Spectrum of molecular alterations in colorectal, upper urinary tract, endocervical, and renal carcinomas arising in a patient with hereditary non-polyposis colorectal cancer

Hereditary nonpolyposis colon cancer (HNPCC) syndrome is the most frequent hereditary cancer syndrome predisposing to cancers of various locations, especially colon, endometrium, stomach, and upper urinary tract. Carcinomas of the kidney parenchyma are not considered as an HNPCC-related tumor. HNPCC tumors are characterized by microsatellite instability (MSI) due to a defect in mismatch repair (MMR) and carry somatic frameshift mutations in mononucleotide repeats within the coding regions of key genes. We report the first case of a papillary carcinoma of the kidney in an HNPCC patient who developed carcinomas of the upper urinary tract, endocervix, and colon. Whereas the HNPCC-related tumors demonstrated MSI phenotype, loss of MSH2 protein expression, and frameshift mutations in several of the 13 target genes analyzed, the kidney cancer displayed MSS phenotype, normal MMR protein expression, and no frameshift mutation in target genes. Our observations do not support the possibility that papillary carcinomas are part of HNPCC syndrome.     

Detection of Tn, sialosyl-Tn and T antigens in hereditary nonpolyposis colorectal cancer

The simple mucin-type carbohydrate antigens Tn, sialosyl-Tn, T and the cryptic sialylated variant of the last represent the mucin core oligosaccharide structures that are produced in the initial steps of the mucin biosynthetic pathway. Utilizing monoclonal antibodies anti-Tn antigen (HB-Tn1), anti-sialosyl-Tn antigen (HB-STn1), anti-T antigen (HB-T1) and the biotinylated Amaranthus caudatus agglutinin (ACA), we have investigated the expression of the simple mucin-type carbohydrate antigens in hereditary nonpolyposis colorectal cancer (HNPCC; 15 cases) compared with sporadic colorectal cancer (CRC; 60 cases) and normal colonic mucosa (30 cases). A variable positivity of Tn, sialosyl-Tn, T and the cryptic sialylated form of this latter antigen was encountered in both HNPCC and sporadic CRC cases; in addition, in normal colonic mucosa a constant reactivity was encountered only for Tn and the cryptic sialylated form of T, while negative results were always obtained for sialosyl-Tn and T antigens. Statistical analysis, performed using a Chi-square test, showed significantly lower (P=0.037) expression of sialosyl-Tn and higher (P=0.022) expression of T in HNPCC than in sporadic CRC, suggesting a greater presence of 1,3 galactosyl-transferase activity in HNPCC than in sporadic CRC. We were unable to identify a peculiar phenotype for HNPCC with simultaneous evaluation of reactivity for HB-Tn1, HB-STn1, HB-T1 and ACA; the biological significance of the preferential expression of T antigen in HNPCC remains to be investigated.     

遗传性非息肉病性结直肠癌的家系和染色体脆性部位研究

目的：报道一个遗传性非息肉病性结直肠癌的家系和细胞遗传学特征。方法：家系调查通过查阅患者病历,走访经治医生和知情成员所获得。细胞遗传学研究采用了外周血淋巴细胞脆性部位培养技术和G显带分析方法。结果：该家族患者符合阿姆斯特丹诊断标准,先证者祖父母后代发病呈常染色体显性遗传,致病基因来源于先证者祖母。细胞遗传学研究显示9例成员染色体异常率高达55．6％,其中1例正常成员亦检到脆性部位,是重点监测和随访的末病对象;表现为显性遗传的先证者祖父母后代5例成员与5例患者染色体异常率均达80％（4／5）。结论：根据系谱中发病规律和患者很高的染色体脆性部位检出率为该家族成员的发病预测、筛查、早诊断、早治疗具有简便、实用、经济的特点和应用价值,可让部分家族成员避免反复检查的痛苦。     

Detection of microsatellite instability in human colorectal carcinomas using a non-radioactive PCR-based screening technique

