Suspected hereditary nonpolyposis colorectal cancer

PURPOSE: The aim of this study was to determine the frequency of mutations in the mismatch repair genes in families suspected of having hereditary nonpolyposis colorectal cancer. METHODS: We devised two criteria for families suspected of having hereditary nonpolyposis colorectal cancer (Criteria I and II). Criteria I consist of at least two first-degree relatives affected with colorectal cancer with at least one of the following: development of multiple colorectal tumors including adenomatous polyp, at least one colorectal cancer case diagnosed before the age of 50, and occurrence of a hereditary nonpolyposis colorectal cancer extracolonic cancer (endometrium, urinary tract, small intestine, stomach, hepatobiliary system, or ovary) in family members. Criteria II consist of one colorectal cancer patient with at least one of the following: early age of onset (<40 years); endometrial, urinary tract, or small intestine cancer in the index patient or a sibling (one aged <50 years); and two siblings with other integral hereditary nonpolyposis colorectal cancer extracolonic cancers (one aged <50 years). A questionnaire was mailed to members of the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer to determine the mutation detection rate in mismatch repair genes from the families fulfilling these criteria. For comparison the mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria in each institution was also obtained. RESULTS: Data were obtained from eight different institutions (in 7 different countries). In a total of 123 patients from 123 families (67 families fulfilling Criteria I and 56 families fulfilling Criteria II), genetic testing for germline mismatch repair gene variants was performed. Germline mutations of the hMLH1 or hMSH2 genes were identified in 24 families (20 percent). Of these, the mutation detection rate for families fulfilling Criteria I was 28 percent (19/67). The mutation detection rate for families fulfilling Criteria II was 9 percent (5/56). In these eight institutions, the overall mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria was 50 percent (77/154). CONCLUSION: The Criteria I for suspected hereditary nonpolyposis colorectal cancer have the advantages that they can be applied to nuclear families and they can include extracolonic cancers. The results of this study suggest that families fulfilling Criteria I should be offered genetic testing. The relatively low mutation detection rate in those families fulfilling Criteria II suggests that, using current techniques, genetic testing in these families is not practical.     

Frequency of hereditary non-polyposis colorectal cancer in Danish colorectal cancer patients.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome, characterised by familial aggregation of HNPCC related cancers, germline mutations in mismatch repair genes, and/or microsatellite instability (MSI) in tumour tissue. AIM: To estimate the frequency of HNPCC among non-selected Danish patients with colorectal cancer (CRC), and to evaluate the value of MSI analysis as a pre-screen test. METHODS: This was a prospective population based study on consecutive CRC patients. A family history of malignancy was obtained and suspected HNPCC cases were screened for hMLH1/hMSH2 mutations and subjected to MSI analysis. Patients with germline mutations and/or those with Amsterdam criteria I or II families were categorised as HNPCC patients. RESULTS: Among 1328 eligible CRC patients, 1200 (90.4%) completed a questionnaire. A total of 1.7% (95% confidence interval (CI) 1.0-2.4) (20 cases) were categorised as HNPCC patients. Amsterdam criteria I or II were met in 18 cases (1.5%), and in another two cases (0.2%) pathogenic hMLH1/hMSH2 mutations were detected without fulfillment of the Amsterdam criteria I or II. Among 77 patients younger than 50 years of age, 11 cases (14.3%) were categorised as HNPCC. The Amsterdam criteria I or II were met in eight of 10 gene carriers (80%). The MSI-high phenotype was demonstrated in all 10 gene carriers. CONCLUSION: The frequency of HNPCC was approximately 1.7% among all CRC cases and 14.3% among patients younger than 50 years of age. MSI analysis is a reliable pre-screen test for hMLH1/hMSH2 mutations in families suspected of having HNPCC.     

Frequency of replication errors in colorectal cancer and their association with family history

Background—Replication errors (RERs) characterisetumours of hereditary non-polyposis colorectal cancer (HNPCC). RERstatus may therefore improve identification of such families previously diagnosed by family history alone.
Aims—To assess RER and HNPCC frequency within apopulation of colorectal cancer patients and a regional population offamily history defined (Amsterdam criteria) HNPCC families.
Methods—Family history was assessed by personalinterview in a population of 479 patients with colorectal cancerattending one follow up clinic. Seven fluorescently labelledmicrosatellites were used to investigate RER frequency in colorectalcancers from 89 patients of this population with varying degrees offamily history and 20 Amsterdam criteria positive families (four with aknown germline mutation, 16 with unknown mutation status) from theregional population.
Results—Only four of the follow up population(0.8%) came from families meeting the Amsterdam criteria with only oneshowing RERs. The frequency of RERs was similar in the early onsetcancer group (less than 50 years of age), those with a family history, and those with no family history of colorectal cancer. From the regional population, RERs were identified in 4/4 families with amutation but only 8/16 families with unknown mutation status.
Conclusions—No correlation was seen between RERstatus and strength of family history except in HNPCC families. Resultsalso indicate that half of the Amsterdam criteria defined families donot exhibit RERs, perhaps suggesting a different mechanism of tumorigenesis.

