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.

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

条款世袭 Non-Polyposis Colorectal 癌症(HNPCC ) 是林奇描述的症候群的一个差的描述符。在最后十年，条款被用于满足有限临床的标准的家庭的异构的组，例如阿姆斯特丹标准。并非所有阿姆斯特丹标准积极的家庭有 Lynch 症候群，现在是明显的。条款 HNPCC 也被用于有 DNA 微卫星不稳定性的 CRC 在，但是在在哪个没有一个改变的 DNA 失配修理(MMR ) 的垂直传播被诊断，但是在哪个的临床的情形基因。有多重、互相不兼容的意思的一项条款是高度有问题的，特别地当它可以影响一个单个家庭的管理时。Lynch 症候群最好作为遗传素因被理解到恶意被一个细菌线变化在 DNA MMR 基因解释。诊断不在绝对意义取决于任何特别家庭家谱结构或恶意的发作的年龄。有颜色的强壮的家庭历史的家庭没有林奇症候群的表面的癌症作为“家庭 Colorectal 癌症 Type-X ”被组织了。在描绘这些癌症家庭的第一步是把他们与林奇症候群区分开来。术语 HNPCC 不再服务任何有用目的并且应该被逐步停止。

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.

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.

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.

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

瞄准：为了调查一个模糊逻辑模型是否能预言肤色，表面的癌症(CRC ) 风险由在世袭 non-polyposis 肤色吸表面的癌症(HNPCC ) 病人产生了。方法：从 Creighton 大学世袭癌症研究所登记的 340 个 HNPCC 失配修理(MMR ) 变化搬运人为当模特儿被选择。年龄依赖者曲线被产生阐明开发 CRC 的概率上的在基因变化(hMLH1 或 hMSH2 ) 之间的联合效果，性，和吸烟地位。结果：在男 hMSH2 变化搬运人的吸烟显著地增加的 CRC 风险(P 【 0.05 ) 。hMLH1 变化为男性相对 hMSH2 变化搬运人扩充了 CRC 风险(P 【 0.05 ) 。男性们非为 hMLH1 比女性有 CRC 的显著地更高的风险吸烟者(P 【 0.05 ) ， hMLH1 吸烟者(P 【 0.1 ) 并且 hMSH2 吸烟者(P 【 0.1 ) 。以在在男性的 hMSH2 的一种剂量依赖者方式的吸烟支持的 CRC (P 【 0.05 ) 。有 hMSH2 变化的女性和与 hMLH1 组一起的两性仅仅在广泛的吸烟历史以后表明了吸烟效果(P 【 0.05 ) 。结论：由在 HNPCC 病人吸烟的 CRC 提升依赖于基因变化，性和年龄。这些数据证明模糊建模可以启用临床的风险分数的明确的表达，从而允许 CRC 预防策略的 individualization。

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, MLH1 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 MLH1 protein was per- formed 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 MLH1 gene promoter methylation were detected in 18 Chinese HNPCC fami- lies with MSI-H phenotype but without germline muta- tions in MSH2, MLH1 and MSH6 genes. Two of the five probands from families H10 and H29 displayed exhaus- tive-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 ful- filled 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 MSH2, MLH1 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 posi- tive 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 pro- tein. MLH1 promoter methylation analysis is a promis- ing tool for molecular genetics screening for HNPCC.

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

瞄准：检测 MLH1 的细菌线变化，并且在世袭 non-polyposis 颜色的肿瘤纸巾调查微卫星不稳定性和 MLH1 的表示有二个新奇细菌的表面的癌症(HNPCC ) 衬里变化，并且进一步调查 MLH1 的二个新奇变化的病理学。方法：RNA 从为 HNPCC 完成了阿姆斯特丹 II 标准的 12 个不同家庭从 12 个病人的外部血被提取。MLH1 的 Germline 变化被 RT-PCR 决定，由定序分析的 cDNA 列在后面。PCR-GeneScan 分析被用来与新奇变化在二个病人的肿瘤纸巾检测 MLH1 蛋白质的表示的组织化学的染色与五个微卫星标记(BAT26， BAT25， D5S346， D2S123 和 mfd15 ) 的一块面板调查微卫星不稳定性，与免疫一起。结果：三个细菌线变化在四个病人，被发现变化之一以前被报导了，但是其它二，在 8 上的 217 前和在 16 上的 581 前上的鳕鱼的 CCG 右箭头 CTG 上的鳕鱼的 CGC 右箭头 TGC，没被报导。二个病人有新奇变化的肿瘤纸巾有显示出超过二不稳定的部位的高周波的微卫星不稳定性，并且两个肿瘤失去了他们的 MLH1 蛋白质表示。结论：在 HNPCC 家庭的 MLH1 的二个新奇细菌线变化即在 8 上的 217 前和在 16 上的 581 前上的鳕鱼的 CCG 右箭头 CTG 上的鳕鱼的 CGC 右箭头 TGC，是很可能的有病理学的意义。