The aim of the present study was to establish a rapid, non-radioactive screening method for the detection of microsatellite instability (MIN). MIN is the primary characteristic of the mutator phenotype in tumours constituting hereditary non-polyposis colon cancers (HNPCC). We investigated 30 patients suffering from colorectal cancer using a non-radioactive PCR-based technique. MIN was present in 7 of 30 (23%) of the cases. There was a statistically significant correlation between MIN and localization of the tumour. Five of 7 (72%) tumours with MIN but only 4 of 23 (17%) tumours without MIN were localized in the proximal colon (P<0.01). There was a tendency to higher MIN frequency in tumours of patients with familial clustering of cancers. However, this was statistically not significant (P>0.05). In addition, no correlation between MIN and tumour grade and stage was found. For the investigations in the present study we used a non-radioactive PCR-based method followed by denaturating polyacrylamide gel electrophoresis and silver staining. This method is highly sensitive and reproducible. Thus, PCR-based analysis using a non-radioactive staining technique represents a comprehensive tool for MIN screening in diagnostic pathology.     

Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature

Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair-deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum. Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families. As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome.     

Novel germline mutations of hMSH2 in a patient with hereditary nonpolyposis colorectal cancer (HNPCC) and in a patient with six primary cancers

We screened for germline mutations of mismatch repair genes, hMLH1 and hMSH2, in five Japanese families carrying hereditary nonpolyposis colorectal cancer (HNPCC) and in a patient with multiple primary cancers. Screening the entire coding regions of both genes using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, we found two novel germline mutations in hMSH2. One was a 1-bp insertion in exon 12, detected in a patient who had undergone surgery six times for independent tumors (four primary colorectal carcinomas, a small intestinal carcinoma, and an endometrial cancer). The other, in a second patient, was a missense mutation from CTT to TTT at codon 390 in exon 7 that resulted in substitution of phenylalanine for leucine. This conservative alteration was not found in any of 50 normal controls, but we cannot exclude the possibility that it may represent a rare polymorphism rather than a factor in the disease. Received: November 13, 1997 / Accepted: January 14, 1998     

遗传性非息肉性大肠癌患者中hMLH1和hMSH2基因遗传性突变的分析

目的通过分析遗传性非息肉性大肠癌（ＨＮＰＣＣ）患者错配修复基因的遗传性突变，对患者的家族成员进行遗传咨询和症状前的基因诊断。方法用ＰＣＲ－异源双链体形成、ＰＣＲ－ＳＳＣＰ和ＤＮＡ序列分析技术，检测１４例ＨＮＰＣＣ、１０例有家族史大肠癌患者的外周血细胞ＤＮＡ，分析其错配修复基因ｈＭＬＨ１、ｈＭＳＨ２的所有３５个外显子。结果确认４／１４的ＨＮＰＣＣ、１／１０有家族史的大肠癌患者携带遗传性错配修复基因的突变，其中２例见于ｈＭＬＨ１基因，３例ｈＭＳＨ２基因。突变类型：３例由碱基缺失导致的移码突变，１例无义突变，１例错义突变。结论ＨＮＰＣＣ的发生与错配修复基因的突变密切相关；在大肠癌患者中检测遗传性错配修复基因的突变不宜仅限于严格符合临床诊断标准的ＨＮＰＣＣ患者。     

Chromosomal instability and APC gene mutations in human sporadic colorectal adenomas