Keywords:hereditary non-polyposis colorectal cancer; replication errors

     

Varying features of early age-of-onset “Sporadic” and hereditary nonpolyposis colorectal cancer patients

PURPOSE: Although the criteria for clinical diagnosis of hereditary nonpolyposis colorectal cancer are not fully agreed on, young age seems to be a common trait. The purpose of this study is to identify clinicopathologic features of hereditary nonpolyposis colorectal cancer in early age-of-onset colorectal cancer patients stratified as a function of family cancer history. METHODS: Two hundred thirty consecutive colorectal cancer patients 40 years or older at time of diagnosis were registered into an ongoing database during a ten-year period. Accurate family history was obtained via medical records, telephone calls, and questionnaires on 146 patients. According to extent of family history of cancer, patients were stratified into seven groups: 1) fulfilling Amsterdam criteria, 2) fulfilling less strict criteria, 3) having at least one first-degree relative with colorectal cancer, 4) having at least one distant relative with colorectal cancer, 5) having at least one first-degree relative with any cancer, 6) having at least one distant relative with any cancer, 7) having no family history of cancer. RESULTS: Twenty-two of 146 patients fulfilled Amsterdam and less strict hereditary nonpolyposis colorectal cancer criteria (15 percent). These hereditary nonpolyposis colorectal cancer patients were significantly younger (31 vs. 35 years; P = 0.0003) and had more metachronous colorectal cancer (27 percent vs. 2 percent; P = 0.007) and less colorectal cancer with nodal or metastatic spread than the non-hereditary nonpolyposis colorectal cancer patients (35 percent vs. 65 percent; P = 0.01). CONCLUSION: Precise familial cancer assessment in early age-of-onset colorectal cancer increases the yield of hereditary nonpolyposis colorectal cancer diagnosis. Because of the frequent development of metachronous colorectal cancer and favorable prognosis, extensive rather than segmental surgery should be considered in early age-of-onset colorectal cancer patients belonging to hereditary nonpolyposis colorectal cancer families.     

Microsatellite instability—a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer

BACKGROUND: Clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the clinical criteria may be missed. AIMS: To examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype relation in families with verified mutations. METHODS: Systematic search for germline mutations (hMSH2 and hMLH1 genes) was performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) and 12 the looser HNPCC criteria (group 2). Seventeen patients showed familial clustering of cancers (group 3) and 10 patients under 50 years had sporadic cancer (group 4), the latter of whom all exhibited MSI+ tumours. RESULTS: A similar proportion of germline mutations was found in patients who fulfilled the clinical criteria of HNPCC and had MSI+ tumours (groups 1 and 2; 15/39) compared with patients who did not meet these clinical criteria but who had MSI+ tumours (groups 3 and 4; 8/27 patients). Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations. CONCLUSIONS: MSI in tumour tissue is a useful criterion for selecting patients who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hMSH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.     

Frequency of the Amsterdam criteria in a regional German cohort of patients with colorectal cancer

Estimates of the colon cancer burden associated with hereditary nonpolyposis colorectal cancer (HNPCC) vary from less than 1 % to more than 5 %. Amsterdam criteria fulfilled within a kindred (classic Amsterdam and Amsterdam II criteria) are widely used to identify patients prone to HNPCC. The present study was initiated to assess the frequency of the Amsterdam criteria within a regional German cohort of 207 patients with a history of colorectal cancer (CRC). Data on individual and family cancer histories were available in 154 patients (73 women, 81 men; mean age at diagnosis 62.4 +/- 13.3 years). A total of 843 first degree relatives have been identified within the kindreds of whom 121 had verified cancers. In 28 of 154 families (18 %), at least one first degree relative of the index patient had CRC. With respect to a typical family history, five kindreds (3.2 %) were likely to suffer from HNPCC on a clinical basis (4 kindreds met the classic Amsterdam criteria and one kindred the Amsterdam II criteria). Testing for microsatellite instability could additionally be performed in 4 of 5 patients who met the Amsterdam criteria and revealed DNA instability in 3 cases. Moreover, a missense mutation of MSH2 (Gly965Asp) was detected in one patient with microsatellite instability. Based on the classic Amsterdam and Amsterdam II criteria approximately 3 % of a regional German cohort of patients with CRC are likely to suffer from HNPCC. However, the final diagnosis of HNPCC can only be established by detection of pathogenic germline mutations within the DNA mismatch repair genes.     

