSI-H. Exhaustive-methylation of MLH1 gene can silence the expression of MLH1 protein. MLH1 promoter methylation analysis is a promising tool for molecular genetics screening for HNPCC.

Three novel missense germline mutations in different exons of MSH6 gene in Chinese hereditary non-polyposis colorectal cancer families

AIM: To investigate the germline mutations of MSH6 gene in probands of Chinese hereditary non-polyposis colorectal cancer (HNPCC) families fulfilling different clinical criteria. METHODS: Germline mutations of MSH6 gene were detected by PCR-based DNA sequencing in 39 unrelated HNPCC probands fulfilling different clinical criteria in which MSH2 and MLH1 mutations were excluded. To further investigate the pathological effects of detected missense mutations, we analyzed the above related MSH6 exons using PCR-based sequencing in 137 healthy persons with no family history. The clinicopathological features were collected from the Archive Library of Cancer Hospital, Fudan University and analyzed. RESULTS: Four germline missense mutations distributed in the 4th, 6th and 9th exons were observed. Of them, three were not found in international HNPCC databases and did not occur in 137 healthy controls, indicating that they were novel missense mutations. The remaining mutation which is consistent with the case H14 at c.3488A>T of exon 6 of MSH6 gene was also found in the controls, the rate was approximately 3.65% (5/137) and the type of mutation was not found in the international HNPCC mutational and SNP databases, suggesting that this missense mutation was a new SNP unreported up to date. CONCLUSION: Three novel missense mutations and a new SNP observed in the probands of Chinese HNPCC families, may play an important role in the development of HNPCC.

Clinicopathological features of typical and nontypical hereditary non-polyposis colorectal cancer and their germline mutation of hMLH_1 and hMSH_2

Objective To study the clinicopathological features of the Chinese hereditary non-polyposis colorectal cancer and its germline mutation of hMLH1 and hMSH2. Methods Thirteen typical Chinese hereditary non-polyposis colorectal carcinoma (HNPC) C kindreds and 19 nontypical HNPCC families were registered and followed up. The germline mutation of the hMLH1 and hMSH2 of 12 index cases of 6 typical and 6 nontypical NHPCC were screened by PCR-SSCP. Samples with abnormal mobility were sequenced direcdy. Results The average age of typical HNPCC was 47, no difference existed between sexs. Location of the tumors of typical HNPCC represented 44.7% on the right half colon and non-typical HNPCC 65. 8% on the rectum. The rate of the metachronos cancer was 11.5%. The 3 - , 5 - and 10 -year survival rate was 64. 0%, 45. 3% and 31. 2% respectively. Among 12 cases, 8 showed abnormal mobility. Except for an intron polymorphinism, six exons abnormalities were found in 5 of 12 proband. Sequencing showed 4 missense,7

Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer

Colorectal cancer is the second most leading cause of cancer related deaths in the western countries. One of the forms of colorectal cancer is hereditary non-polyposis colorectal cancer (HNPCC), also known as "Lynch syndrome". It is the most common hereditary form of cancer accounting for 5%-10% of all colon cancers. HNPCC is a dominant autosomal genetic disorder caused by germ line mutations in mismatch repair genes. Human mismatch repair genes play a crucial role in genetic stability of DNA, the inactivation of which results in an increased rate of mutation and often a loss of mismatch repair function. Recent studies have shown that certain mismatch repair genes are involved in the regulation of key cellular processes including apoptosis. Thus, differential expression of mismatch repair genes particularly the contributions of MLH1 and MSH2 play important roles in therapeutic resistance to certain cytotoxic drugs such as cisplatin that is used normally as chemoprevention. An understanding of the role of mismatch repair genes in molecular signaling mechanism of apoptosis and its involvement in HNPCC needs attention for further work into this important area of cancer research, and this review article is intended to accomplish that goal of linkage of apoptosis with HNPCC. The current review was not intended to provide a comprehensive enumeration of the entire body of literature in the area of HNPCC or mismatch repair system or apoptosis; it is rather intended to focus primarily on the current state of knowledge of the role of mismatch repair proteins in molecular signaling mechanism of apoptosis as it relates to understanding of HNPCC.