The mechanisms by which adenomatous polyposis coli (APC) gene mutations contribute to colorectal tumourigenesis and progression are still not fully understood. Using in vitro mouse embryonic stem cells, APC mutations have been proposed to dysregulate the interactions between kinetochores and microtubules during mitosis, leading to chromosomal instability (CIN) and aneuploidy. A link between APC mutations and aneuploidy in vivo among human sporadic colorectal adenomas has not been reported previously and was therefore investigated in the present series of 61 adenomas. Multi-parameter flow cytometry, based on scattering and fluorescence from the DNA-specific 4,6-diamidino-2-phenylindole-2-hydrochloride (DAPI) dye, which separates epithelial from stromal lymphocyte nuclei, was used to evaluate the DNA index (DI) and to sort epithelial nuclei. Additionally, DNA extracted from these sorted nuclei was used to analyse APC mutations by DNA sequencing. Aneuploidy was present in 20 of 61 adenomas (33%), with 15 of these 20 cases (75%) having a near-diploid DI (DI different from 1 and less than 1.3). APC mutations were detected in 19 adenomas (31%): 12 were within or downstream of the mutation cluster region (MCR), roughly defined by codons 1200-1500, and seven were upstream of the MCR. Overall, the prevalence of aneuploidy in APC wild-type and mutated adenomas was 26% and 47%, respectively, and no statistically significant association was found between APC status and DI (p = 0.142). However, when APC mutations were subdivided into two groups, ie occurring within/downstream of the MCR and upstream of the MCR, the association of APC mutations within and downstream of the MCR with aneuploidy was statistically significant (p = 0.017). In conclusion, the present data suggest that the type of APC mutation may play a role in the origin of CIN in vivo in human sporadic colorectal adenomas and that APC mutations within and downstream of the MCR, and large-scale chromosomal alterations, may co-operate in the progression of a subgroup of adenomas.     

An appendix carcinoid tumor in a patient with hereditary nonpolyposis colorectal cancer

Gastrointestinal carcinoid tumors are often associated with other tumors, particularly colon adenocarcinomas; but the association between carcinoid tumors and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has not yet been explored. We report an unusual case of a 28-year-old woman with HNPCC who underwent surgery for a transverse colon adenocarcinoma in whom an appendix carcinoid tumor was incidentally found. To assess whether the carcinoid tumor displayed the characteristic molecular features of HNPCC tumors, we investigated the expression of mismatch-repair (MMR) proteins and microsatellite instability (MSI) status in both tumors. Both tumors demonstrated normal expression of the MMR proteins hMLH1, hMSH2, hMSH6, and hPMS2. Interestingly, the adenocarcinoma exhibited an MSI phenotype but the carcinoid tumor did not, indicating that these 2 tumors arose through different molecular pathways.     

Microsatellite instability in sporadic mucinous colorectal carcinomas: relationship to clinico-pathological variables

A series of 44 sporadic mucinous colorectal carcinomas was analysed for microsatellite instability; 30 consecutive sporadic non-mucinous colorectal cancers served as controls. Mucinous carcinomas showed microsatellite instability more frequently than non-mucinous cancers: 26/44 and 8/30, respectively (P=0·005); the difference was higher for cancers with two or more microsatellite alterations: 12 of the 44 mucinous carcinomas versus one of the 30 non-mucinous carcinomas (P=0·007). On comparing the clinico-pathological features of mucinous carcinomas with and without microsatellite instabilities, no differences were found with respect to the following variables: sex ratio, tumour localization, tumour size, peritumoural lymphocytic infiltration, Crohn's-like lymphoid reaction, peritumoural fibrosis, Dukes' stage, and relationship with adenoma. Mucinous cancers with DNA replication errors were characterized by three features: onset in younger patients (P<0·05); exophytic gross shape (P=0·03); and an expanding pattern of growth (P=0·003). Of the 12 mucinous carcinomas with instability in two or more microsatellites, ten (83·3 per cent) exhibited an expanding pattern of growth, while mucinous cancers with instability in one microsatellite or without genomic instability showed no distinctive growth pattern. This study confirms the relationship between microsatellite instabilities and mucin production in colorectal carcinomas, but shows that replication error RER-positive and RER-negative mucinous cancers differ in few clinico-pathological features. These differences are only in part similar to those previously reported in RER-positive colorectal carcinomas. These data indicate that mucinous carcinoma of the large bowel could represent a histological subset separate from other histotypes. © 1997 John Wiley & Sons, Ltd.     

