Runs of homozygosity and testicular cancer risk.

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. DISCUSSION AND CONCLUSION: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

BOADICEA breast cancer risk prediction model: updates to cancer incidences, tumour pathology and web interface.

BACKGROUND: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction model that is used to compute probabilities of carrying mutations in the high-risk breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, and to estimate the future risks of developing breast or ovarian cancer. In this paper, we describe updates to the BOADICEA model that extend its capabilities, make it easier to use in a clinical setting and yield more accurate predictions. METHODS: We describe: (1) updates to the statistical model to include cancer incidences from multiple populations; (2) updates to the distributions of tumour pathology characteristics using new data on BRCA1 and BRCA2 mutation carriers and women with breast cancer from the general population; (3) improvements to the computational efficiency of the algorithm so that risk calculations now run substantially faster; and (4) updates to the model's web interface to accommodate these new features and to make it easier to use in a clinical setting. RESULTS: We present results derived using the updated model, and demonstrate that the changes have a significant impact on risk predictions. CONCLUSION: All updates have been implemented in a new version of the BOADICEA web interface that is now available for general use: http://ccge.medschl.cam.ac.uk/boadicea/.

Decreased breast cancer risk in systemic lupus erythematosus: the search for a genetic basis continues.

PURPOSE: Recent work has demonstrated an important decrease in breast cancers for women with systemic lupus erythematosus (SLE). The reason behind this phenomenon is unknown. Our purpose was to explore whether the single nucleotide polymorphisms (SNPs) predisposing to SLE might be protective against breast cancer (in women in the general population). METHODS: We focused on loci relevant to 10 SNPs associated with SLE (with a p value of <10(-9)). We determined whether we could establish a decreased frequency of these SNPs in breast cancer cases versus controls, within the general population. To do this we used a large breast cancer genome-wide association study (GWAS) dataset, involving 3,659 breast cancer cases and 4,897 controls. These subjects were all primarily of European ancestry. RESULTS: The population-based GWAS breast cancer data we examined suggested little evidence for important associations between breast cancer and SLE-related SNPs. Within the general population GWAS data, a cytosine(C) nucleotide substitution at rs9888739 (on chromosome 16p11.2) showed a very weak inverse association with breast cancer. The odds ratio (OR) for the rs9888739-C allele was 0.907551 (p value 0.049899) in the GWAS breast cancer sample, compared to controls. There was a slightly stronger, positive, association with breast cancer for rs6445975-G (Guanine) on chromosome 3p14.3, with a breast cancer OR of 1.0911 (p value 0.0097). CONCLUSIONS: Within this large breast cancer dataset, we did not demonstrate important associations with 10 lupus-associated SNPs. If decreased breast cancer risk in SLE is influenced by genetic profiles, this may be due to complex interactions and/or epigenetic factors.

Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours.

BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T. METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity. RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype. CONCLUSION: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.

Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript.

Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

Polygenic susceptibility to prostate and breast cancer: implications for personalised screening.

BACKGROUND: We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone. METHODS: We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 and N=18, respectively). RESULTS: Compared with screening men based on age alone (aged 55-79: 10-year absolute risk ≥2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47-79: 10-year absolute risk ≥2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases. CONCLUSION: Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis.

BACKGROUND: The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours. METHODS: Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan-Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing. RESULTS: Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se. CONCLUSION: BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease.

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

A recurrent truncating germline mutation in the BRIP1/FANCJ gene and susceptibility to prostate cancer.

Although prostate cancer (PrCa) is one of the most common cancers in men in Western countries, little is known about the inherited factors that influence PrCa risk. On the basis of the fact that BRIP1/FANCJ interacts with BRCA1 and functions as a regulator of DNA double-strand break repair pathways, and that germline mutations within the BRIP1/FANCJ gene predispose to breast cancer, we chose this gene as a candidate for mutation screening in familial and young-onset PrCa cases. We identified a truncating mutation, R798X, in the BRIP1/FANCJ gene in 4 out of 2714 UK PrCa cases enriched for familial (2 out of 641; 0.3%) and young-onset cases (2 out of 2073; 0.1%). On screening 2045 controls from the UK population, we found one R798X sequence alteration (0.05%; odds ratio 2.4 (95% CI 0.25-23.4)). In addition, using our data from a genome-wide association study, we analysed 25 SNPs in the genomic region of the BRIP1/FANCJ gene. Two SNPs showed evidence of association with familial and young-onset PrCa (rs6504074; P(trend)=0.04 and rs8076727; P(trend)=0.01). These results suggest that truncating mutations in BRIP1/FANCJ might confer an increased risk of PrCa and common SNPs might also contribute to the alteration of risk, but larger case-control series will be required to confirm or refute this association.

Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics.

