DNA methylation profiling identifies two distinct subgroups in breast cancers with low hormone receptor expression, mainly associated with HER2 amplification status
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PROVIDER: PRJNA686423 | ENA |
REPOSITORIES: ENA
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Project description:Current clinical guidelines suggest that breast cancers with low hormone receptor expression (LowHR) in 1% to 10% of tumor cells should be regarded as hormone receptor positive tumors. However, clinical data shows that patients with such tumors have a worse outcome compared to patients with hormone receptor expression above 10 %. Further, gene expression studies suggest that these tumors have a TNBC-like signature similar to triple negative breast cancers (TNBC). The goal of this study was to use DNA methylation-based classification to clarify the status for this infrequent but important patient subgroup. We performed whole genome DNA methylation profiling on 23 LowHR breast cancer specimens, including 13 samples with HER2 amplification and compared our results with a reference breast cancer cohort from The Cancer Genome Atlas. Unsupervised clustering and dimensionality reduction revealed that breast cancers with low hormone receptor expression that lacked HER2 amplification usually clustered with TNBC reference samples (8/10; “LowHR TNBC-like”). In contrast, most specimens with low hormone receptor expression and HER2 amplification grouped with hormone receptor positive cancers (11/13; “LowHR HRpos-like”). We observed highly similar DNA methylation patterns of LowHR TNBC-like samples and true TNBCs with almost no differential methylation. Furthermore, the Ki67 proliferation index of LowHR TNBC-like samples as well as clinical outcome parameters were more similar to TNBCs and differed from LowHR_HRpos-like cases. We here demonstrate that LowHR breast cancer comprises two molecularly distinct groups that can be separated by DNA methylation profiling. More clinical data is required for a definite classification of these tumors, but our data strongly suggests that LowHR TNBC-like samples are molecularly, histologically and clinically closely related to TNBC, while LowHR HRpos-like specimens are closely related to hormone receptor positive tumors.
2021-10-01 | GSE163521 | GEO
Project description:BackgroundCurrent clinical guidelines suggest that breast cancers with low hormone receptor expression (LowHR) in 1-10% of tumor cells should be regarded as hormone receptor positive. However, clinical data show that these patients have worse outcome compared to patients with hormone receptor expression above 10%. We performed DNA methylation profiling on 23 LowHR breast cancer specimens, including 13 samples with HER2 amplification and compared our results with a reference breast cancer cohort from The Cancer Genome Atlas to clarify the status for this infrequent but important patient subgroup.ResultsIn unsupervised clustering and dimensionality reduction, breast cancers with low hormone receptor expression that lacked HER2 amplification usually clustered with triple negative breast cancer (TNBC) reference samples (8/10; "LowHR TNBC-like"). In contrast, most specimens with low hormone receptor expression and HER2 amplification grouped with hormone receptor positive cancers (11/13; "LowHR HRpos-like"). We observed highly similar DNA methylation patterns of LowHR TNBC-like samples and true TNBCs. Furthermore, the Ki67 proliferation index of LowHR TNBC-like samples and clinical outcome parameters were more similar to TNBCs and differed from LowHR HRpos-like cases.ConclusionsWe here demonstrate that LowHR breast cancer comprises two epigenetically distinct groups. Our data strongly suggest that LowHR TNBC-like samples are molecularly, histologically and clinically closely related to TNBC, while LowHR HRpos-like specimens are closely related to hormone receptor positive tumors.
| S-EPMC8489064 | biostudies-literature
Project description:We separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. Our results indicate that even driver genetic alterations, such as HER2, can be heterogeneously distributed in a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification.
2015-04-16 | GSE67908 | GEO
Project description:HER2 gene amplification and protein overexpression (HER2+) define a clinically challenging subgroup of breast cancer with variable prognosis and response to therapy. Although gene expression profiling has identified an ERBB2 molecular subtype of breast cancer, it is clear that HER2+ tumors reside in all molecular subtypes and represent a genomically and biologically heterogeneous group. Genome-wide DNA copy number profiling, using BAC array comparative genomic hybridization (aCGH) were performed on 200 tumors with mixed clinical characteristics and amplification of HER2. Genomic Identification of Significant Targets in Cancer (GISTIC) was used to identify significant copy number aberrations (CNAs) in HER2+ tumors. This analysis sheds further light on the genomically complex and heterogeneous nature of HER2+ tumors in relation to other subgroups of breast cancer.