Limitations of family cancer history assessment at initial surgical consultation

PURPOSE: Although important for the diagnosis of familial clustering of colorectal cancer and hereditary nonpolyposis colorectal cancer, the accuracy of familial cancer history assessment in the office setting has been questioned. Furthermore, there are few publications describing the optimal method for accurately capturing a family cancer history. The purpose of this study was to determine how well family cancer history is assessed in patients with early age-of-onset colorectal cancer at initial surgical consultation compared with a telephone interview and mailed questionnaire. METHODS: Medical records of patients 40 years old or younger at the time of colorectal cancer surgery were reviewed for documentation of family cancer history at initial surgical consultation. In addition, family cancer history was solicited from surviving patients or their next of kin by telephone and a mailed questionnaire. The kappa coefficient was used to measure degree of correlation between family cancer history obtained at initial surgical consultation and subsequent telephone interview and questionnaire. RESULTS: One hundred twenty-five patients were available for analysis. Family cancer history was documented on the initial surgical consultation report in 78 percent of cases. Although 31.2 percent were identified as having no family cancer history at initial surgical consultation, this proportion decreased to 13.5 percent after telephone interviews and questionnaires. Family history assessment at initial surgical consultation also failed to identify 7 of 11 individuals meeting Amsterdam criteria for hereditary nonpolyposis colorectal cancer and 10 of 16 individuals meeting modified clinical criteria for hereditary nonpolyposis colorectal cancer. CONCLUSIONS: Although family cancer history was commonly obtained during the initial surgical consultation of patients with colorectal cancer, there was a tendency to underestimate the extent of familial cancer. A telephone interview and questionnaire conducted at a later date may reveal a more comprehensive family cancer history. This is an important observation, because individuals identified as high-risk for hereditary nonpolyposis colorectal cancer or familial clustering of colorectal cancer require special consideration with respect to screening, surveillance, and surgical management.     

Correlation of polyp number and family history of colon cancer with germline MYH mutations.

BACKGROUND & AIMS: Affected individuals with biallelic MYH mutations are believed to display multiple adenomatous polyps without evidence of vertical transmission. Our goal was to determine the detection rate of germline MYH mutations in a high-risk gastrointestinal cancer clinic population by using polyp number as a selection criterion. METHODS: Patients were screened for the 2 most common MYH mutations: Y165C and G382D. The complete MYH coding region was sequenced in cases with a heterozygous mutation. RESULTS: Among 45 patients with more than 15 adenomatous polyps not diagnosed with familial adenomatous polyposis, 7 (15.6%) had biallelic MYH mutations. When 122 participants from a high-risk gastrointestinal cancer clinic who did not fulfill these criteria were tested, 2 additional patients with biallelic mutations were identified. Both had young-onset colorectal cancer (age, <50 y) with fewer than 15 polyps. Surprisingly, most of the 9 patients with biallelic MYH mutations reported family histories consistent with the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), with 7 cases meeting at least 1 of the Bethesda criteria, 5 cases fulfilling 3 Bethesda criteria, and 2 cases fulfilling the Amsterdam II criteria. CONCLUSIONS: Most individuals with MYH mutations exhibit multiple adenomatous polyps. However, 22% of cases were missed when this was the sole criterion for germline testing. A significant number reported a strong family history of cancer that was consistent with HNPCC. MYH testing thus can be considered for patients who meet clinical criteria for HNPCC in the absence of DNA mismatch repair gene mutations.     

Clinical heterogeneity of familial colorectal cancer and its influence on screening protocols.

