Hereditary colon cancer is caused by mutations in several different loci. The APC gene on chromosome 5 causing adenomatous polyposis coli represents a minority of the inherited colon cancer cases, ...while hereditary-non polyposis colon cancer (HNPCC) may cause five percent of all human colon cancer. One gene causing HNPCC was recently mapped to chromosome 2 but the same study also showed that at least one additional locus may cause HNPCC. We now present tight linkage between a polymorphic marker on the short arm of chromosome 3 and the disease locus, and find that these families also manifest signs of a general DNA replication disorder.
Background: The estrogen receptor alpha (ESR1) mediates the effect of estrogen in target tissues. Estrogen is important in
breast cancer development and several polymorphic variants in the ESR1 gene ...have been investigated for association with breast
cancer. The C975G variant is the most extensively studied and has been suggested to be a risk factor. Materials and Methods:
The frequency of the C975G variant was investigated in 288 sporadic, 197 low-risk non-BRCA1/2 familial and 191 high-risk non-BRCA1/2
familial breast cancer cases and 653 controls. Results: There was a lower frequency of the C975G variant in high-risk familial
breast cancer cases compared to the controls (18% versus 22%, p=0.046). The odds ratio (OR) for the GG homozygotes was 0.2
(95% CI: 0.06-0.8) compared to the CC homozygotes. No association was seen with sporadic or low-risk familial breast cancer.
Conclusion: The results of this study indicated that the common C975G variant may have an effect on familial breast cancer
susceptibility.
Hereditary nonpolyposis colorectal cancer (HNPCC) is commonly associated with at least three currently known DNA mismatch repair genes: (a) hMSH2; (b) hMLH1; and (c) hMSH6. A majority of HNPCC ...families has identifiable mutations in hMLH1 and hMSH2. When these mutations cause an inherited risk of colorectal cancer, they are also most often associated with microsatellite instability in the tumors. Recently, hMLH3 was suggested to be causative in HNPCC. We screened 70 index patients suggestive of a genetic predisposition for germ-line mutations in hMLH3 with denaturing high-performance liquid chromatography. One frameshift mutation and 11 missense mutations were identified in 16 index patients (23%). Most families presented evidence against hMLH3 as a high risk factor in familial colorectal cancer, and most of the mutations were found in the low risk patients, suggesting hMLH3 to be a low risk gene for colorectal cancer. We demonstrate in one family that a hMLH3 mutation segregated with disease together with a missense mutation in hMSH2, which makes us hypothesize that these mutations work together in an additive manner and result in an elevated risk of colorectal tumors in the family. None of the tumors with hMLH3 mutations showed microsatellite instability, which demonstrates that hMLH3 does not make its contribution to carcinogenesis through an impaired DNA mismatch repair function.
The CCCTC-binding factor (CTCF), known as a versatile transcription factor and chromatin insulator and to be involved in X inactivation, has also been suggested to be a tumour suppressor on 16q. We ...investigated 153 patients with familial non-BRCA1/BRCA2 breast cancer for germline mutations in the CTCF gene.
Mutation screening of CTCF was performed by denaturing high-performance liquid chromatography followed by cycle sequencing.
We found two sequence variants, 240G-->A in the 5' untranslated region and 1455C-->T (S388S) in exon 4, in five familial breast cancer cases. Three of these five cases had both variants. Cases and controls showed the same prevalence for the two variants, which were found in linkage disequilibrium in most cases and controls.
The present study suggests that germline mutations in CTCF are not important as a risk factor for breast cancer.
Three loci have been implicated in the etiology of familial breast cancer; the BRCA1 locus on 17q, the p53 gene on 17p, and the androgen receptor gene on the X chromosome. However, it has been ...estimated that in approximately 50% of all breast cancer families the predisposing genetic defect is not linked to any of these three loci. In an attempt to identify chromosomal regions harboring putative breast cancer genes we performed allelotyping in 82 familial breast carcinomas. Polymorphic markers representing 45 different loci were analyzed and the most frequently involved chromosomal arms were 8p, 16q, 17p, 17q, and 19p.
Using molecular cloning, we earlier isolated the "retinoblastoma gene"; mutations or deletions at this locus are associated with the hereditary predisposition to some human cancers, especially ...retinoblastoma and osteosarcoma. To develop diagnostic tests for such a predisposition, we identified restriction-fragment-length polymorphisms (RFLPs) within the retinoblastoma gene and tested their usefulness in predicting the risk of cancer in 20 families with members who had hereditary retinoblastoma. We were able to make predictions in 19 of the 20 kindreds. In 18 kindreds, we demonstrated a consistent association of marker RFLPs with the mutation predisposing to retinoblastoma. In the 19th kindred, there may be a lack of cosegregation of the DNA polymorphisms within the gene and the site of the mutation predisposing to retinoblastoma. However, there is uncertainty about the clinical diagnosis of the retinal lesion in a key member of this kindred; if the lesion is not a retinoblastoma, there is no discrepancy between the DNA polymorphisms and the retinoblastoma trait. We conclude that it is feasible and clinically useful to use these DNA polymorphisms to determine the risk of cancer.
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