Probability estimation models for prediction of BRCA1 and BRCA2 mutation carriers: COS compares favourably with other models.

BACKGROUND: Accurate risk assessment is essential to genetic counselling for a family history of cancer. Several empiric and computer-based risk assessment models have been developed to estimate a counselee's probability of being a carrier of mutation in BRCA1 and/or 2 genes, and to predict the risk of developing breast cancer. The COS model was developed from the better-known BRCAPro model to estimate risk of carriage of BRCA1 or 2 mutation. The COS model remains to be validated in a population discrete from that used for its development. METHODS: Four probability estimation models including COS, Manchester scoring system (MSS), BOADICEA and Tyrer-Cuzick (T-C) were applied to 275 Scottish families tested for BRCA1/2 mutations ascertained through regional genetics centres to ascertain models' sensitivity, specificity and accuracy. A subset of 130 families from Grampian (North and Northeast Scotland) was used to assess the models' ability to estimate the prevalence of BRCA1/2 mutation carriers. Sensitivity, specificity and ROC plots were used to ascertain models' individual performance, in terms of number of cancer cases, type of cancer and age of diagnosis of breast cancer. RESULTS: The COS and MSS models demonstrated the greatest sensitivities and area under ROC curves for the majority of family structures. They also showed the highest sensitivities (91-92%) and AUCs (76-78%) for the entire dataset overall. However, BOADICEA and T-C had the highest specificities for the majority of the family structures. BOADICEA and T-C generated the best estimates for the prevalence of mutations in the population; BOADICEA was more accurate for BRCA1 and T-C for BRCA2. CONCLUSION: The COS and MSS models are the most effective models for use in clinical practice to select families for mutation analysis, but BOADICEA and T-C are more accurate for estimating mutation prevalence within a population.

Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, intakes of folate and related B vitamins and colorectal cancer: a case-control study in a population with relatively low folate intake.

Folate is key in one-carbon metabolism, disruption of which can interfere with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires other B vitamins and the optimal activity of enzymes including 5,10-methylenetetrahydrofolate reductase (MTHFR). We report a population-based case-control study of folate intake, related dietary factors and MTHFR polymorphisms (C677T, A1298C) and colorectal cancer in a population with relatively high colorectal cancer incidence and relatively low folate intake. A total of 264 cases with histologically confirmed incident colorectal cancer and 408 controls participated. There was no clear trend in risk with reported intakes of total, or dietary, folate, riboflavin, vitamin B12 or vitamin B6, nor were there interactions between folate intake and the other B vitamins or alcohol. For C677T, risk decreased with increasing variant alleles (multivariate OR for CT v. CC = 0.77 (95 % CI 0.52, 1.16); OR for TT v. CC = 0.62 (95 % CI 0.31, 1.24)), which, although not statistically significant, was consistent with previous studies. For A1298C, compared with AA subjects, CC subjects had modest, non-significant, reduced risk (multivariate OR = 0.81 (95 % CI 0.45, 1.49)). There were significant interactions between total folate and C677T (P = 0.029) and A1298C (P = 0.025), and total vitamin B6 and both polymorphisms (C677T, P = 0.016; A1298C, P = 0.033), although the patterns observed differed from previous studies. Seen against the setting of low folate intake, the results suggest that the role of folate metabolism in colorectal cancer aetiology may be more complex than previously thought. Investigation of particular folate vitamers (for example, tetrahydrofolate, 5,10-methylenetetrahydrofolate) may help clarify carcinogenesis pathways.

Human fetal testis Leydig cell disruption by exposure to the pesticide dieldrin at low concentrations.