The age at onset of non-polyposis colorectal cancer (CRC) was investigated in 49 families with at least three relatives affected in two successive generations. Forty one of these families satisfy the accepted minimum criteria for hereditary non-polyposis CRC. The remaining eight families were distinguished by a late age of disease onset and, hence, could not be included in the group. The condition in these latter families has been designated provisionally, as late onset familial CRC. The hereditary non-polyposis CRC families include 194 patients, 110 men and 84 women (mean age at diagnosis: 44 years; range: 16-74 years). Ninety two per cent of the patients were diagnosed by age 60. Colorectal cancer was diagnosed at progressively earlier ages in successive generations (p < 0.0005). The late onset CRC families comprised 30 patients, 20 men and 10 women (mean age at diagnosis: 62 years; range: 51-77 years). Fifty eight per cent of the CRCs in the patients belonging to the hereditary non-polyposis CRC families were located in the right colon compared with 13% in the late onset familial CRC group (p < 0.001). Multiple CRCs were found in 23% of the cases in the former but in only 3% in the latter families (p < 0.05). Adenomas associated with CRC were reported in 14.5% of the cases in the hereditary non-polyposis CRC families and in 30% of the cases in the late onset familial CRC group (p = NS). Extracolonic cancers, frequently encountered in hereditary non-polyposis CRC, were not found in the late onset CRC families. These findings indicate that there is a distinct clinical entity of non-polyposis CRC in which colorectal cancer develops at a more advanced age than in hereditary non-polyposis CRC. Future molecular genetic studies should confirm this hypothesis. In the meantime, recognition of these late onset familial CRC families, which will rest on clinical observations, is important because of the implications for the screening protocol.     

Variables associated with the risk of colorectal adenomas in asymptomatic patients with a family history of colorectal cancer.

The results of screening individuals referred to the Family Cancer Clinic at St Mark's Hospital from 1986 are presented. Colonoscopy was performed in 644 asymptomatic individuals (from 436 families) with a family history of colorectal cancer. Sixty nine (15.8%) of the families fulfilled the Amsterdam criteria for the hereditary non-polyposis colorectal cancer syndromes (HNPCC). Seven cases of colorectal cancer were diagnosed at an average age of 49 years; six at Dukes's stage A and one at stage C, four in subjects from Amsterdam criteria families. One hundred and forty four (22.4%) subjects had one or more adenomas. The prevalence of adenomas in the subjects from Amsterdam criteria families was 34 of 127 (26.8%) compared with 110 of 517 (21.3%) in those from other families; the age and sex adjusted odds ratio (OR) was 1.76 (p = 0.02). Factors influencing the prevalence of adenomas in screened individuals were evaluated. Multivariate analysis showed that independent variables significantly related to the risk of adenomas were: age (p < 0.0001), sex (p = 0.0002), and the number of generations (> or = 2 v 1) of relatives affected by either colorectal cancer or adenomas (p = 0.0006). The latter variable was more highly predictive of the probability of finding an adenoma at colonoscopy than a family history of two generations with cancer only (p = 0.056). The OR of having colorectal adenomas increased with age, by about twofold for each decade, and was twice as high in men than women, and in subjects with two or more generations relative to those with one generation affected by colorectal cancer or adenomas. Six of seven patients with cancer and 46 of 144 (31.9%) with adenomas had lesions proximal to the splenic flexure only. The proportion of individuals with proximal adenomas only was 47.1% in Amsterdam criteria families and 27.3% in the others (p=0.03). These findings support the view that colonoscopy rather than sigmoidoscopy is the method of choice for screening high risk groups.     

Genetic and molecular biology techniques for the analysis of hereditary colorectal cancer

The knowledge acquired in genetics and molecular biology over the last 2 decades has led to advances in the molecular diagnosis of some diseases, among them hereditary forms of colorectal cancer such as hereditary non-polyposis colorectal cancer and familial adenomatous polyposis. Moreover, the discovery of the genes causing these diseases has had implications beyond hereditary diseases since the same genes that cause hereditary forms of cancer also play a role in the much more frequent sporadic forms. Genetic diagnosis allows clinical diagnosis to be confirmed, as well as presymptomatic and even prenatal diagnoses to be made, with implications for patients with these hereditary diseases and their families.     

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.     