OBJECTIVES: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals. DESIGN: We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions. RESULTS: Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p<0.05) than all models except BRCAPRO (area under the receiver operating characteristic curve statistics: BOADICEA = 0.77, BRCAPRO = 0.76, IBIS = 0.74, Manchester = 0.75, Myriad = 0.72). All models underpredicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category. CONCLUSIONS: Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing.

Common variants in mismatch repair genes and risk of colorectal cancer.

BACKGROUND AND AIMS: The mismatch repair (MMR) genes are in charge of maintaining genomic integrity. Mutations in the MMR genes are at the origin of a familial form of colorectal cancer (CRC). This syndrome accounts for only a small proportion of the excess familial risk of CRC. The characteristics of the alleles that account for the remainder of cases are unknown. To assess the putative associations between common variants in MMR genes and CRC, we performed a genetic case-control study using a single-nucleotide polymorphism (SNP) tagging approach. PATIENTS AND METHODS: A total of 2299 cases and 2284 unrelated controls were genotyped for 68 tagging SNPs in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were measured in cases and controls and analysed using univariate analysis. Haplotypes were constructed and analysed using logistic regression. We also carried out a two-locus interaction analysis and a global test analysis. RESULTS: Genotype frequencies were found to be marginally different in cases and controls for MSH3 rs26279 with a rare homozygote OR = 1.31 [95% confidence interval (CI) 1.05 to 1.62], p(trend) = 0.04. We found a rare MLH1 (frequency <5%) haplotype, increasing the risk of colorectal cancer: (OR = 9.76; 95% CI, 1.25 to 76.29; p = 0.03). The two-locus interaction analysis has exhibited signs of interaction between SNPs located in genes MSH6 and MSH2. Global testing has showed no evidence of interaction. CONCLUSION: It is unlikely that common variants in MMR genes contribute significantly to colorectal cancer.

The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions.

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).

Testicular microlithiasis as a familial risk factor for testicular germ cell tumour.

Testicular microlithiasis (TM) is characterised by small intratesticular calcifications, which can be visualised by ultrasound. Men with testicular germ cell tumour (TGCT) have a higher frequency of TM than men without TGCT. To clarify the association between TGCT and TM and to investigate the relationship between TGCT susceptibility and TM, we recruited TGCT patients with and without family history of TGCT, unaffected male relatives and healthy male controls from the UK. Testicular ultrasound data were analysed from 328 men. Testicular microlithiasis was more frequent in TGCT cases than controls (36.7 vs 17.8%, age adjusted P<0.0001) and in unaffected male relatives than controls (34.5 vs 17.8%, age adjusted P=0.02). Testicular germ cell tumour case and matched relative pairs showed greater concordance for TM than would be expected by chance (P=0.05). We show that TM is present at a higher frequency in relatives of TGCT cases than expected by chance indicating that TM is a familial risk factor for TGCT. Although the familiality of TM could be due to shared exposures, it is likely that there exists a genetic susceptibility to TM that also predisposes to TGCT. We suggest that TM is an alternative manifestation of a TGCT susceptibility allele.

HapMap-based study of the 17q21 ERBB2 amplicon in susceptibility to breast cancer.

ERBB2 is frequently amplified in breast tumours as part of a wide region of amplification on chromosome 17q21. This amplicon contains many candidate genes for breast cancer susceptibility. We used a genetic association study design to determine if common genetic variation (frequency>or=5%) in a 400-kb region surrounding ERBB2 and containing the PPARBP, CRK7, NEUROD2, PPP1R1B, STARD3, TCAP, PNMT, CAB2, ERBB2, C17ORF37, GRB7 and ZNFN1A3 genes, was associated with breast cancer risk. Sixteen tagging single-nucleotide polymorphisms (tSNPs) selected within blocks of linkage disequilibrium from the HapMap database, one HapMap singleton SNP, and six additional SNPs randomly selected from dbSNP were genotyped using Taqman in a large study set of British women (2275 cases, 2280 controls). We observed no association between any of the genotypes or associated haplotypes and disease risk. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 90% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common variants present in our population. In summary, we found no association between common genetic variation in the 17q21 ERBB2 amplicon and breast cancer risk in British women.

Models of genetic susceptibility to breast cancer.

One of the most important risk factors for breast cancer is family history of the disease, indicating that genetic factors are important determinants of breast cancer risk. A number of breast cancer susceptibility genes have been identified, the most important being BRCA1 and BRCA2. However, it is estimated that all the currently known breast cancer susceptibility genes accounts for less than 25% of the familial aggregation of breast cancer. In this paper, we review the evidence for other breast cancer susceptibility genes arising from twin studies, pedigree analysis and studies of phenotypes associated with breast cancer, and the progress towards finding other breast cancer susceptibility genes through linkage and association studies. Taken together, the available evidence indicates that susceptibility to breast cancer is mediated through variants in many genes, each conferring a moderate risk of the disease. Such a model of susceptibility has implications for both risk prediction and for future gene identification studies.

