ABSTRACT
We identified 4316 unselected incident cases of early-onset breast cancers (<51 ears of age at diagnosis) in 18 Polish hospitals between 1996 and 2003. We were able to obtain a blood sample for DNA analysis from 3472 of these (80.4%). All cases were tested for the presence of three founder mutations in BRCA1. The proportion of cases with a BRCA1 mutation was 5.7%. The hereditary proportions were higher than this for women with breast cancer diagnosed before age 40 (9%), for women with cancer of medullary or atypical medullary histology (28%), for those with bilateral cancer (29%) or with a family history of breast or ovarian cancer (13%). It is reasonable to offer genetic testing to women with early-onset breast cancer in Poland.
Subject(s)
BRCA1 Protein/biosynthesis , Breast Neoplasms/epidemiology , Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Genes, BRCA1 , Genetic Predisposition to Disease , Mutation , Adult , Breast Neoplasms/metabolism , DNA Mutational Analysis , Female , Humans , Middle Aged , Models, Statistical , Poland , Prospective StudiesABSTRACT
Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non-polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA-testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty-six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty-four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation-dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.
Subject(s)
Carrier Proteins/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Germ-Line Mutation , MutS Homolog 2 Protein/genetics , Nuclear Proteins/genetics , Adaptor Proteins, Signal Transducing , Base Sequence , Cohort Studies , DNA Mutational Analysis/methods , Family Health , Female , Humans , Ligase Chain Reaction/methods , Male , Molecular Sequence Data , MutL Protein Homolog 1 , PolandABSTRACT
BACKGROUND: A common missense variant of the CDKN2A gene (A148T) predisposes to malignant melanoma in Poland. An association between malignant melanoma and breast cancer has been reported in several families with CDKN2A mutations, OBJECTIVE: To determine whether this variant also predisposes to breast cancer. METHODS: Genotyping was undertaken in 4209 cases of breast cancer, unselected for family history, from 18 hospitals throughout Poland and in 3000 controls. RESULTS: The odds ratio (OR) associated with the CDKN2A allele for women diagnosed with breast cancer before the age of 50 was 1.5 (p = 0.002) and after age 50 it was 1.3 (p = 0.2). The effect was particularly strong for patients diagnosed at or before the age of 30 (OR = 3.8; p = 0.0002). CONCLUSIONS: CDKN2A appears to be a low penetrance breast cancer susceptibility gene in Poland. The association should be confirmed in other populations.
Subject(s)
Breast Neoplasms/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Genes, p16 , Genetic Predisposition to Disease , Genetic Variation , Adult , Alleles , Female , Genotype , Humans , Middle Aged , Odds Ratio , Poland , RiskABSTRACT
Both hereditary and environmental factors are important in the aetiology of malignant melanoma. Among the risk factors for malignant melanoma are immunodeficiency and immunosuppression. The recently identified NOD2 gene is involved in the regulation of immune function through activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Three common NOD2 mutations -- 3020insC, G908R and R702W -- have been shown to be associated with chronic inflammatory disease such as Crohn's disease, the 3020insC also with human malignancy colorectal cancer. We examined the frequency of the NOD2 variants in 424 patients with malignant melanoma and 649 controls. The 3020insC mutation was present in 6.9% of unselected cases and 7% of the controls (odds ratio (OR) 1.0; P not significant). The mutation was present in 6.8% of 162 cases diagnosed under the age of 50 and in 7.1% of cases diagnosed after the age of 50. A mutation was present in the index case in 5% of 40 familial melanomas (OR 0.7; P not significant). There were no statistically significant differences between prevalence of G908R and R702W in malignant melanoma patients and controls. In conclusion, the three common NOD2 mutations are not associated with increased risk of development of malignant melanoma.