Colonoscopy surveillance of individuals at risk of familial colorectal cancer

BACKGROUND: Individuals with first degree relatives affected with colorectal cancer (CRC) at a young age, or more than one relative affected but who do not fulfil the Amsterdam criteria for a diagnosis of hereditary non-polyposis colon cancer (HNPCC), are believed to be at an increased risk of CRC. However, there is a paucity of prospective data on the potential benefit of colonoscopic surveillance in such groups categorised by empiric family history criteria. We report a prospective study of 448 individuals seeking counselling about their perceived family history of CRC. PATIENTS AND METHODS: Following pedigree tracing, verification, and risk assignment by genetic counsellors, colonoscopy was undertaken for those at a moderate or high risk (HNPCC). Those classified as low risk were reassured and discharged without surveillance. Here we report our findings at the prevalence screen in the 176 patients of the 448 assessed who underwent colonoscopy. RESULTS: Fifty three individuals had a family history that met Amsterdam criteria (median age 43 years) and 123 individuals were classed as moderate risk (median age 43 years). No cancers were detected at colonoscopy in any group. Four individuals (8% (95% confidence limits (CL) 0.4-15%)) in the high risk group had an adenoma detected at a median age of 46 years and all four were less than 50 years of age. Five (4% (95% CL 0.6- 8%)) of the moderate risk individuals had an adenoma at a median age of 54 years, two of whom were less than 50 years of age. CONCLUSIONS: These findings indicate that the prevalence of significant neoplasia in groups defined by family history is low, particularly in younger age groups. These prospective data call into question the value of colonoscopy before the age of 50 years in moderate risk individuals.     

Hereditary nonpolyposis colorectal cancer

Sporadic cancer develops approximately at 65 years of age. Epidemiologic data suggest that dietary factors probably are the most influential in colorectal carcinogenesis. In contrast, individuals who have relatives with colorectal neoplasia have an increased risk of these tumors themselves, which will appear earlier in life. The actual incidence of hereditary colorectal cancer is unknown. However, the incidence is much higher compared with well-known hereditary colorectal diseases, such as familial adenomatous polyposis. OBJECTIVE: An overview of the recent progress in the field of both clinical and basic research on hereditary colorectal cancer must be made. MATERIALS AND METHODS: Twenty-two family pedigrees were analyzed at Hamamatsu University School of Medicine, including the largest family pedigree in Japan, which contained 24 cases of colorectal cancer occurring over five generations. In 1995, when the International Symposium on Hereditary Cancer was held in Hamamatsu, 4,109 family pedigrees were investigated and analyzed, including 394 cases in 109 family pedigrees that met the Amsterdam Minimum Criteria. Information was collected by sending questionnaires to major hospitals in Japan. Basic updated data presented at the eighth and ninth International Collaborative Group on Hereditary Colorectal Cancer were also quoted. RESULTS AND CONCLUSIONS: Because of the discovery of mismatch repair genes as that responsible for hereditary nonpolyposis colorectal cancer, modification of the Amsterdam Criteria is necessary. Replication error, as a mutator phenotype of mismatch repair genes, is a useful predictor of second primary malignancies. Surveillance or prophylactic surgery is still a controversial issue.     

Detection of hMSH2 and hMLH1 mutations in Chinese hereditary non-polyposis colorectal cancer kindreds

AIM： To establish and validate the mutation testing for identification and characterization of hereditary non-polyposis colorectal cancer （HNPCC） in suspected Chinese patients.
METHODS： Five independent Chinese kindreds with HNPCC fulfilling the classical Amsterdam criteria were collected. Genomic DNA was extracted after informed consent was obtained. The coding region of hMSH2 and hMLH1 genes was detected by polymerase chain reaction （PCR） and denaturing high-performance liquid chromatography （DHPLC）. Mutations identified in the proband by DHPLC were directly sequenced using a 377 DNA sequencer, analyzed with a basic local alignment tool （BLAST）, and tested in the corresponding family members by direct DNA sequencing.
RESULTS： Mutations were identified in two Chinese HNPCC kindreds. One was the missense mutation of hMSH2 c.1808A→G resulting in Asp 603 Gly identified in the proband of the fifth HNPCC （HNPCCS） kindred. In the HNP5 kindred, three family members were found to have this mutation and two of them had colorectal cancer. The other mutation of hMLH1 c.1882A→G was identified in the HNP2 kindred＇s proband, which might be the nonsense mutation analyzed by BLAST.
CONCLUSION： Pedigree investigation and mutation testing of hMSH2 and hMLH1 are the practical methods to identify high-risk HNPCC patients in China.     

