Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatosis polyposis (FAP) are well-known high-risk cancer syndromes. Hereditary colorectal cancer (HCRC) with at least three relatives with colorectal cancer and a dominant pattern of inheritance but with no specifications for age at onset and two close relatives with colorectal cancer (TCR) are other forms of familial clustering known to carry an increased risk of the disease. The frequency of the total burden of familial colorectal cancer is not well known. We therefore investigated the family history of 400/411 (97%) eligible patients with recently diagnosed colorectal cancer in Västmanland county, Sweden, during a 3-year period. Records or death certificates confirmed the diagnoses of relatives. Five patients (1.2%, 95% CI 0.15-2.2) were diagnosed as having HNPCC, eight (1.9%, 95% CI 0.6-3.2) as having HCRC and thirty-four (8.3%, 95% CI 5.6-11.0) were identified as having TCR. In total, 47 patients (11.4%, 95% CI 8.3-14.5) were found to have a contributing familial background. The implication is thus that every ninth patient with colorectal cancer represents a highly or intermediately increased risk of the disease among relatives. We conclude that the low frequency of individuals identified by family history alone makes the establishment of surveillance programs feasible.
A pilot study which is part of both a larger provincial initiative and a network is in progress to address the question of genetic pre-disposition to non-polyposis colorectal cancer in eastern Ontario (population 1,200,000). It is modeled along a dual process of recruitment of at-risk individuals based on either prior documentation of family histories or a close relationship to patients who are hospitalized for colorectal cancer treatment. The molecular diagnostic and genetic counseling components of the project are in their initial phase of operation while follow-up strategies are being planned.
To determine the prevalence of Lynch syndrome mutations in a Canadian hereditary cancer clinic population, and to determine the effectiveness of the program's referral criteria and testing algorithm.
A retrospective chart review of all patients who were referred for and received genetic counselling at the BC Cancer Agency's Hereditary Cancer Program for a family history of colon cancer from August 1, 2004, to September 1, 2006, was performed. Charts were reviewed for referral criteria met, cancer history, whether testing was offered and the outcome of testing.
Lynch syndrome was confirmed or highly suspected in 14.3% of index test patients (eight of 56) by the identification of a deleterious mutation or variant likely to be deleterious in either of the hMLH1 or hMSH2 mismatch repair genes. In the program, the two most effective criteria were a personal diagnosis of two or more primary Lynch syndrome-related cancers (one diagnosed at younger than 50 years of age) or two first-degree relatives with a Lynch syndrome-related cancer (both diagnosed at younger than 50 years of age). The respective positive predictive values of these two criteria were calculated to be 66.7% (95% CI 40% to 93%) and 58.3% (95% CI 30.4% to 86.2%).
The Hereditary Cancer Program developed and successfully implemented an approach that selected individuals at risk for Lynch syndrome with a significant pretest probability of mutation of 14.3%. Improved ascertainment of families with Lynch syndrome will require greater physician awareness of referral criteria, program advances in the testing algorithm and a population-based approach to screening incident colon cancers.
Cites: World J Gastroenterol. 2006 Aug 21;12(31):4943-5016937488
Cancer morbidity and mortality can be dramatically reduced by colonoscopic screening of individuals with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, creating a need to identify HNPCC. We studied how HNPCC identification should be carried out on a large scale in a sensitive and efficient manner.
Colorectal cancer specimens from consecutive newly diagnosed patients were studied for microsatellite instability (MSI). Germline mutations in the MLH1 and MSH2 genes were searched for in MSI(+) individuals.
Among 535 colorectal cancer patients, 66 (12%) were MSI(+). Among these, 18 (3.4% of the total) had disease-causing germline mutations in MLH1 or MSH2. Among these 18 patients, five were less than 50 years old, seven had a previous or synchronous colorectal or endometrial cancer, and 15 had at least one first-degree relative with colorectal or endometrial cancer. Notably, 17 (94%) of 18 patients had at least one of these three features, which were present in 22% of all 535 patients. Combining these data with a previous study of 509 patients, mutation-positive HNPCC accounts for 28 (2.7%) of 1,044 cases of colorectal cancer, predicting a greater than one in 740 incidence of mutation-positive individuals in this population.