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 descr ibe 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 50patients (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

瞄准：与世袭 nonpolyposis 颜色在病人检测微卫星不稳定性(MSI ) 表面的癌症或平常的世袭颜色表面的癌症并且为与世袭 nonpolyposis 颜色屏蔽家族提供标准在分子的水平的表面的癌症。方法：MSI 与 HNPCC 从 20 个盒子在标本被检测，有平常的世袭颜色的 20 个盒子有分散的颜色的表面的癌症和 20 个盒子借助于聚合酶链反应单人赛的表面的癌症搁浅符合构造多型性。结果：MSI 的积极的率是 85%(17/20 ) 在 HNPCC 组织， 40%(8/20 ) 在平常的世袭颜色，表面的癌症组织并且 10%(2/20 ) 在分散的颜色，表面的癌症分别地组织。差别是重要的。三个组的吝啬的年龄分别地是 43.6， 52.2，和 61.8 年，它逐渐地增加了。正确的半结肠癌的发生分别地是 64.7% ， 37.5% ，和 0% ，它逐渐地减少了并且有有效差量。BAT26 和 BAT25 的表示比率分别地是 94.1% ，它在地点学习了的 5 基因是最高的。糟糕区分的腺癌的发生在在高频率之中的 HNPCC 组是 70.6% 分别地有 50% 和 50% 的微卫星不稳定性(MSI-H ) 比另外的二个组高，。结论：MSI-H 的发生在 HNPCC 组是更高的。MSI 的察觉简单、节俭并且与 HNPCC 和罐头的临床病理特征有高关联被用作一个屏蔽方法检测失配修理基因的细菌线变化。

Clinical and genetic characteristics of Chinese hereditary nonpolyposis colorectal cancer families

瞄准：到分析，中国世袭 nonpolyposis 的临床的特征渲染表面的癌症(HNPCC ) 家庭并且到屏幕，细菌在职业人员乐队衬里人的失配修理基因 hMLH1 和 hMSH2 的变化。方法：31 个独立中国 HNPCC 家庭在浙江省被收集。所有他们满足了中国 HNPCC 标准。关于耐心的性的临床的数据，颜色的地点表面的癌症，发作的年龄，多重颜色的历史表面的癌症，联系额外的结肠的癌症被记录。PCR 和使中毒的高效液相色谱法(DHPLC ) 被采用屏蔽变化。定序分析被用来发现准确变化地点和显示出反常 DHPLC 侧面的样品的特征。结果：136 个恶意的瘤包括 14 多重癌症在 107 个病人被发现。当， 136 个瘤(77.9%) 中的 106 个被诊断渲染表面的癌症，与在 48.57 +/- 的发作的平均年龄 29.00 年。胃的癌症在这些家庭是最普通的额外的结肠的癌症(10.3%) 。在 hMLHl 和 hMSH2 基因的 23 个不同顺序变化在这 17 个家庭被检测。十五个顺序变化位于前 ons，包括 5 SNP， 3 个沉默变化， 3 个错误感觉变化， 2 个胡说八道变化和 2 框架移动变化。后者七个变化似乎病原。结论：hMLH1 和 hMSH2 基因的 Germline 变化在完成中国 HNPCC 标准的大约三分之一个个 HNPCC 家族被识别。中国 HNPCC 家庭有一些特别临床的特征，例如左边的优势，同步的更少或异时颜色胃的癌症的表面的癌症，和经常的出现。

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.

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.

Genetic predisposition to colorectal cancer:Where we stand and future perspectives

The development of colorectal cancer(CRC)can be influenced by genetic factors in both familial cases and sporadic cases.Familial CRC has been associated with genetic changes in high-,moderate-and low-penetrance susceptibility genes.However,despite the availability of current gene-identification techniques,the genetic causes of a considerable proportion of hereditary cases remain unknown.Genome-wide association studies of CRC have identified a number of common lowpenetrance alleles associated with a slightly increased or decreased risk of CRC.The accumulation of low-risk variants may partly explain the familial risk of CRC,and some of these variants may modify the risk of cancer in patients with mutations in high-penetrance genes.Understanding the predisposition to develop CRC will require investigators to address the following challenges:the identification of genes that cause uncharacterized hereditary cases of CRC such as familial CRC type X and serrated polyposis;the classification of variants of unknown significance in known CRC-predisposing genes;and the identification of additional cancer risk modifiers that can be used to perform risk assessments for individual mutation carriers.We performed a comprehensive review of the genetically characterized and uncharacterized hereditary CRC syndromes and of lowand moderate-penetrance loci and variants identified through genome-wide association studies and candidate-gene approaches.Current challenges and future perspectives in the field of CRC predisposition are also discussed.