scholarly journals Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

2021 ◽  
Author(s):  
Lilibeth Lanceta ◽  
Nadiia Lypova ◽  
Conor O’Neill ◽  
Xiaohong Li ◽  
Eric Rouchka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pathway Analysis ◽  
Fatty Acid Biosynthesis ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Rna Seq ◽  
Kegg Database ◽  
Cyclin Dependent Kinases ◽  
Transcriptomic Sequencing ◽  
Differential Gene

Abstract Purpose The management of triple-negative breast cancer (TNBC) remains a significant clinical challenge due to the lack of effective targeted therapies. Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6) are emerging as promising therapeutic agents against TNBC; however, cells can rapidly acquire resistance through multiple mechanisms that are yet to be identified. Therefore, determining the mechanisms underlying resistance to CDK4/6 inhibition is crucial to develop combination therapies that can extend the efficacy of the CDK4/6 inhibitors or delay resistance. This study aims to identify differentially expressed genes (DEG) associated with acquired resistance to palbociclib in ER− breast cancer cells. Methods We performed next-generation transcriptomic sequencing (RNA-seq) and pathway analysis in ER− MDA-MB-231 palbociclib-sensitive (231/pS) and palbociclib-resistant (231/pR) cells. Results We identified 2247 up-regulated and 1427 down-regulated transcripts in 231/pR compared to 231/pS cells. DEGs were subjected to functional analysis using Gene Ontology (GO) and the KEGG database which identified many transduction pathways associated with breast cancer, including the PI3K/AKT, PTEN and mTOR pathways. Additionally, Ingenuity Pathway Analysis (IPA) revealed that resistance to palbociclib is closely associated with altered cholesterol and fatty acid biosynthesis suggesting that resistance to palbociclib may be dependent on lipid metabolic reprograming. Conclusion This study provides evidence that lipid metabolism is altered in TNBC with acquired resistance to palbociclib. Further studies are needed to determine if the observed lipid metabolic rewiring can be exploited to overcome therapy resistance in TNBC.

scholarly journals Transcriptomic Profiling Identifies Differentially Expressed Genes in Palbociclib-Resistant ER+ MCF7 Breast Cancer Cells

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 467 ◽  
Author(s):  
Lilibeth Lanceta ◽  
Conor O'Neill ◽  
Nadiia Lypova ◽  
Xiahong Li ◽  
Eric Rouchka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Differentially Expressed Genes ◽  
Pathway Analysis ◽  
Metabolic Pathways ◽  
Acquired Resistance ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Kegg Database ◽  
Cyclin Dependent Kinases ◽  
Estrogen Receptor Positive

Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in estrogen receptor-positive (ER+) breast cancer remains a significant clinical challenge. Efforts to uncover the mechanisms underlying resistance are needed to establish clinically actionable targets effective against resistant tumors. In this study, we sought to identify differentially expressed genes (DEGs) associated with acquired resistance to palbociclib in ER+ breast cancer. We performed next-generation transcriptomic RNA sequencing (RNA-seq) and pathway analysis in ER+ MCF7 palbociclib-sensitive (MCF7/pS) and MCF7 palbociclib-resistant (MCF7/pR) cells. We identified 2183 up-regulated and 1548 down-regulated transcripts in MCF7/pR compared to MCF7/pS cells. Functional analysis of the DEGs using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database identified several pathways associated with breast cancer, including ‘cell cycle’, ‘DNA replication’, ‘DNA repair’ and ‘autophagy’. Additionally, Ingenuity Pathway Analysis (IPA) revealed that resistance to palbociclib is closely associated with deregulation of several key canonical and metabolic pathways. Further studies are needed to determine the utility of these DEGs and pathways as therapeutics targets against ER+ palbociclib-resistant breast cancer.

scholarly journals Role of Differentially Expressed Proteins in Acquired Resistance to Cdk4/6 Inhibitor in Breast Cancer

2021 ◽  
Author(s):  
Binayak Kumar ◽  
Peeyush Prasad ◽  
Ragini Singh ◽  
Ram Krishana Sahu ◽  
Ashutosh Singh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Targets ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Resistant Cell ◽  
Molecular Signature ◽  
Mcf 7 ◽  
Resistant Cells