HNPCC发病中错配修复基因错义突变功能分析的研究进展

遗传性非息肉性结直肠癌(HNPCC)为最常见的常染色体显性遗传病之一，发病的直接原因为患者携带错配修复基因的胚系突变，其中错义突变约占已检突变的三分之一。因此建立有效的错义突变功能评估体系，确定检出突变的病因学作用具有重要意义。基于对错配修复系统功能的认识，目前对其基因编码蛋白质的功能研究，取得了突破性进展，主要从两个方面入手：（1）分析其功能活动过程中存在的蛋白质之间的相互作用，（2）分析错配修复基因功能活动的结果。     

Clinicopathological features and phenotypic classification of de novo‐type colorectal carcinomas differ from those of colorectal carcinomas derived from flat adenomas

Since adenoma components disappear with tumor progression, it is not known whether colorectal carcinomas (CRCs) are derived from an adenoma–carcinoma sequence or are de novo. We compared 38 cases of ≤10‐mm flat CRCs without an adenoma component (de novo type) with 39 cases of ≤10‐mm flat CRCs with an adenoma component (carcinoma in adenoma (CIA) type). Compared to the CIA type, the de novo‐type CRCs were more frequently located in the proximal colon; more frequently invaded submucosa, and more frequently had venous permeation. Regarding the phenotypic classification based on the immunohistochemical expressions of CD10, MUC2 and MUC5AC, the incidence of unclassified type (CD10?, MUC2? and MUC5AC?) was significantly more frequent in the de novo (32%) than CIA (5%) type. In one de novo‐type case, mismatch repair (MMR) protein loss was judged, because MLH1 and PMS2 protein expressions were immunohistochemically negative. BRAF mutation (V600E) was seen in one de novo‐type case and two CIA‐type cases, but none of these cases had MMR protein loss. In conclusion, small‐intestinal type (CD10+ and MUC5AC?) is the most common in flat CRC and unclassified type is mainly characteristic of de novo type. In this study, small flat CRCs with BRAF mutation do not have MMR protein loss.     

Microsatellite instability: new aspects in the carcinogenesis of colorectal carcinoma

Very recently a new molecular mechanism in the tumorigenesis of colorectal carcinoma has been described which is closely linked to hereditary non-polyposis colonic cancer (HNPCC). Ubiquitous changes in the length of simple repetitive DNA sequences between constitutional and tumour DNA occur in about 90% of cases of HNPCC and in about 15% of cases of non-familial, sporadic colorectal carcinoma. Such microsatellite instabilities have been shown to be the phenotypical marker of mutations in the human homologues of prokaryotic mismatch repair genes (MutS, MutL, MutH). These data provide crucial new tools in the detection of patients at high risk of developing colon cancer and other HNPCC-related carcinomas. In addition, these developments provide new insights into a new, presumably primary event in oncogenesis, i.e. the occurrence of mutations in genomic stability genes leading to an increased cellular mutation rate (mutator phenotype) and thus to cancer.     

Expression profile of mucin-associated sialyl-Tn antigen in Chinese patients with different colorectal lesions (adenomas,carcinomas)

Background: The sialyl-Tn (sTn) antigen is a mucin-associated carbohydrate antigen expressed by numerous human carcinomas, and is also claimed to be a prognostic factor in colorectal cancer. But the associations between sTn and colorectal cancer remain elusive and controversial. Here, we investigated the expression profile of sTn antigen in a series of human colorectal tissue samples including normal colon, colorectal adenomas, and colorectal carcinomas (CRCs), with an aim to analyzing whether sTn plays a role in the progression and development of Chinese patients with CRCs. Methods: Immunohistochemical staining of sTn antigen was performed in formalin-fixed, paraffin-embedded colonic sections from 4 healthy controls, 44 patients with colorectal adenomas, and 186 patients with primary CRCs. Results: No sTn antigen was detected in normal colonic tissues. There were 41 of 44 patients with colorectal adenomas (93.2%), and 141 of 186 patients with CRCs (75.8%) found to express sTn antigen. The patterns of sTn localization were different in adenomas and carcinomas of colonic tissues. Colorectal adenomas showed predominant supranuclear distribution of sTn antigen, while carcinomas revealed apical membrane, mucin droplet and diffuse cytoplasmic localization. Notably, sTn was significantly associated with the degree of differentiation (P = 0.006) and perineural invasion (P = 0.041) of the tumors, but was independent of age, gender, tumor location, depth of penetration, status of lymph nodes, lymphovascular invasion and TNM stage. Conclusions: These results indicate that sTn may play a role in initiating colorectal carcinogenesis and promoting tumor progression. Determination of sTn expression and localization may assist in evaluating malignant status of colorectal lesions.     