Hereditary colorectal cancer]

Hereditary syndromes cause approximately 5 to 15% of overall colorectal cancer (CRC) cases. Hereditary CRC is conventionally divided into two major categories: hereditary non-polyposis colorectal cancer (HNPCC) and those related to polyposis syndromes including familial adenomatous polyposis (FAP), Peutz-Jegher syndrome (PJS), and juvenile polyposis (JP). The screening for the cancer and methods of treatment applied to patients with hereditary CRC are quite different from those applied to the general population. The genes responsible for these syndromes has recently identified, as a result, genetic testing has become the most important determining factor in clinical decisions. Germ-line mutation of the APC gene induces FAP, an autosomal dominant disorder, characterized by the development of hundreds to thousands of colonic adenomas. CRC appears in almost all affected individuals by the time they are 50 years of age. An affected individual should undergo colectomy by his/her late teens. Furthermore, according to the findings of genetic testing, at-risk family members also need endoscopic surveillance and surgery. Recently, a mutation on the MYH gene is increasingly being investigated in patients with multiple polyps, and autosomal recessive MYH polyposis is considered to be a new category of polyposis. More common than FAP, HNPCC is caused by germ-line mutations in DNA mismatch repair genes, mainly MLH1 and MSH2. Although there is no polyposis, polyps seem to be more villous and dysplastic and appear to grow rapidly into CRCs. The aggregate lifetime risk of CRC is about 80% for mutation carriers. The risk for other types of cancer, such as endometrial, ovarian, small bowel, and transitional cell cancer, is also increased. The Amsterdam criteria and Bethesda guidelines are the best-known tools for diagnosis and genetic testing, and colectomy followed by endoscopic follow-up is the standard treatment. PJS and JP are reported to be characterized by hamartomatous polyps throughout the GI tract and germ-line mutations in the STK11 gene (PJS) and the DPC4/BMPR1A gene (JP).     

Treatment of hereditary colorectal cancer syndromes

Opinion statement Colorectal cancer is the second leading cause of cancer-related death in the United States. Although most colorectal cancers are sporadic, about 25% have a familial predisposition and 5% to 7% are hereditary and occur in genetically distinct high-risk families. Advances in treatment options and management of hereditary colorectal cancer syndromes that have occurred over the past years have been principally due to advances in the understanding of the genetics of these syndromes and in additional options for testing. This has led to the possibility of preclinical diagnosis and early surveillance and treatment. In addition, improvements in medical and surgical management have also occurred. This article focuses on four hereditary colon cancer syndromes: familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, juvenile polyposis syndrome, and Peutz-Jeghers syndrome.     

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.     

Hereditary familial non polypoid colorectal cancer

The most common form of hereditary CRC is hereditary non-polyposis colorectal cancer (HNPCC), several mutator genes have been identified in this syndrome. The molecular genetic discoveries are providing news insights into the pathogenesis of CRC. The CRC in Lynch syndrome shows microsatellite instability and it also shows a special histology now referred to as an undifferentiated medullary or solid cribriform carcinoma. This histology is uncommon in various populations. In addition CRC in HNPCC shows an excess of mucoid features as well as peritumoral lymphocyte infiltration and Crohn-like reaction. It is very important to make a diagnosis based on the natural history features of a particular cancer syndrome in combination with a well orchestrated family history. We report the case of a 44 year old man with colon cancer and adenomatous polyps, without family history of adenomatous polyps but with familial antecedent of colon cancer in his father, with a suspicion of Lynch syndrome.     

遗传性非息肉病性结直肠癌家系及临床病理特征分析

目的 分析比较不同遗传性非息肉病性结直肠癌(HNPCC)临床诊断标准和指导纲要所筛选家系的临床病理特征。方法 58个家系[符合Amsterdam标准(AC)家系24个、日本标准(JC)家系15个、Bethesda指导纲要(BG)患者19例]收入本项临床病理研究。结果 24个符合AC的家系共有恶性肿瘤患者116例，含结直肠癌患者90例。15个符合JC的家系共有恶性肿瘤患者54例，含结直肠癌患者33例。两组家系表现相似的临床特征，发生第1例结直肠癌的平均年龄分别为46．1岁和51．4岁，右半结肠癌分别占55．4％和44.8％，同时或异时结直肠癌发生率分别为25．6％和18．2％。两组共有肠外肿瘤患者55例，以胃癌最多(12例)，子宫内膜癌次之(8例)。两组39个家系中34例临床病理资料完整的结直肠癌与散发性结直肠癌比较显示，外生性生长较多、低分化癌比例高、克罗恩病样淋巴反应常见，并以Dukes分期A／B为主(P＜0．05)。家系先证者中18例术后随访存活时间超过5年，最长达28年。结论 用AC和JC可将临床表现有别于散发性结直肠癌的亚群——HNPCC筛选出来。这部分患者临床病理特点与散发性者明显不同。肠外肿瘤以胃癌、子宫内膜癌为常见。HNPCC患者预后较好。