Interactions between genes involved in the antioxidant defence system and breast cancer risk.

The aim of the study is to examine the association between multilocus genotypes across 10 genes encoding proteins in the antioxidant defence system and breast cancer. The 10 genes are SOD1, SOD2, GPX1, GPX4, GSR, CAT, TXN, TXN2, TXNRD1 and TXNRD2. In all, 2271 cases and 2280 controls were used to examine gene-gene interactions between 52 single nucleotide polymorphisms (SNPs) that are hypothesised to tag all common variants in the 10 genes. The statistical analysis is based on three methods: unconditional logistic regression, multifactor dimensionality reduction and hierarchical cluster analysis. We examined all two- and three-way combinations with unconditional logistic regression and multifactor dimensionality reduction, and used a global approach with all SNPs in the hierarchical cluster analysis. Single-locus studies of an association of genetic variants in the antioxidant defence genes and breast cancer have been contradictory and inconclusive. It is the first time, to our knowledge, the association between multilocus genotypes across genes coding for antioxidant defence enzymes and breast cancer is investigated. We found no evidence of an association with breast cancer with our multilocus approach. The search for two-way interactions gave experiment-wise significance levels of P=0.24 (TXN [t2715c] and TXNRD2 [g23524a]) and P=0.58 (GSR [c39396t] and TXNRD2 [a442g]), for the unconditional logistic regression and multifactor dimensionality reduction, respectively. The experiment-wise significance levels for the three-way interactions were P=0.94 (GPX4 [t2572c], TXN [t2715c] and TXNRD2 [g23524a]) and P=0.29 (GSR [c39396t], TXN [t2715c] and TXNRD2 [a442g]) for the unconditional logistic regression and multifactor dimensionality reduction, respectively. In the hierarchical cluster analysis neither the average across four rounds with replacement of missing values at random (P=0.12) nor a fifth round with more balanced proportion of missing values between cases and controls (P=0.17) was significant.

Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast.

AIMS: Cytokeratin (CK) 14, a myoepithelial marker, is also expressed in a proportion of breast carcinomas. There is evidence that these tumours show a differing metastatic pattern and clinical outcome from other invasive ductal carcinomas (IDCs) and may need different management. Currently, they are not identified in routine practice and no morphological guidelines exist to aid their identification. The aim of this study was to analyse the histological features of CK14+ IDC. METHODS AND RESULTS: A detailed histological review of 453 grade 3 IDCs revealed 88 (19.4%) that expressed CK14. Assessment was made independently by two pathologists using a standardized 'tick-box' proforma covering grade, architectural and cytological features. The results were analysed using logistic regression to identify features that predicted for basal phenotype. Concordance between the two pathologists was fair to good for most parameters (kappa 0.4-0.6). On multiple logistic regression, the basal phenotype was highly significantly associated with the presence of a central scar (P = 0.005), tumour necrosis (P < 0.0001), presence of spindle cells (P = 0.006) or squamous metaplasia (P < 0.0001), high total mitotic count (> 40 per 10 high-power field) (P = 0.0002) and high nuclear-cytoplasmic ratio (P = 0.0002). CONCLUSIONS: Specific morphological features are strongly associated with basal-like breast carcinoma. These could be used in routine diagnostic practice to identify this important subset of tumours.

Single-nucleotide polymorphisms in the RB1 gene and association with breast cancer in the British population.

A substantial proportion of the familial risk of breast cancer may be attributable to genetic variants each contributing a small effect. pRb controls the cell cycle and polymorphisms within it are candidates for such low penetrance susceptibility alleles, since the gene has been implicated in several human tumours, particularly breast cancer. The purpose of this study was to determine whether common variants in the RB1 gene are associated with breast cancer risk. We assessed 15 tagging single-nucleotide polymorphisms (SNPs) using a case-control study design (n< or = 4474 cases and n < or = 4560 controls). A difference in genotype frequencies was found between cases and controls for rs2854344 in intron 17 (P-trend = 0.007) and rs198580 in intron 19 (P-trend = 0.018). Carrying the minor allele of these SNPs appears to confer a protective effect on breast cancer risk (odd ratio (OR) = 0.86 (0.76-0.96) for rs2854344 and OR = 0.80 (0.66-0.96) for rs198580). However, after adjusting for multiple testing these associations were borderline with an adjusted P-trend = 0.068 for the most significant SNP (rs2854344). The RB1 gene is not known to contain any coding SNPs with allele frequencies > or = 5% but several intronic variants are in perfect linkage disequilibrium with the associated SNPs. Replication studies are needed to confirm the associations with breast cancer.

Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies.

A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.