Pathological features of colorectal carcinomas in MYH-associated polyposis

Aims:  MYH is a DNA glycosylase in the base excision repair pathway. Germ-line biallelic mutations in the MYH gene are associated with the development of multiple colorectal adenomas and colorectal carcinoma (CRC). A slightly increased risk of CRC is suggested in monoallelic MYH mutation carriers. The aim was to characterize the histopathological features of carcinomas from biallelics and monoallelics.
Methods and results:  Clinicopathological features of 57 colorectal carcinomas from 50 patients identified in familial CRC registries were recorded. These included 16 cancers from 14 MYH biallelics; 25 cancers from 22 MYH monoallelics; and 16 cancers from 14 controls. Carcinomas in biallelics demonstrated tubular, papillary or cribriform patterns as the predominant histological subtype, and main histological groups differed according to mutation status ( P  = 0.0053). All biallelic cancers were low grade, with high-grade tumours more common in monoallelics and controls ( P  = 0.002). Synchronous polyps were observed in 75% of biallelics, 33% of monoallelics and 43% of controls ( P  = 0.035). Serrated carcinoma was the predominant type in 12% (3/25) of the monoallelics but in none of the biallelics or controls. MYH immunohistochemistry failed to distinguish between groups.
Conclusions:  Neither pathological features nor immunohistochemistry could predict the MYH mutation status of CRCs in this study.     

Hereditary gastrointestinal carcinomas and their precursors: An algorithm for genetic testing

Recognition of hereditary forms of gastrointestinal cancer is of great importance for patients and their families and pathologists play a crucial role in this. This review recapitulates the clinical, pathological and molecular aspects of Hereditary Diffuse Gastric Cancer and Gastric Adenocarcinoma and Proximal Polyposis of the Stomach, as well as hereditary colorectal cancer syndromes such as Lynch syndrome and gastrointestinal polyposis syndromes (including Familial Adenomatous Polyposis, Peutz-Jeghers syndrome and Juvenile Polyposis syndrome). Histopathological clues to recognize hereditary forms of gastrointestinal cancer and possible ancillary studies that can support an underlying syndrome and guide genetic testing are discussed.     

Microsatellite instability in young patients with colorectal cancer

Genetic instability Is closely correlated to the pathogenesis of hereditary non-palyposis colon cancer (HNPCC), which is clinicaily characterized by a family history and early onset. To investigate the role of genetic instabllity in young patients with colorectal cancer (CRC), 22 CRC patients, who were aged younger than 30 at the time of diagnosis, were studied. Patients with famllial adenomatous polyposis were excluded. Among the 22 cases, seven were identifled as microsateillte instability posltive (MI+), and more than five microsatellite markers among the 15 tested markers showed an additlonal band pattern in the tumor tissue. None of the remaining 15 cases showed instability in any microsatellite marker. Two of seven MI+ cases were classic HNPCC. While all MI+ cases had one or no metastatic lymph node, 53.3% of MI- cases showed metastasls in two or more reglonal lymph nodes. Allelic deletion of the 17p12–13 chromosome around the p53 locus occurred in 16.7% of MI+ cases, and 80.0% of MI- cases showed loss of het-erozygosity at that locus. hMSH2 Protein expression, assessed by immunohistochemistry, was absent in two cases, both of which were MI+. When we tested two to four sites of MI+ tumors, transforming growth factor β receptor type II was mutated in a homogeneous pattern in five MI+ cases. in addition, frame-shift mutations of BAX , insulin-like growth factor II receptor, hMSH3 and hMSH6 were found in three cases, five cases, five cases and one case, respectively. In contrast to the consistent mutatlon of the transforming growth factor-β receptor type II gene, mutations of other genes varied in different portions of the tumors.     