Abstract CDK4/6 inhibitors (Abemaciclib, Ab and Palbociclib, Pb) stop the G1-phase in cell-cycle being used to cure advanced stage of breast cancer (BC). Acquired resistance is a major challenge in BC therapy. The molecular signature of the therapy resistance for Ab and Pb drugs in BC should be explored. Here, we developed Ab/Pb-resistant cell-models and explored the molecular changes. Drug’s resistance cells were developed in MCF-7 cells by continuous drug treatment and it was confirmed by MTT-assay, PI-staining-microscopy, and real-time-qPCR. Global proteome profiling done by Labelled-free-Proteome-Orbitrap-Fusion-MS-MS technique. Bioinformatics tools used to analyse the proteome data. Ab-resistant and Pb-resistant MCF-7 cells showed increased tolerance for the respective drug. The BCL-2 and MCL-1 survival genes were up-regulated, while the apoptosis genes BAD, BAX, CASP-3 and PARP-1were down-regulated in the resistant cells. Expression of the MDR-1, ABCG2, ESR-1, CDK4, CDK6, and Cyclin-D1 genes were increased in both resistance cells. For proteomics, 237 and 239 proteins were expressed differently in the resistant Ab and Pb cells, respectively. The NUDT5, PEPD, ABAT, ATP1B1, GGCT, and SELENBP1 proteins were down-regulated and the SBSN, HSD17B10, CD9, PDIA3, PSMB4, SLC2A1, and VTN proteins were up-regulated in Ab-resistant cells. The NUDT5, PEPD, and GGCT proteins were down-regulated, while CD47, HIST1H2BN, LMNA, VTN, PSMB5, HBB, PSMA7, FLNB, PRDX4, VDAC1, GOT2, HSPA5, SERPINH1, EIF4A2, FTH, and VIM proteins were up-regulated in Pb-resistant cells. These proteins are a new set of prognostic markers and drug targets for overcoming the respective drug resistance. However, it is necessary to perform an in vivo or clinical assessment.

scholarly journals Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Devchand Paul ◽  
Svetislava J. Vukelja ◽  
Frankie Ann Holmes ◽  
Joanne L. Blum ◽  
Kristi J. McIntyre ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Therapy Resistance ◽  
Breast Cancer Patients ◽  
Er Positive

Abstract The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

scholarly journals Stem cell-like breast cancer cells with acquired resistance to metformin are sensitive to inhibitors of NADH-dependent CtBP dimerization

2019 ◽  
Vol 40 (7) ◽  
pp. 871-882 ◽  
Author(s):  
Arindam Banerjee ◽  
Charles N Birts ◽  
Matthew Darley ◽  
Rachel Parker ◽  
Alex H Mirnezami ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Stem Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cyclic Peptide ◽  
Cell Metabolism ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Cell Gene Expression

AbstractAltered flux through major metabolic pathways is a hallmark of cancer cells and provides opportunities for therapy. Stem cell-like cancer (SCLC) cells can cause metastasis and therapy resistance. They possess metabolic plasticity, theoretically enabling resistance to therapies targeting a specific metabolic state. The C-terminal binding protein (CtBP) transcriptional regulators are potential therapeutic targets in highly glycolytic cancer cells, as they are activated by the glycolytic coenzyme nicotinamide adenine dinucleotide (NADH). However, SCLC cells commonly exist in an oxidative state with low rates of glycolysis. Metformin inhibits complex I of the mitochondrial electron transport chain; it can kill oxidative SCLC cells and has anti-cancer activity in patients. SCLC cells can acquire resistance to metformin through increased glycolysis. Given the potential for long-term metformin therapy, we have studied acquired metformin resistance in cells from the claudin-low subtype of breast cancer. Cells cultured for 8 weeks in sub-IC50 metformin concentration proliferated comparably to untreated cells and exhibited higher rates of glucose uptake. SCLC cells were enriched in metformin-adapted cultures. These SCLC cells acquired sensitivity to multiple methods of inhibition of CtBP function, including a cyclic peptide inhibitor of NADH-induced CtBP dimerization. Single-cell mRNA sequencing identified a reprogramming of epithelial–mesenchymal and stem cell gene expression in the metformin-adapted SCLC cells. These SCLC cells demonstrated an acquired dependency on one of these genes, Tenascin C. Thus, in addition to acquisition of sensitivity to glycolysis-targeting therapeutic strategies, the reprograming of gene expression in the metformin-adapted SCLC cells renders them sensitive to potential therapeutic approaches not directly linked to cell metabolism.