2010-04-14 | GSE21259 | GEO
Project description:HER2 gene amplification and protein overexpression (HER2+) define a clinically challenging subgroup of breast cancer with variable prognosis and response to therapy. Although gene expression profiling has identified an ERBB2 molecular subtype of breast cancer, it is clear that HER2+ tumors reside in all molecular subtypes and represent a genomically and biologically heterogeneous group. Genome-wide DNA copy number profiling, using BAC array comparative genomic hybridization (aCGH) were performed on 200 tumors with mixed clinical characteristics and amplification of HER2. Genomic Identification of Significant Targets in Cancer (GISTIC) was used to identify significant copy number aberrations (CNAs) in HER2+ tumors. This analysis sheds further light on the genomically complex and heterogeneous nature of HER2+ tumors in relation to other subgroups of breast cancer. Genomic profiling of 200 breast tumors using tiling BAC aCGH (32K, 33K and 38K). A number of cases were hybridized as replicates or dye-swaps.
2010-04-14 | E-GEOD-21259 | biostudies-arrayexpress
Project description:Breast cancer is a major health problem affecting millions of women worldwide. Over 200,000 new cases are diagnosed annually in the USA, with approximately 40,000 of these cases resulting in death. HER2-positive (HER2+) breast tumors, representing 20–30 % of early-stage breast cancer diagnoses, are characterized by the amplification of the HER2 gene. However, the critical genes and pathways that become affected by HER2 amplification in humans are yet to be specifically identified. Furthermore, it is yet to be determined if HER2 amplification also affects the expression of long intervening non-coding (linc)RNAs, which are involved in the epigenetic regulation of gene expression. We examined changes in gene expression by next generation RNA sequencing in human tumors pre- and post- HER2 inhibition by trastuzumab in vivo, and changes in gene expression in response to HER2 knock down in cell culture models. We integrated our results with gene expression analysis of HER2+ tumors vs matched normal tissue from The Cancer Genome Atlas. The integrative analyses of these datasets led to the identification of a small set of mRNAs, and the associated biological pathways that become deregulated by HER2 amplification. Furthermore, our analyses identified three lincRNAs that become deregulated in response to HER2 amplification both in vitro and in vivo. Our results should provide the foundation for functional studies of these candidate mRNAs and lincRNAs to further our understanding of how HER2 amplification results in tumorigenesis. Also, the identified lincRNAs could potentially open the door for future RNA-based biomarkers and therapeutics in HER2+ breast cancer.
2015-03-10 | GSE60182 | GEO
Project description:Estrogen (ER) and progesterone (PgR) receptors and HER2 are crucial in the assessment of breast cancer specimens due to their prognostic and predictive significance. Single hormone receptor-positive breast cancers are less common and their clinical course is less favorable than ER(+)/PgR(+) tumors. Their molecular features, especially microRNA (miRNA) profiles, have not been investigated to date. Tumor specimens from 36 chemonaive breast cancer patients with known ER and PgR status (18 ER(+)/PgR(-) and 18 ER(-)/PgR(+) cases) were enrolled to the study. The expression of 829 miRNAs was evaluated with nCounter Human v3 miRNA expression Assay (NanoString). miRNAs differentiating between ER/PgR/HER2 phenotypes were selected based on fold change (FC) calculated for the mean normalized counts of each probe in compared groups. The differences were estimated with Student's T-test or Two-Way ANOVA (considering also the HER2 status). The results were validated using The Cancer Genome Atlas (TCGA) dataset. Following quality control of raw data, fourcases were excluded due to low sample quality, leaving 14 ER(+)/PgR(-) and 18 ER(-)/PgR(+) cases. After correction for multiple comparisons, we did not find miRNA signature differentiating between ER(-)/PgR(+) and ER(+)/PgR(-) breast cancers. However, a trend for differing expression (p-value ≤ 0.05; FDR > 0.2; ANOVA) in eight miRNAs was observed. The ER(+)/PgR(-) group demonstrated elevated levels of four miRNAs-miR-30a-5p, miR-29c-3p, miR-141-3p and miR-423-5p-while the ER(-)/PgR(+) tumors were enriched in another four miRNAs-miR-514b-5p, miR-424-5p, miR-495-3p, and miR-92a-3p. For one of the miRNAs-miR-29c-3p-the association with the ER(+)/PgR(-) phenotype was confirmed in the TCGA cohort (p-value = 0.024; T-test). HER2 amplification/overexpression in the NanoString cohort was related to significant differences observed in 33 miRNA expression levels (FDR ≤ 0.2; ANOVA). The association with HER2 status was confirmed in the TCGA cohort for four miRNAs (miR-1180-3p, miR-223-3p, miR-30d-5p, and miR-195-5p). The main differences in miRNA expression amongst single hormone receptor-positive tumors were identified according to their HER2 status. However, ER(+)/PgR(-) cases tended to express higher levels of miRNAs associated with ER-positivity (miR-30a-5p, miR-29c-3p, miR-141-3p), whereas ER(-)/PgR(+) cancers showed elevated levels of miRNAs characteristic for double- and triple-negative tumors (miR-92a-3p, miR-424-5p). Further studies are necessary to comprehensively analyze miRNA signatures characteristic of ER(-)/PgR(+) and ER(+)/PgR(-) tumors.