Two novel germline mutations of MLH1 and investigation of their pathobiology in hereditary non-polyposis colorectal cancer families in China

AIM： To detect germline mutations of MLH1, and investigate microsatellite instability and expression of MLH1 in tumor tissues of hereditary non-polyposis colorectal cancer （HNPCC） with two novel germline mutations, and further investigate the pathobiology of the two novel mutations of MLH1. METHODS： RNA was extracted from the peripheral blood of 12 patients from 12 different families that fulfilled the Amsterdam 11 Criteria for HNPCC. Germline mutations of MLH1 were determined by RT-PCR, followed by cDNA sequencing analysis. PCR-GeneScan analysis was used to investigate microsatellite instability with a panel of five microsatellite markers （BAT26, BAT25, D5S346, D2S123 and mfd15）, along with immunohistochemical staining to detect the expression of MLH1 protein in two patients＇ tumor tissues with novel mutations. RESULTS： Three germline mutations were found in four patients, one of the mutations has previously been reported, but the other two, CGC→TGC at codon 217 of exon 8 and CCG→CTG at codon 581 of exon 16, have not been reported. The two patients＇ tumor tissues with novel mutations had high-frequency microsatellite instability that showed more than two unstable loci, and both tumors lost their MLH1 protein expression. CONCLUSION： The two novel germline mutations of MLH1 in HNPCC families i.e. CGC→TGC at codon 217 of exon 8 and CCG→CTG at codon 581 of exon 16, are very likely to have pathological significance.

Dual primary gastric and colorectal cancer:The known hereditary causes and underlying mechanisms

In this editorial,I commented on the paper by Lin et al,published in this issue of the World Journal of Gastrointestinal Oncology.The work aimed at analysing the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with dual primary gastric and colorectal cancer(CRC).The authors concluded the necessity for regular surveillance for metachronous cancer during postoperative follow-up and reported the prognosis is influenced by the gastric cancer(GC)stage rather than the CRC stage.Although surveillance was recommended in the conclusion,the authors did not explore this area in their study and did not include tests used for such surveillance.This editorial focuses on the most characterized gastrointestinal cancer susceptibility syndromes concerning dual gastric and CRCs.These include hereditary diffuse GC,familial adenomatous polyposis,hereditary nonpolyposis colon cancer,Lynch syndrome,and three major hamartomatous polyposis syndromes associated with CRC and GC,namely Peutz-Jeghers syndrome,juvenile polyposis syndrome,and PTEN hamartoma syndrome.Careful assessment of these syndromes/conditions,including inheritance,risk of gastric and colorectal or other cancer development,genetic mutations and recommended genetic investigations,is crucial for optimum management of these patients.

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 worldwide.It follows a birth-cohort effect which probably reflects a change in exposure to CRC risk factors.Its incidence is predicted to double until 2030,which makes EO-CRC a serious public health issue.Both modifiable and non-modifiable risk factors have been identified-some are potential targets for preventive measures.EO-CRC is often diagnosed at advanced stages and histological features associated with poor prognosis have been described.EO-CRC presents some distinctive features:Microsatellite instability is common,but another subtype of tumours,both microsatellite and chromosome stable also seems relevant.There are no age-specific treatment protocols and studies on EO-CRC survival rates have shown conflicting data.Due to the higher germline pathological mutations found in EO-CRC patients,an accurate genetic risk evaluation should be performed.In this review,we summarize the current evidence on epidemiological,clinical,histopathological and molecular features of EO-CRC and discuss the contribution of genetics and lifestyle risk factors.We further comment on screening strategies and specific dimensions to consider when dealing with a younger cancer patient.

Germline mutation analysis of hPMS2 gene in Chinese families with hereditary nonpolyposis colorectal cancer

AIM: To study the germline mutation of hPMS2 gene in 26 unrelated Chinese hereditary nonpolyposis colorectal cancer (HNPCC) probands and to fulfill the screening strategy for HNPCC in Chinese. METHODS: Genomic DNA was extracted from the peripheral blood. To avoid the interference of pseudogene in detection of the remaining 11 exons (exon 1-5, 9, 11-15), long-range polymerase chain reaction (PCR) was conducted to amplify the complete coding region of hPMS2 gene firstly. Then 1/8 of the PCR productswere used as template to amplify the individual exon respectively and DNA sequencing was done. Direct DNA sequencing of the conventional PCR products of exon 6, 7, 8 and 10 of hPMS2 gene was performed. The same analysis was made in 130 healthy persons without family histories of HNPCC to further investigate the pathological effects of the detected missense mutation. RESULTS: One HNPCC proband fulf illed Bethesda guidelines and was found to carry the germline mutation of hPMS2 gene, which has not been reported in Chinese HNPCC families. It was a missense mutation at c.1532C>T of exon 11. It was detected in three controls as well with an occurrence rate of 2.3% (3/130). Since it could not be found in the PMS2-single nucleotide polymorphism (SNP) database, this missense mutation is a new SNP unreported up to date. Meanwhile, 260 reported SNPs of hPMS2 gene were detected in the 26 HNPCC probands. The 2nd and 5th exons were probably the hot SNP regions of hPMS2 gene in Chinese HNPCC families involving 53.1% of all reported SNP. CONCLUSION: The germline mutation of hPMS2 gene may be rare in Chinese HNPCC families. The 2nd and 5th exons are hot SNP regions of hPMS2 gene.

