ONLINE MUTATION REPORT Search for genetic variants associated with cutaneous malignant melanoma in the Ashkenazi Jewish population
نویسندگان
چکیده
C utaneous malignant melanoma (CMM; MIM#155601) comprises about 1% of all cancer cases in European populations, but its mortality is over 2% because of the propensity of this tumour to metastasise. Surveillance of CMM-prone individuals and populations should decrease the morbidity and mortality associated with this disease. In approximately 5–12% of all melanoma cases, there is a family history of the disease, defined as having one or more affected first degree relatives. Germline mutations of CDKN2A, located on chromosome 9p21, cosegregate with affected cases in an estimated 20% of melanoma families worldwide (reviewed by Goldstein). CDKN2A encodes two different tumour suppressor proteins: the CDK4/6 cell cycle inhibitor p16 from exons 1a, 2, and 3; and the MDM2 inhibitor p14 from exons 1b, 2, and 3. The frequency of discovering a CDKN2A mutation within a family increases with the number of affected relatives, ranging from ,15% in families with two affected members, to 20–40% in those with three, and 70% in those with four or more (unpublished data from Hogg’s laboratory; Kefford and Mann). In addition, mutations in the CDK4 gene 4 and polymorphisms in the MC1R gene have been implicated rarely in melanoma predisposition. To date, mutations in the two major predisposition genes, CDKN2A and CDK4, account for melanoma susceptibility in less than half of all melanoma families, and the genetic bases of the disease in the remaining families have not been found. Gillanders et al recently provided strong evidence for another melanoma predisposition locus at chromosome 1p22. Current research in melanoma genetics is hindered by the allelic and locus heterogeneities, which render whole genome linkage analysis difficult. In addition, the sample sizes required to study the effects of weak or modifier alleles in a genetically heterogeneous population are large. To address the problem of both allelic and locus heterogeneities, we have focused on populations that have undergone genetic bottlenecks and are genetically isolated. We hypothesise that familial melanoma patients within such populations arose from a limited number of founders and thus display a restricted number of melanoma predisposition alleles. These alleles are in linkage disequilibrium with adjacent markers. By searching for melanoma associated alleles and genotypes, we can isolate the predisposition loci and subsequently determine the variant or variants responsible. Ashkenazi Jews originated in the Near East, and subsequently migrated to eastern and central Europe. Throughout history, the Ashkenazi Jewish population has experienced numerous bottlenecks which led to highly altered allele frequencies relative to the diverse ancestral population. This genetic drift is evident from the high incidences of multiple genetic disorders, attributable to founder mutations, 11 and the population bottlenecks and the practice of endogamy have also decreased genetic variability. 12 The incidence of melanoma in Ashkenazi Jews is relatively high (table 1), but no CDKN2A mutations have been found in any Ashkenazi Jewish families. This population is therefore considered to be a promising setting for the identification of novel melanoma susceptibility genes. In this report we present the results of our search for CDKN2A mutations and polymorphisms, as well as 9p21 and 1p22 alleles and genotypes that are associated with melanoma, in our collection of Ashkenazi Jewish melanoma patients.
منابع مشابه
Search for genetic variants associated with cutaneous malignant melanoma in the Ashkenazi Jewish population.
C utaneous malignant melanoma (CMM; MIM#155601) comprises about 1% of all cancer cases in European populations, but its mortality is over 2% because of the propensity of this tumour to metastasise. Surveillance of CMM-prone individuals and populations should decrease the morbidity and mortality associated with this disease. In approximately 5–12% of all melanoma cases, there is a family history...
متن کاملGenetic Complexity of Crohn’s Disease in Two Large Ashkenazi Jewish Families
BACKGROUND & AIMS Crohn's disease (CD) is a highly heritable disease that is particularly common in the Ashkenazi Jewish population. We studied 2 large Ashkenazi Jewish families with a high prevalence of CD in an attempt to identify novel genetic risk variants. METHODS Ashkenazi Jewish patients with CD and a positive family history were recruited from the University College London Hospital. W...
متن کاملP53 antigen expression in cutaneous Melanoma and its relation to tumor thickness
Background: P53 tumor suppressor gene mutation is one of the most common genetic alterations in human malignancies. The mutated from of the gene is stable and can be detected with immunohistochemistry methods. There is much controversy about the expression rate of this gene in malignant melanoma. Objective: To determine the frequency of the P53 antigen expression by sex, age, type and thickness...
متن کاملCase report: BRCA in the Ashkenazi population: are current testing guidelines too exclusive?
The BRCA1/2 genes account for a significant portion of hereditary breast and ovarian cancers and they are especially prevalent in the Ashkenazi Jewish population. Women who have a mutation can prevent breast and ovarian cancer with surgical intervention. We describe an Ashkenazi Jewish patient who illustrates that current testing criteria are too restrictive, particularly for this population of...
متن کاملONLINE MUTATION REPORT Haplotype and cancer risk analysis of two common mutations, BRCA1 4184del4 and BRCA2 2157delG, in high risk northwest England breast/ovarian families
T he prevalence of BRCA1 and BRCA2 mutations in families with breast and ovarian cancers depends on the type of cancer found, the number of cases, and the ethnic background of the family. The proportion of breast cancers attributable to BRCA1 or BRCA2 may also depend on the ethnic origin of families. Several mutations have been identified that are found only in specific countries or ethnic grou...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره شماره
صفحات -
تاریخ انتشار 2005