[Show abstract][Hide abstract] ABSTRACT: In Austria, 700 women are diagnosed every year with ovarian carcinoma. Approximately 15 % of the patients with epithelial ovarian cancer have a germline mutation in the BRCA1 or BRCA2 genes. The increased incidence of breast and/or ovarian cancer in genetically related family members has given rise to the term "hereditary breast and ovarian cancer syndrome" (HBOC). Some 25-55 % of these in-family diseases are attributed to germline mutations of BRCA1 or BRCA2, and approximately 5-10 % to other known tumor predisposition syndromes. The remaining persons may carry mutations in as yet unidentified genes. HBOC caused by BRCA1 and BRCA2 mutations is an autosomal dominant disorder with high penetrance. BRCA1 and BRCA2 encode for so-called tumor suppressor proteins. Inherited functional mutations of these genes cause loss of function of the respective allele. Loss of function of the second allele causes complete loss of the corresponding protein and facilitates the development of a malignancy.The Association of Gynecologic Oncology recommends that testing for a germline mutation in BRCA1 or BRCA2 should be offered to all patients with epithelial ovarian cancer. When mutations in BRCA1, BRCA2, or other cancer-susceptibility genes have been identified, patients with ovarian carcinoma can be treated with new, innovative therapies. This recommendation is intended as a standard guideline for genetic testing of patients with an ovarian carcinoma.
Wiener klinische Wochenschrift 06/2015; DOI:10.1007/s00508-015-0814-7 · 0.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Given the adverse effect of alcohol in the development of breast cancer among women in the general population, we evaluated whether a similar association exists among women with a BRCA1 or BRCA2 mutation. Information regarding baseline daily alcohol consumption was abstracted from a research questionnaire for 3067 BRCA mutation carriers enrolled in a prospective cohort study. Women were followed biennially until the date of the last follow-up questionnaire, date of breast cancer diagnosis, date of prophylactic bilateral mastectomy, or date of death. Cox proportional hazards models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for invasive breast cancer associated with alcohol consumed at or prior to completion of the baseline questionnaire. After a mean of 5.4 years of follow-up, we observed 259 incident cases of primary invasive breast cancer. Compared with non-users, the adjusted RRs were 1.06 (95 % CI 0.78-1.44) for ever use and 1.08 (0.79-1.47) for current alcohol use. For women in the highest versus lowest quintile of cumulative alcohol consumption, the RR was 0.94 (95 % CI 0.63-1.40; P trend = 0.65). Our findings suggest that alcohol consumption is not a risk factor for breast cancer among women with a BRCA1 or BRCA2 mutation.
Breast Cancer Research and Treatment 05/2015; DOI:10.1007/s10549-015-3393-4 · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.
[Show abstract][Hide abstract] ABSTRACT: Individuals carrying pathogenic mutations in BRCA1/2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals from different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. Here we test the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
We genotyped 22214 (11421 affected, 10793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched for affected or unaffected individuals.
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers than the rest of clade T, (Hazard Ratio (HR) = 0.55 (95% Confidence Interval (CI) 0.34-0.88, p-value = 0.01). Compared with the most frequent haplogroup in the general population i.e. H and T clade, the T1a1 haplogroup has an HR = 0.62 (95% CI = 0.40-0.95, p-value = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
This study illustrates how original approaches like the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Breast cancer research: BCR 04/2015; 17(1):61. DOI:10.1186/s13058-015-0567-2 · 5.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
OBJECTIVE:To identify mutation-specific cancer risks for carriers of BRCA1/2.
DESIGN, SETTING, AND PARTICIPANTS:Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.
EXPOSURES:Mutations of BRCA1 or BRCA2.
MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.
RESULTS:Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.
CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
JAMA The Journal of the American Medical Association 04/2015; 313(13):1347-61. DOI:10.1001/jama.2014.5985 · 30.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10-4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
PMID: 25830658 [PubMed - in process]
PLoS ONE 04/2015; 10(4). DOI:10.1371/journal.pone.0120020 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Special focus and aim of our research activities at AIT, the Austrian Institute of Technology, is to define reliable biomarkers suitable for early and non-invasive disease diagnosis from body fluids such as serum/plasma and saliva. Along a selection of research projects, which are described in more detail underneath, we will present and introduce the broad portfolio of high throughput technologies we successfully apply for diagnostic biomarker discovery and validation. As a first show case of successful non-invasive disease biomarker discovery we will present a study where we investigated and compared the genome wide methylation levels of lung cancer patients, patients suffering from lung fibrosis, patients with COPD (chronic obstructive pulmonary disease), and DNA samples derived from healthy lungs. Along this study we could identify specific methylation patterns for each of these lung diseases. After quantitative PCR validation of 240 disease specific methylation markers in the discovery sample set, the 90 top markers were picked and applied for serum testing (n=204). When we applied gradient boosting classification for differential diagnosis of tested lung diseases and healthy controls an AUC value of 0.95 was reached here to separate cancer from all other non-cancer samples whereas in differential diagnosis of healthy-, COPD and fibrosis patients AUC values of 0.71 and 0.49 were obtained for fibrosis, respectively COPD. Thus in case of COPD the presented method may be used to monitor cancer risk within COPD patients. Our second show case comprises a study where we screened cancer patients’ sera for tumor-specific antibody profiles using an in-house developed 16k protein-microarray. This methodology, which will be described in detail, enabled us to define different tumor-associated antigen (TAA) classifier panels for the big 4 cancer entities (breast, colon, prostate and lung cancer) which all showed very promising classification successes in distinction of patients versus controls. We will further present preliminary data obtained when comparing serum and saliva autoantibody profiles of breast-cancer patients and healthy controls.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
[Show abstract][Hide abstract] ABSTRACT: Introduction
More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.
We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.
The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.
Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0492-9) contains supplementary material, which is available to authorized users.
Breast Cancer Research 12/2014; 16(6). DOI:10.1186/s13058-014-0492-9 · 5.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Approximately 6-15 % of breast cancer patients are diagnosed with primary ulcerated breast cancer (ULBC). ULBC is known to be associated with short recurrence free and poor overall survival. Therefore, the purpose of this study was to characterize ULBC and compare the histopathological findings with those of non-ulcerative breast cancer (NULBC). A total of 152 ULBCs were evaluated and compared to 304 consecutive non-ulcerated, age-matched breast malignancies. Patients mean age was 65 years (SD = 13.0 ULBC, SD = 14.0 NULBC). ULBC was associated with a higher rate of poorly differentiated tumors (p = <0.001), as well as larger tumor sizes (p = <0.001). As expected, the rate of axillary lymph node involvement was higher in ULBC patients (p = <0.001). In addition to that, ULBC was associated with a higher rate of triple negative breast cancer (p = 0.002), and higher Ki67 expression (p = <0.001). ULBC showed more aggressive histopathological features in comparison to NULBC which may contribute to the generally known poorer prognosis of women with ULBC.