TGFBR1 variants TGFBR1(*)6A and Int7G24A are not associated with an increased familial colorectal cancer risk.

Variants of the transforming growth factor-beta receptor type 1 (TGFBR1) gene, TGFBR1*6A and Int7G24A, have been suggested to act as low-penetrance tumour susceptibility alleles with TGFBR1*6A being causally responsible for some cases of familial colorectal cancer (CRC). We performed a case-control study of 262 unrelated familial CRC cases; 83 hereditary non-polyposis colorectal cancer (HNPCC) and 179 non-HNPCC. Patients were genotyped for TGFBR1*6A and Int7G24A and compared with 856 controls. Further, we screened the coding region of TGFBR1 in affected members of a large family with CRC linked to 9q22.32-31.1. TGFBR1*6A allelic frequency was not significantly different in all of the familial cases compared with controls (0.107 and 0.106, respectively; P=0.915). In a subgroup analysis allele frequencies were, however, different between HNPCC and non-HNPCC familial cases (0.157 and 0.084, respectively; P=0.013). TGFBR1*6A genotype did not influence age of onset. Int7G24A allele frequencies were similar in cases and controls. No germ-line mutation was identified in the family with CRC linked to this chromosomal region. Our study provides no substantial support for the hypothesis that the polymorphic variants TGFBR1*6A or Int7G24A contribute to familial CRC risk. We cannot, however, exclude the possibility that TGFBR1 variants have a modifying effect on inherited risk per se.

Estrogen receptor beta in breast cancer.

Estrogen is essential for normal growth and differentiation in the mammary gland. It also supports growth of approximately 50% of primary breast cancers. For this reason, removal of estrogen or blocking of its action with the anti-estrogen, tamoxifen, is the main treatment for estrogen receptor alpha (ERalpha)-positive tumors. In 1996, when oncologists became aware of a second ER, ERbeta, there was some doubt as to whether this receptor would be of importance in breast cancer because the clinical consensus was that responsiveness to tamoxifen is related to the presence of ERalpha in breast cancer. Today we know that ERalpha and ERbeta have distinct cellular distributions, regulate separate sets of genes and can oppose each other's actions on some genes. We also know that ERbeta is widely expressed in both the normal and malignant breast and that there are proliferating cells in the breast which express ERbeta. In this review we summarize what is known about ERbeta in breast cancer and examine the possibility that ERbeta-selective ligands may well represent a useful class of pharmacological tools with a novel target, namely proliferating cells expressing ERbeta.

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

A screening for BRCA1 mutations in breast and breast-ovarian cancer families from the Stockholm region.

To identify BRCA1 germ-line mutations in the breast and breast-ovarian cancer families in the Stockholm region, a total of 127 families were screened. DNA from 174 patients from these families were studied using various mutation screening techniques, followed by direct DNA sequencing. Mutations were identified in 7 of 20 families with breast and ovarian cancer and in one family with ovarian cancer only, whereas only 1 family of 106 with breast cancer showed a mutation. Thus, germ-line mutations in BRCA1 were found in one-third of the families with both breast and ovarian cancer, but in only 1% of the breast cancer families. The low frequency of germ-line mutations in the site-specific breast cancer families means that other genes are likely to segregate in these families.

Screening for TP53 mutations in patients and tumours from 109 Swedish breast cancer families.

To estimate the prevalence of TP53 mutations in familial breast cancer, constant denaturant gel electrophoresis (CDGE) was used to screen exons 5-8 of the TP53 gene for germline mutations. Genomic DNA from 128 breast cancer patients belonging to 109 families with familial cancer were screened. No germline mutations were found in any of the patients. We also studied TP53 mutations in tumour DNA from 51 of the same individuals and found mutations in 14%. This is similar to what has been reported in sporadic breast cancer.

Genetic rearrangements in sporadic and familial gastric carcinomas detected with microsatellite markers.

Ten gastric carcinomas were studied for loss of heterozygosity by analysis of 21 microsatellite markers from 14 different chromosomes. Four patients had a family history of gastro-intestinal cancer, and six tumours were considered sporadic. We also studied a new mechanism in tumourigenesis recently reported in hereditary non polyposis colon cancer, a defect in mismatch repair that is seen as gain of new bands by the use of dinucleotide repeat markers. Loss of heterozygosity was detected with two markers in one primary tumour and with the majority of markers in one metastasis from a sporadic gastric tumour. Gain of microsatellite bands was seen in one tumour from a gene carrier in a family with hereditary non-polyposis colon cancer and in one sporadic tumour. Two tumours from patients with a family history of gastric cancer showed no rearrangements. Our results suggest that different types of genes are involved in initiation and progression of gastric cancer in sporadic and familial gastric cancer.

Loss of heterozygosity studies in tumors from families with breast-ovarian cancer syndrome.

A gene (BRCA1) predisposing for familial breast and ovarian cancer has been mapped to chromosome band 17q12-21. Based on the observation that ovarian tumors from families with breast and ovarian cancer lose the wild-type allele in the region for the BRCA1 locus, it has been suggested that the gene functions as a tumor suppressor gene. We have studied chromosomal deletions in the BRCA1 region in seven breast tumors, three ovarian tumors, one bladder cancer, and one colon cancer from patients in six families with breast-ovarian cancer, in order to test the hypothesis of the tumor suppressor mechanism at this locus. We have found a low frequency of loss of heterozygosity at this region, and our results do not support the idea that BRCA1 is a tumor suppressor gene. Alternatively, the disease segregating in these families is linked to one or more different loci.

High expression of the EGFR in fibroadenomas compared to breast carcinomas.

The epidermal growth factor receptor and its ligands have been implicated as being involved in normal mammary development and breast cancer genesis. Northern blotting was used to assay the mRNA levels of the epidermal growth factor receptor and three of its ligands: the epidermal growth factor, the transforming growth factor alpha and the Amphiregulin in 16 primary carcinomas, 2 metastases and 5 fibroadenomas. In addition, the mRNA levels of the other members of the epidermal growth factor receptor family, erbB2 and erbB3 were also analysed. We found limited expression in the breast carcinomas while all the fibroadenomas showed expression at high levels. Therefore we suggest that the epidermal growth factor receptor plays an important role in the development of fibroadenomas. The erbB2 and erbB3 were more strongly expressed than the epidermal growth factor receptor in the primary carcinomas. This suggests that they could be of importance in breast carcinogenesis.