Clinical phenotype and prevalence of hereditary nonpolyposis colorectal cancer syndrome in Chinese population

AIM: To describe systematically the clinical characteristics and phenotype of HNPCC families and the prevalence of HNPCC in the general population of CRC patients in China. METHODS: HNPCC kindreds and CRC patients were from two sources. One was that we consecutively investigated kindreds and patients by ourselves. And the other was the published Chinese and foreign literature related to Chinese HNPCC syndrome. There were 142 HNPCC families fulfilling AC I and/or AC II including 57 families with detailed data, and 3874 general primary CRC patients in all. All statistical tests were two-sided. RESULTS: In AC I families, the number of Lynch syndrome I and II families were 25 (47.2%) and 28 (52.8%) respectively. There were 215 patients (82.4%) with CRC, 67 patients (25.7%) with extracolonic cancer and 50 patients (19.2%) with multiple primary cancers. In all CRC patients, multiple primary CRC were in 41 patients (19.1%), and the first-CRC was right-sided colorectal cancer in 143 patients (66.5%) and rectal cancer in 44 patients (20.5%). 8.8% and 19.2% of the first cancer were CRC and extracolonic cancers. Among those patients whose first cancer was CRC, 66.8% and 19.9% were right-sided colorectal cancer and rectal cancer, respectively. The similar results were found in AC II families. Normal distribution was only found in the distribution of the age of diagnosis of the first cancer in both AC I families (coefficient of skewness: u = 0.81, 0.20<0.40<P<0.50; coefficient of kurtosis: u = 1.13, 0.20<P<0.40,α=0.20) and AC II families (coefficient of skewness: u=0.63, P>0.5> 0.20; coefficient of kurtosis: u = 0.84, 0.20<0.40<P<0.50, α=0.20), but not found in the distribution of the age of diagnosis of the first CRC. When patients with HNPCC-associated cancer suffered from the first malignant tumor in HNPCC families diagnosed by AC I and AC II, the mean age and median age were 45.1±12.7 years and 44.0 years, 45.2±12.7 years and 44.5 years, respectively. The median age of diagnosis of the first tumor of the patients in the later generation was younger than that in the previous generation. Many extracolonic cancers were found to be associated with HNPCC syndrome. Gastric cancer was the most frequent extracolonic cancer followed by endometrial cancer and hepatocarcinoma. In general population of CRC patients, the prevalence of HNPCC diagnosed by AC I and AC II were 1.3% and 2.2%, respectively. CONCLUSION: The clinical phenotype and prevalence of Chinese HNPCC syndrome are similar to those of Europeans and Americans. Gastric cancer is the most common extracolonic malignant tumor. The age of diagnosis of the first malignant tumor tends to be increasingly younger in patients with HNPCC-related tumors.

Role of detection of microsatellite instability in Chinese with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer

AIM： To detect microsatellite instability （MSI） in patients with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer and to provide criteria for screening the kindreds with hereditary nonpolyposis colorectal cancer at molecular level.METHODS： MSI was detected in the specimens from 20 cases with HNPCC, 20 cases with ordinary hereditary colorectal cancer and 20 cases with sporadic colorectal cancer by means of polymerase chain reaction-single strand conformation polymorphism. RESULTS： The positive rate of MSI was 85% （17/20） in HNPCC group, 40% （8/20） in ordinary hereditary colorectal cancer group and 10% （2/20） in the sporadic colorectal cancer group respectively. The differences were significant. The mean ages of the three groups were 43.6, 52.2, and 61.8 years respectively, which increased gradually. The incidence of right hemicolon cancer was 64.7%, 37.5%, and 0% respectively, which decreased gradually and had significant difference. The expression ratio of BAT26 and BAT25 was 94.1% respectively, which was highest in the 5 gene sites studied. The incidence of poorly differentiated adenocarcinoma was 70.6% in HNPCC group among high frequency microsatellite instability （MSI-H）, which was higher than the other two groups, which had 50% and 50% respectively. CONCLUSION： The incidence of MSI-H is higher in HNPCC group. The detection of MSI is simple and economical and has high correlation with the clinicopathologic feature of HNPCC and can be used as a screening method to detect the germ line mutation of the mismatch repair gene.

