Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.
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.
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.
Mutations and diminished expression of the E-cadherin gene (CDH1) have been identified in a number of epithelial malignancies. Although somatic CDH1 mutations were detected in lobular breast cancer with a frequency ranging from 10 -56%, CDH1 alterations in more frequent ductal tumors appear to be rare. Here we have analyzed the coding region of CDH1 for mutations using denaturing high performance liquid chromatography and found 4 mutations in 83 ductal carcinomas (5%) and 3 mutations in 25 lobular carcinomas (12%). The germline of 13 patients with familial lobular tumors was also analyzed for mutations, but none were detected. In a case-control study, we also tested whether a variant adenine allele in the promoter polymorphism ؊161C3 A with a putative influence on the transcriptional activity of CDH1 in vitro confers any detectable risk of breast cancer. No significant difference in the allelic frequency between patients with breast cancer (326/1,152, 28.3%) and controls (190/696, 27.3%, p > 0.05; relative risk 1.05, 95% confidence interval 0.85-1.30) was found. A novel promoter polymorphism was identified at position ؊152, but the frequency of the variant cytosine allele was also similar in patients with breast cancer and controls (0.71% vs. 0.21%, p ؍ 0.23). Transient transfection experiments using reporter constructs containing the nucleotide substitutions ؊161C/ ؊152C and ؊161A/؊152T showed only a slight decrease in the transcription activity compared to the wild-type construct. These results do not support CDH1 as a prominent low-penetrance cancer susceptibility gene, but indicate that CDH1 mutations contribute to the progression of both lobular and ductal tumors. © 2002 Wiley-Liss, Inc. Key words: E-cadherin; mutation; breast cancer; promoter; SNPThe E-cadherin gene (CDH1, OMIM 192090) encodes an adhesion molecule important for establishing cell polarity and maintaining normal tissue morphology and cellular differentiation. 1 E-cadherin was suggested to act as an invasion and metastasis suppressor since its loss in benign tumors could lead to a rapid progression into invasive, metastatic carcinomas. 2 CDH1 was mapped to the chromosome region 16q22.1, 3 which shows frequent allelic imbalance in a variety of tumors and is believed to harbor a tumor-suppressor gene. Mutation analysis of the coding region has been carried out in endometrial and ovarian carcinomas, 4 thyroid, 5 prostate, 6 bladder, 7 colorectal, 8 gastric, 9 breast 10 -14 and colon cancer, 15 but frequent CDH1 mutations were only found in diffuse gastric and infiltrative lobular breast carcinomas. 10,11,16 Although ductal tumors are much more common than lobular breast cancer, CDH1 mutations have been observed in lobular carcinomas at a frequency exceeding 50%, 11 but were not found in ductal tumors in several studies, 10,11,16,17 suggesting a differential role for CDH1 in the development of the 2 malignancies. However, recent studies reported CDH1 alterations in cell lines derived from ductal tumors 18 and in a single case of ductal carcinom...
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