Large-scale molecular screening for HNPCC can be done by the described two-stage procedure of MSI determination followed by mutation analysis. Efficiency can be greatly improved by using three high-risk features to select 22% of all patients for MSI analysis, whereby only 6% need to have mutation analysis. Sensitivity is only slightly impaired by this procedure.
Lynch syndrome is caused by inherited mutations in DNA mismatch repair genes (primarily MSH2, MLH1, MSH6, and PMS2) and is one of the most prevalent inherited cancer syndromes. Several models have been developed to predict the occurrence of Lynch syndrome in high-risk patients and families, but it is not known how these models compare with one another or how they perform for colorectal cancer patients from the general population. We used data from such patients to test the ability of four models--Leiden, MMRpredict, PREMM(1,2), and MMRpro--to distinguish between those who did and did not carry DNA mismatch repair gene mutations.
We studied a consecutive series of 725 patients who were younger than 75 years at colorectal cancer diagnosis and whose DNA mismatch repair gene mutation status was available; 18 of the 725 patients carried such a mutation. For each model, we calculated the risk score, compared the observed number of mutations with the expected number, and determined the receiver operating characteristics. All statistical tests were two-sided.
Although all four models overestimated the probability of a mutation (range = 1.2- to 4.3-fold), especially in low-risk patients, they could discriminate between carriers and noncarriers of a mismatch repair mutation. The areas under the receiver operating characteristics curves from the four models ranged from 0.91 to 0.96. Carriers of mutations in the MSH6 or PMS2 genes had lower risk scores than carriers of MSH2 or MLH1 mutations. For example, the MMRpredict model gave median risk scores of 24% and 94% (P
Hereditary non-polyposis colorectal cancer is a dominant inherited disease, with development of colorectal cancer (CRC) and other cancers too. About 3% of all CRC-cases belong to an HNPCC-family. Mutations responsible for the disease has been identified in five genes, all of them involved in DNA mismatch repair. Since the establishment of the Danish HNPCC Register 345 families have been referred, and 101 of these families had HNPCC. Median age of onset for CRC was 50 years: Approximately 60% of the tumors were situated on the right side, 9% had synchronous tumors and the risk of metachronous tumours was 40% in 20 years. Tumours were localised in 64% of the cases, and the 5-year crude survival rate was better in HNPCC compared to sporadic CRC. The number of CRC diagnosed as Dukes A in HNPCC has risen since 1990, and the survival after CRC in HNPCC has increased. The disease specific mutation is identified in 21 families, from which 152 persons at risk have had a molecular genetic diagnose, and 83 could afterwards evade screening protocols. Few years after the establishment of the HNPCC-registry, it is indicated that information, registration and screening lead to an earlier diagnosis and a better prognosis after CRC.
The Canadian province of Newfoundland and Labrador (NL) reports one of the highest incidence rates of familial colorectal cancer (CRC) worldwide. The NL population is an invaluable resource for studying genetic disorders because of a unique ancestry, and a willingness to participate in research studies. Familial colorectal cancer type X (FCCTX) describes a cluster of families with strong predisposition for CRC, of unknown etiology. A putative link between FCCTX and BMPR1a mutations has been identified in the Finnish population; however these findings have not been independently replicated. To investigate a potential connection between BMPR1a and FCCTX, we screened a cohort of 22 probands from unrelated NL FCCTX families using Sanger sequencing. This analysis did not independently replicate findings seen in Finland; as no candidate pathogenic BMPR1a mutations were uncovered. Our findings highlight that BMPR1a mutations are not a major contributor of FCCTX incidence in NL. Further investigation of additional FCCTX populations may assist in delineating a role for BMPR1a, if any, in FCCTX globally.