Clinical and genetic characteristics of Chinese hereditary nonpolyposis colorectal cancer families

AIM： To analyze the clinical characteristics of Chinese hereditary nonpolyposis colorectal cancer （HNPCC） families and to screen the germline mutations of human mismatch repair genes hMLH1 and hMSH2 in the probands. METHODS： Thirty-one independent Chinese HNPCC families were collected in Zhejiang Province. All of them met Chinese HNPCC criteria. Clinical data about patient gender, site of colorectal cancer, age of onset, history of multiple colorectal cancer, associated extracolonic cancer were recorded. PCR and denaturing high performance liquid chromatography （DHPLC） were employed to screen the mutations. Sequencing analysis was used to find out the exact mutation site and characteristics of the samples showing abnormal DHPLC profiles. RESULTS： One hundred and thirty-six malignant neoplasms were found in 107 patients including 14 multiple cancers. One hundred and six of the 136 neoplasms （77.9%） were diagnosed as colorectal cancer, with an average age of onset at 48.57 ±29.00 years. Gastric cancer was the most common extracolonic cancer （10.3%） in these families. Twenty-three different sequence variations in hMLHI and hMSH2 genes were detected in these 17 families. Fifteen sequence variations were located in the exons, including 5 SNPs, 3 silent mutations, 3 missense mutations, 2 nonsense mutations and 2 frameshift mutations. The latter seven mutations seemed to be pathogenic. CONCLUSION： Germline mutations of hMLH1 and hMSH2 genes are identified in about one-third HNPCC kindreds fulfilling Chinese HNPCC criteria. Chinese HNPCC families have some particular clinical characteristics, such as a left-sided predominance, less synchronous or metachronous colorectal cancer, and frequent occurrence of gastric cancer.

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.

Early-onset colorectal cancer:A sporadic or inherited disease?

Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a &#x0201c;sporadic&#x0201d; subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the &#x0201c;sporadic&#x0201d; subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this &#x0201c;sporadic&#x0201d; early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.

Colorectal cancer in young adults: A difficult challenge

Sporadic colorectal cancer(CRC) is traditionally diagnosed after the sixth decade of life,and current recommendations for surveillance include only patients older than 50 years of age. However,an increasing incidence of CRC in patients less than 40 years of age has been reported. This occurrence has been attributed to different molecular features and low suspicion of CRC in young symptomatic individuals. When confronting young-onset CRC with older patients,issues such as biological aggressiveness,stage at diagnosis and clinical outcomes seem to differ in many aspects. In the future,the identification of the molecular profile underlying the early development of sporadic CRC will help to plan tailored screening recommendations and improve management. Besides that,differential diagnosis with CRC linked with hereditary syndromes is necessary to provide adequate patient treatment and family screening. Until we find the answers to some of these doubts,doctors should raise suspicion when evaluating an young adult and be aware of this risk and consequences of a late diagnosis.

Young-onset colorectal cancer:A review

Despite the general decrease in overall incidence of colorectal cancer since the early 1990s,the incidence of colorectal cancer in patients less than 50 years old has nearly doubled.A systematic review was performed using the PubMed database(2011-2020)and Cochrane Database of Systematic Reviews(2011-2021)to identify studies(published in English)evaluating epidemiologic,clinical,hereditary,and molecular features;as well as evaluation,management,and prognosis of youngonset colorectal cancer patients.Our search yielded a total of 3401 articles,after applying our inclusion criteria.We fully reviewed 94 full-length studies.This systematic review demonstrates the increasing incidence of young-onset colorectal cancer and highlights the importance of being hypervigilant for the differential diagnosis colorectal cancer when evaluating a young adult who presents with gastrointestinal symptoms.