BACKGROUND: Declining human reproductive health over the last 60 years has been proposed to be due to effects of environmental chemicals, especially endocrine disrupting compounds, on fetal development. We investigated whether a model pesticide, dieldrin, at concentrations within both maternal circulation and environmental ranges (1 pmol/l = 0.0004 p.p.b. = 380.9 pg/l), could disrupt the human fetal testis. METHODS: Human fetal testes were collected during the second trimester, a critical period of male sexual differentiation (development and masculinization). Testis explants were cultured for 24 h in the presence and absence of LH (10-1000 IU LH/l) and dieldrin (1 pmol and 1 nmol/l). Endocrine, immunohistological and proteome characteristics of the tissues were investigated. RESULTS: Exposure to dieldrin reduced LH-induced testosterone secretion (P < 0.05) and tissue protein concentrations of LH receptor and steroid acute regulatory protein (P < 0.05). Dieldrin altered proteins associated with cancer, apoptosis, transcription and development. Wnt-2b was reduced 3-fold and immunolocalized to Leydig and Sertoli cells. Dieldrin also reversed some LH-induced changes in protein expression, supporting the conclusion that Leydig cell function is at risk from environmental chemicals. CONCLUSIONS: Our findings indicate that exposure to very low, biologically relevant, concentrations of environmental chemicals could affect the fetal human Leydig cell, reducing testosterone secretion and potentially leading to subtle dysregulation of reproductive development and adult fecundity.

Information recovery in cancer families: value for risk estimations.

BACKGROUND: Drawing an informative pedigree is fundamental in genetic counselling. It is very common for some parts of pedigrees to remain ambiguous because of the proband's inability to recall the past history of her/his family. Current age, date of birth, date of death and age of diagnosis are the commonest missing information in pedigrees. METHODS: The Scottish Social Statistics website, National Statistics website and English language literature were used to model extrapolations. About 172 Grampian families and three high-risk Grampian families with complete information were chosen to evaluate the influence of extrapolations on models' performance. Differences between original data and extrapolated data were assessed by independent samples t-test. RESULTS: Changes made by extrapolations in age- and cancer-related information were not statistically significant (P > 0.05) in comparison with original data, except for average age of diagnosis of breast cancer (P = 0.03). The differences made by extrapolations in estimated probabilities generated by probability assessment models were small and ignorable except that for Tyrer-Cuzick model for Grampian family 3. CONCLUSION: Extrapolations based on National Health Statistics can scientifically cover missing information in a defined population with minimum effect on performance of probability assessment models.

Colorectal cancer and genetic polymorphisms of CYP1A1, GSTM1 and GSTT1: a case-control study in the Grampian region of Scotland.

Cytochrome P-450 CYP1A1 is involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs) that are derived from meat intake and tobacco smoking. Expression of the CYP1A1 gene is induced by compounds present in cruciferous vegetables. The glutathione S-transferases play a central role in the detoxification of carcinogens, including PAHs. We investigated the association between colorectal cancer and three variants (CYP1A1*2A, CYP1A1*2C, CYP1A1*4) of the CYP1A1 gene, and homozygosity for the null deletion of the GSTM1 and GSTT1 genes, and the joint effects of these genotypes and smoking, meat intake and intake of green leafy vegetables in a population-based study of 264 cases and 408 controls in Northeast Scotland. There was an inverse association with the CYP1A1*4 (m4) variant (OR 0.3, 95% CI 0.13-0.70). The OR for the CYP1A1*2C (m2) variant was 1.3 (95% CI 0.59-2.91), which is similar to a combined estimate for previous studies (OR 1.2, 95% CI 0.95-1.41). We observed no association with the CYP1A1*2A (m1) variant, or the GSTM1 and GSTT1 polymorphisms. Significant interactions between all 3 CYP1A1 variants and meat intake, and between the m1 and m2 variants and intake of green leafy vegetables, were observed. There was no evidence of interaction between CYP1A1 and smoking, and no evidence of interaction between the GSTM1 or GSTT1 polymorphisms and smoking, meat intake, green leafy vegetable intake, CYP1A1 variants or each other.

Genomic changes identified by comparative genomic hybridisation in docetaxel-resistant breast cancer cell lines.

Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. In this study high-level, docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) were created, and comparative genomic hybridisation was used to identify genomic regions associated with resistance to docetaxel. MCF-7 resistant cells showed an amplification of chromosomes 7q21.11-q22.1, 17q23-q24.3, 18, and deletion of chromosomes 6p, 10q11.2-qter and 12p. MDA-MB-231 resistant cells showed a gain of chromosomes 5p, 7q11.1-q35, 9, and loss of chromosomes 4, 8q24.1-qter, 10, 11q23.1-qter, 12q15-q24.31, 14q and 18. Whole chromosome paints confirmed these findings. Amplification of 7q21 and loss of 10q may represent a common mechanism of acquired docetaxel resistance in breast cancer cells. This study is the first description of a genomic approach specifically to identify genomic regions involved in resistance to docetaxel.