| S-EPMC7555149 | biostudies-literature
Project description:Amplification of chromosome 17q23 is a frequent genomic event that occurs in ~ 11% of human breast cancers. The 17q23 amplification is enriched in HER2+ breast cancers, which is significantly correlated with poor clinical outcomes. Previous studies have identified the oncogenic phosphatase WIP1 gene in the amplicon, which functions as a master inhibitor in DNA damage response. While the possibility of any other protein-coding oncogenes in the WIP1-containing 17q23 amplicon was ruled out, our analysis of human breast cancer genomics uncovered an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing amplicons. Interestingly, DEAD-box helicase 5 (DDX5), co-amplified with WIP1 and MIR21 in the 17q23 amplicon, facilitates the essential processing of primary miR-21 transcripts. Accordingly, the 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 using small molecular inhibitor against WIP1 (GSK2830371) and anti-miR-21 oligonucleotides selectively inhibits the proliferation, survival and tumorigenic potential of HER2+ breast cancer cells harboring 17q23 amplification. However, the in vivo bioavailability of the two agents in their free form is poor. To overcome the resistance of trastuzumab-based therapies in vivo, we developed pH-sensitive nanoparticles for specific co-delivery of the two agents into breast tumors. The nanoparticles consist of four materials approved by the Food and Drug Administration (FDA) for medical use: Poly (d,l-lactide-co-glycolide) (PLGA), Pluronic F127 (PF127), chitosan, and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC). Moreover, chitosan was modified with guanidine to form chitosan-guanidine (CG), which not only can improve the encapsulation efficiency of anti-miR-21 oligonucleotides but also effectively capture carbon dioxide (CO2) into the nanoparticle to achieve the ‘nano-bomb’ effect for triggered drug release under the reduced pH in tumors. The two agents (inhibitors of miR-21 and WIP1)-laden nanoparticles can be used to efficiently kill trastuzumab-resistant HER2+ breast cancer cells, leading to a profound reduction of the tumor growth in vivo. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the HER2+ breast cancers resistant to anti-HER2-based therapies.
2018-10-03 | GSE119210 | GEO
Project description:<p>DNA Inverted Repeats as an At-risk Motif for Palindromic Gene Amplificatio defines oncogene amplification that is configured as a series of inverted duplications (palindromic gene amplification). There are several, recurrently amplified oncogenes throughout the human genome. However, it remains unclear whether this recurrent amplification is solely a manifestation of increased fitness resulting from random amplification mechanisms, or if genomic locus-specific amplification mechanism plays a role. </p> <p>In this study, we show that the ERBB2 oncogene at 17q12 is susceptible to palindromic gene amplification in HER2-positive breast tumors. We investigated eight tumors in this study, of which five tumors were HER2-positive, and three tumors were HER2-negative. HER2-status was determined by clinical FISH tests. We applied three genomic approaches to investigate the amplification mechanism: (1) copy number analysis by array-CGH on the Affymetrix SNP6.0 platform (8 files), (2) sequencing of DNA libraries enriched with tumor-derived palindromic DNA (Genome-wide Analysis of Palindrome Formation, GAPF-seq) (8 files) and (3) unbiased whole genome sequencing (WGS) (1 file). These molecular data is made available in the dbGaP. </p> <p>Genomic studies using tumor DNA was approved under the Internal Institutional Review Board at the Cleveland Clinic (IRB07-136: EXEMPT: Chromosome Breakage and DNA Palindrome Formation). Specimens were obtained and methods were carried out under the auspices of IRB 7881 (Evaluation of Genetic and Molecular Markers in Patients with Breast Cancer). All patients consented to allow their cancer specimens to be used by researchers in an anonymized fashion. The consent form indicates that publication will take place without identifiers to protect the identity of any specific individual.</p> <p>We observed significant and enrichment of palindromic DNA within amplified ERBB2 genomic segments in four out of five HER2-positive tumors. None of three HER2-negative tumors showed such enrichment. Palindromic DNA was particularly enriched at amplification peaks and boundaries between amplified and normal copy-number regions. Thus, palindromic gene amplification shaped the amplified ERBB2 locus. The moderate enrichment of palindromic DNA throughout the amplified segments leads us to propose that the ERBB2 locus is amplified through a mechanism that repeatedly generates palindromic DNA, such as Breakage-Fusion-Bridge cycles. Our results reveal a potential interaction between local genomic environments and gene amplification mechanisms. </p> <p>This study is published under the title "Palindromic amplification of the ERBB2 oncogene in primary HER2-positive breast tumors" <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=28211519" target="_blank">(PMID:28211519)</a>. </p>
| phs001261 | dbGaP
Project description:Background: Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. Methods: In this work, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples (N = 40 patients, 20 with EGFR amplification). Results: In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. Conclusion: Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.
2023-01-25 | GSE222515 | GEO