Homo sapiens
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PROVIDER: PRJNA837602 | ENA |
REPOSITORIES: ENA
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Project description:NGS-based multiple gene panel resequencing in combination with a high resolution CGH-array was used to identify genetic risk factors for hereditary breast and/or ovarian cancer in 237 high risk patients who were previously tested negative for pathogenic BRCA1/2 variants. All patients were screened for pathogenic variants in 94 different cancer predisposing genes. We identified 32 pathogenic variants in 14 different genes (ATM, BLM, BRCA1, CDH1, CHEK2, FANCG, FANCM, FH, HRAS, PALB2, PMS2, PTEN, RAD51C and NBN) in 30 patients (12.7%). Two pathogenic BRCA1 variants that were previously undetected due to less comprehensive and sensitive methods were found. Five pathogenic variants are novel, three of which occur in genes yet unrelated to hereditary breast and/or ovarian cancer (FANCG, FH and HRAS). In our cohort we discovered a remarkably high frequency of truncating variants in FANCM (2.1%), which has recently been suggested as a susceptibility gene for hereditary breast cancer. Two patients of our cohort carried two different pathogenic variants each and ten other patients in whom a pathogenic variant was confirmed also harbored a variant of unknown significance in a breast and ovarian cancer susceptibility gene. We were able to identify pathogenic variants predisposing for tumor formation in 12.3% of BRCA1/2 negative breast and/or ovarian cancer patients.
2018-10-31 | GSE121968 | GEO
Project description:89 tumors from women that were eligible for, and subjected to, routine diagnostic testing according to the HBOC criteria but were negative for pathogenic BRCA1/2-mutations or carried an UV in either BRCA1/2 A BRCA2-classifier was built using array-CGH profiles of 28 BRCA2-mutated and 28 sporadic breast tumors. The classifier was validated on an independent group of 19 BRCA2-mutated and 19 sporadic breast tumors. Subsequently, we tested 89 breast tumors from suspected hereditary breast (and ovarian) cancer (HBOC) families, in which either no BRCA1/2 mutation or an UV had been found by routine diagnostics.
2010-07-05 | E-GEOD-22481 | biostudies-arrayexpress
Project description:We have analyzed, using DNA microarrays, putative differences in gene-expression level between hereditary BRCA1 mutation-linked and sporadic breast cancer. Our results show that a previously reported marked difference between BRCA1-mutation linked and sporadic breast cancer was probably due to uneven stratification of samples with different ER status and basal-like versus luminal-like subtype. We observed that apparent difference between BRCA1-linked and other types of breast cancer found in univariate analysis was diminished when data were corrected for ER status and molecular subtype in multivariate analyses. In fact, the difference in gene expression pattern of BRCA1-mutated and sporadic cancer is very discrete. These conclusions were supported by the results of Q-PCR validation. We also found that BRCA1 gene inactivation due to promoter hypermethylation had similar effect on general gene expression profile as mutation-induced protein truncation. This suggests that in the molecular studies of hereditary breast cancer, BRCA1 gene methylation should be recognized and considered together with gene mutation. We analyzed 35 breast cancer specimens. Surgical samples obtained during mastectomy were flash-frozen in liquid nitrogen and stored at -80°C. Only samples from patients without neoadjuvant chemotherapy were used in this study as chemotherapy may seriously affect gene expression profile. All tissue samples were collected at the Pomeranian Medical University in Szczecin. Seventeen tumor samples were collected from patients with hereditary breast cancer: 12 were derived from tumors affecting women with hereditary BRCA1 mutation, the only one from a woman with BRCA2 mutation, while another eight cases had familial history of breast/ovarian cancer, but were negative for the BRCA1/2 mutations (so called BRCAx cases). Proportion of BRCA1 and BRCA2 mutated tumors was typical for the Polish population. Ten samples were derived from patients with apparently sporadic disease (no familial history of cancer) while 4 patients had a history of familial cancer aggregation (FCA) but without prevalence of breast/ovarian cancers. Thus, these samples were merged with sporadic samples in most of the analyses. All BRCA1 mutation-linked tumors in our study were negative for estrogen receptor (by immunohistochemistry, standard procedures for ER, PGR and HER2 staining were applied), while the only BRCA2-mutated tumor was ER-positive. There were 26 ductal and 5 medullary carcinomas within the study group, which is consistent with the distribution of histopathological types in BRCA1 mutation carriers. Patients were diagnosed at stage T1-2, N0-1 and M0. Caution: this submission contains the data from 6 microarrays done on the normal/pathologically unchanged breast tissue from breast cancer patiets. The data from normal tissues was not analyzed in the paper BRCA1-related gene signature in breast cancer is strongly influenced by ER status and molecular type by Lisowska et al., 2011, Front Biosci (Elite Ed). 2011 Jan 1;3:125-36
2013-09-05 | E-GEOD-50567 | biostudies-arrayexpress
Project description:Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement (“BRCAness”) by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors. Gene expression profiling of 183 breast tumor samples. Breast tumors from hereditary breast cancer patients carrying a pathogenic BRCA1 (n=33) or BRCA2 (n=22) germ-line mutation were included in the study. Serving as a representative control group, primary breast tumor samples (n=128) were randomly selected. The study was conducted using Agilent-029949 Custom SurePrint G3 Human GE 8x60K Microarray platform. For cross-platform validation, a subset of the tumor samples (92 of the 183 samples) were analyzed by our in-house spotted microarray platform.