Analysis of copy number changes suggests chromosomal instability in a minority of large colorectal adenomas

We have examined chromosomal-scale mutations in 34 large colorectal adenomas (CRAs). A small number of changes (median = 2, IQR = 0-4) were found by array-comparative genomic hybridization (aCGH) in most tumours. The most common changes were deletions of chromosomes 1p, 9q, 17, 19, and 22, and gains of chromosomes 13 and 21. SNP-LOH analysis and pseudo-digital SNP-PCR analysis detected occasional copy-neutral LOH. Some aCGH changes found frequently in colorectal carcinomas, such as deletions of chromosomes 4q and 18q, were very infrequent in the adenomas. Almost all copy number changes were of small magnitude, far below the predicted levels even for single copy gain/loss; investigation suggested that these changes were either artefactual or occurred in sub-clones within the tumours. In some cases, these sub-clones may have represented progression towards carcinoma, but comparison with aCGH data from carcinomas showed this to be unlikely in most cases. In two adenomas, there was evidence of a large, outlying number of copy number changes, mostly resulting from part-chromosome deletions. Overall, moreover, there was evidence of a tendency towards part-chromosome deletions-consistent with chromosomal instability (CIN)--in about one-sixth of all tumours. However, there was no evidence of CIN in the form of whole-chromosome copy number changes. Our data did not support previous contentions that CRAs tend to show chromosome breakage at fragile sites owing to CIN associated with an elevated DNA damage response. Chromosomal-scale mutations occur in some CRAs; although CIN is not the norm in these lesions, it probably affects a minority of cases.     

两个遗传性非患肉性结直肠癌家系中MLH1和MSH2基因的突变检测

目的 确定两个遗传性非息肉性结直肠癌(hereditary nonpolyposis colorectal cancer,HNPCC)家系的致病基因,选择MLH1基因和MSH2基因进行突变检测.方法 采用聚合酶链反应结合DNA直接测序法,对两个遗传性非息肉性结直肠癌家系的患者进行MLH1基因和MSH2基因的突变检测;发现变异后,采用PCR-限制性片段长度多态性或直接测序法鉴定此变异是否属于突变.结果 在家系A的患者中发现了位于MLH1基因第3外显子内的新突变c.243_244 insA;在家系B的患者中发现了MSH2基因第7外显子内的c.1215_1218dupCCGA突变,这两个突变都导致了编码蛋白的提前终止.结论 MLH1基因的c.243_244insA突变和MSH2基因的c.1215_1218dupCCGA突变分别是导致家系A和家系B发生遗传性非息肉性结直肠癌的致病突变.     

中国人遗传性非息肉病性结直肠癌MSH6基因胚系突变的测序研究

目的探讨中国人遗传性非息肉病性结直肠癌(hereditary nonpolyposis colorectal cancer,HNPCC)家系中MSH6基因胚系突变。方法采用PCR-直接测序的方法检测39个无胚系MSH2及MLH1基因突变、符合不同临床标准的中国人HNPCC家系先证者MSH6基因各外显子胚系突变;对137名正常人胚系基因组DNA进行错义突变相应外显子的测序分析。应用Envision二步法检测有突变的先证者肿瘤组织MSH6蛋白表达。结果在39个HNPCC先证者中共发现6个MSH6基因的胚系突变,分别位于第4、6、9和第10外显子;突变类型为4个错义突变、1个无义突变、1个剪接区的插入突变;对4个错义突变的相应外显子的测序分析显示:137名正常人胚系基因组DNA5例具有第6外显子1163密码子处的c.3488A>T的错义突变,约占3.65%(5/137),为单核苷酸多态性(single nucleotide polymorphism,SNP);其余错义突变在正常人群中均未发现。在6例有MSH6基因胚系突变家系的肿瘤组织中免疫组化染色除1例为SNP的肿瘤组织MSH6蛋白阳性表达外,其余均为阴性表达。经过查询国际HNPCC突变数据库及SNP数据库证实上述突变中5个为国际上尚未报道的病理性突变,1个为新发现的SNP。结论MSH6基因胚系突变在符合不同临床标准的中国人HNPCC中均起一定作用,对无MSH2及MLH1基因胚系突变的先证者行MSH6基因胚系突变的测序分析对确诊HNPCC家系是必要的。