Length and somatic mosaicism of CAG and GGN repeats in the androgen receptor gene and the risk of prostate cancer in men with benign prostatic hyperplasia.

BACKGROUND: The most common malignancy in men worldwide is cancer of the prostate and determinants of prostate cancer (PRCa) risk remain largely unidentified. Many candidate genes may be involved in PRCa, such as those that are central to cellular growth and differentiation in the prostate gland. We analysed the polymorphic CAG and GGN repeats sequence in exon 1 of the AR gene to determine if the number of repeats might be an indicator of PRCa risk in patients with BPH. METHODS: The study evaluated 28 patients who presented with PRCa at least 6 years after the diagnosis of BPH and 56 matched patients with BPH who did not progress to PRCa over a comparable period. RESULTS: This study showed no evidence for association between the size of AR CAG and GGN repeats and the risk of the development of PRCa in patients with BPH. However, BPH patients with AR CAG instability had a 12-fold increased risk in development of PRCa. CONCLUSIONS: While independent confirmation is required in further studies, these results provide a potential tool to assist prediction strategies for this important disease.

Vitamin D receptor, HER-2 polymorphisms and risk of prostate cancer in men with benign prostate hyperplasia.

OBJECTIVE: Prostate cancer (PRCa) is one of the most common causes of cancer death in men and determinants of PRCa risk remain largely unidentified. Benign prostatic hyperplasia (BPH) is found in the majority of ageing men and has been associated with PRCa. Many candidate genes have been suggested to be involved in PRCa, such as those that are central to cellular growth and differentiation in the prostate gland. The vitamin D receptor (VDR) and HER-2 protooncogene have been shown to be involved in the regulation of cell proliferation and differentiation in prostate cells. Genetic variations of these genes could be useful to detect BPH patients that have a higher risk of developing PRCa. This study used a case-control design to assess the predictive value of 3 polymorphisms in VDR (TaqI and FokI) and HER-2 (Val655Ile) to determine the risk of developing PRCa in patients with BPH. METHODS: Polymorphisms were detected by RFLP analysis. The study evaluated 28 patients who presented with PRCa at least 6 years after the diagnosis of BPH and 56 matched patients with BPH who did not progress to PRCa over a comparable period. The study was carried out in University of Aberdeen, Foresterhill, Aberdeen, United Kingdom in the year 2002. RESULTS: Among the case group, 89% had a TT TaqI genotype, whereas 57% of control had this genotype (odds ratio [OR] = 5.16, 95% confidence interval [CI] = 1.46-18.22). A similar pattern was seen for the FokI genotype, although this was not statistically significant (OR = 2.33, 95% CI = 0.86-6.29). The frequency of the HER-2 Ile/Ile genotype was higher in cases (79%) compared to control subjects (66%), although this was not statistically significant (OR = 1.94, 95% CI = 0.67-5.63). CONCLUSION: This study shows that the VDR TaqI polymorphism is associated with a group of men with BPH who are at an increase risk of PRCa, providing a potential tool to assist prediction strategies for this important disease.

CYP3A4 promoter variant is associated with prostate cancer risk in men with benign prostate hyperplasia.

Prostate cancer (PRCa) is one of the most common causes of cancer death in men and determinants of PRCa risk remain largely unidentified. Benign prostatic hyperplasia (BPH) is found in the majority of ageing men and has been linked with PRCa. CYP3A4 may influence PRCa through its role in testosterone metabolism. This nested case-control study assessed a CYP3A4 single nucleotide polymorphism as a risk factor for developing PRCa in patients with BPH. The CYP3A4 variant allele identified men with BPH who are at increased risk of progressing to PRCa (odds ratio 6.3, 95% CI 2.3-17.3), providing a potential tool to assist prediction strategies for this disease.