2013-06-28 | E-GEOD-40115 | biostudies-arrayexpress
Project description:In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar pathophysiological mechanisms. Grouping into molecularly homogeneous subsets may therefore be of potential value for further genetic analysis in order to identify new high penetrance breast cancer genes. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer patients within the same family. By analyzing a collection of 70 breast tumor biopsies from 58 families, we show that distinct functional subgroupings, similar to the intrinsic molecular breast cancer subtypes, exist. The distribution of subtypes was markedly different from the distribution found among BRCA1/2 mutation carriers. From 11 breast cancer families, breast tumor biopsies from more than one affected family member were included in the study. Notably, in 8 of these families we found that patients from the same family shared the same tumor subtype, showing a tendency of familial aggregation of tumor subtypes (p-value = 1.7e-3). Our finding indicates involvement of hereditary factors in these families in which family members may carry genetic susceptibility not just to breast cancer but to a particular subtype of breast cancer. Using our previously developed BRCA1/2-signatures, we identified 7 non-BRCA1/2 tumors with a BRCA1-like molecular phenotype and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. This is the first study to provide a biological link between breast cancers from family members of high risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly homogeneous subtypes in order to identify new high penetrance susceptibility genes. Gene expression profiling of 253 breast tumor samples. Breast tumor tissue from 125 patients with germline mutations in BRCA1 (n = 33) or BRCA2 (n = 22) or with no detectable germline mutation in BRCA1 or BRCA2 (n = 70) were included in the study. Serving as a representative control group, primary breast tumor samples (n = 128) were randomly selected among available samples originating from the same department and time period as for the hereditary samples. The study was conducted using Agilent-029949 Custom SurePrint G3 Human GE 8x60K Microarray platform.
2015-08-01 | E-GEOD-49481 | biostudies-arrayexpress
Project description:Heredity is a major cause of ovarian cancer. Lynch syndrome is associated with 10-12% risk of ovarian cancer, diagnosis at young age and a predilection for endometrioid and clear cell tumors. Global gene expression profiling applied to 25 Lynch syndrome-associated and 42 sporadic ovarian cancers revealed 335 differentially expressed genes and involvement of the mTOR and the MAPK/ERK pathways. The clear cell tumors had distinct expression profiles with upregulation of HER2 and apoptosis signaling pathways. The distinct expression profiles provide clues relevant for hereditary tumorigenesis and may be relevant for therapeutic strategies and refined diagnostics in ovarian cancer linked to Lynch syndrome. Ovarian cancers linked to Lynch syndrome (n=25) were compared to a matched series of sporadic ovarian cancers (n=42), selected from a population-based consecutive series in which hereditary was excluded based on family history, normal MMR protein staining and lack of mutations in BRCA1 and BRCA2.
2013-10-14 | E-GEOD-37394 | biostudies-arrayexpress
Project description:Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 73 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter-methylation, but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In addition, RB1 was frequently inactivated by gross gene disruption in BRCA1-related hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer, but rarely in BRCA2-hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings demonstrate the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1-status. Gene expression profiling of breast tumors. Dual color common reference gene expression study using 55K oligonucleotide microarrays.
2012-06-26 | E-GEOD-25307 | biostudies-arrayexpress
Project description:A great percentage of patients with multiple primary cancers (MPCs) and family history of cancer are suspected to have a hereditary cancer predisposition syndrome. However, only a small proportion of these cases are explained by mutations in high-penetrance genes, suggesting the involvement of undiscovered genes in cancer predisposition. In this study, we report the molecular and clinical characterization of two unrelated patients with MPCs, a positive family history of cancer, no germline pathogenic mutations in BRCA1, BRCA2 and TP53 genes and large genomic rearrangements mapped on chromosome 7q.
2016-02-15 | GSE77138 | GEO
Project description:The BRCA1 tumor suppressor gene encodes a multi-domain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks (DSBs), which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered sequence variants of uncertain clinical significance (VUS). Using genetically engineered mice, we now show that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupting the interaction with PALB2 leads to embryonic lethality and loss of breast cancer suppression. Brca1 p.L1363P mammary tumors develop with a similar latency as Brca1-null tumors, but show different histopathological features and more stable DNA copy number profiles. Nevertheless, Brca1 p.L1363P mammary tumors are HRR-incompetent and responsive to cisplatin and PARP inhibition.
2022-02-01 | GSE182449 | GEO
Project description:The BRCA1 tumor suppressor gene encodes a multi-domain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks (DSBs), which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered sequence variants of uncertain clinical significance (VUS). Using genetically engineered mice, we now show that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupting the interaction with PALB2 leads to embryonic lethality and loss of breast cancer suppression. Brca1 p.L1363P mammary tumors develop with a similar latency as Brca1-null tumors, but show different histopathological features and more stable DNA copy number profiles. Nevertheless, Brca1 p.L1363P mammary tumors are HRR-incompetent and responsive to cisplatin and PARP inhibition.
2022-02-01 | GSE182448 | GEO