scholarly journals Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

2019 ◽  
Vol 26 (1) ◽  
pp. R15-R30 ◽  
Author(s):  
Neil Portman ◽  
Sarah Alexandrou ◽  
Emma Carson ◽  
Shudong Wang ◽  
Elgene Lim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Therapy Resistance ◽  
Endocrine Therapy Resistance ◽  
Estrogen Receptor Positive ◽  
Multiple Treatments ◽  
Molecular Landscape

Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.

scholarly journals Comparative Transcriptomic Response Of Pancreatic And Breast Cancer Cells To Anacardic Acid Ans Olaparib

2021 ◽  
Author(s):  
Abah Moses Owoicho ◽  
Joseph Luper Tsenum ◽  
Deborah Oganya Ogenyi ◽  
Ogu Stephen ◽  
Ujah Moses Okwori
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Pancreatic Cancer ◽  
Breast Cancer Cells ◽  
Gene Expression Analysis ◽  
Anacardic Acid ◽  
P Value ◽  
Rna Seq ◽  
Transcriptomic Response ◽  
Differential Gene

The study seeks to compare the transcriptomic response of pancreatic and breast cancer cells to Anarcadic Acid and Olaparib via the preparation of Pancreatic Cancer Cell Culture which involves the seeding of PANC-1 cells in 6-well plates (5× 105 cells per well). 24hours later, cells will be untreated or treated by 5mM anacardic acid, 2mM olaparib or a combination of anacardic acid (5mM) and olaparib (2mM) for 48hours; after which Pancreatic Cancer Cell’s mRNA Library will be Prepared and Sequenced using the Illumina TruSeq™ RNA Sample Prep Kit v2. Samples will be sequenced on the Illumina HiSeq 2500, 2× 100bp paired-end reads, to a minimum depth of 30 million reads per sample. Thereafter, the Computational Analyses of Pancreatic Cancer RNA-seq Data will be done by obtaining a total of 240 million obtained reads of high quality clean tags which will then be mapped and annotated via human reference genome using Bioconductor package biomaRt (http://www.bioconductor.org) (Durinck et al 2009). Mapped reads with mapping quality 10 or more will be defined as uniquely mapped reads and used in the downstream analyses. Biological networks and pathways related to anachardic acid, olaparib and the combination will be analyzed with Ingenuity Pathway Analysis (IPA) software (Qiagen, CA, USA). The lists of all genes identified in gene expression analysis will be uploaded into the IPA software. For the analysis of networks and pathways, the cutoff values will be set at P≤ 1× 10−5 and FC≥ |2| respectively.Validation of RNA-seq Results by qRT-PCR via the expression of mRNA which will be determined in all 4 samples using Power SYBR® Green RNA-to-CT™ 1-Step Kit (Life Technologies, CA, USA). The Western blotting for the selected proteins will be performed, as described by Yue (Yue et al 2015). Thereafter, the Breast Cancer Cell Culture will be prepared and treated. Breast Cancer Cell’s mRNA RNA-seq will be prepared. The Truseq Stranded mRNA kit (Illumina) will be used to prepare mRNA libraries from 1 µg total RNA. Libraries will be confirmed on the Agilent 2100 Bioanalyzer and quantitated using the Illumina Library Quantification Kit, ABI Prism qPCR Mix from Kapa Biosystems and the ABI7900HT real-time PCR instrument. The differential Gene Expression will be analysed RNA-seq reads will be assembled according to the hg19.gtf annotation file (downloaded from ENSEMBL) (Flicek et al 2014) using Cufflinks (version 2.2.1) (Trapnell et al 2012). For each comparison, both cufflinks assemblies shall be merged, and the resulting merged gtf file serves as the transcript input for differential gene expression analysis in Gene Ontology and KEGG pathways. For three of the comparisons, a p-value cutoff ≤0.05 shall be used to determine differential expression. In-silico pathway and network analysis of differentially expressed genes shall be performed in MetaCore version 6.27 (GeneGO, Thomson Reuters, New York, N.Y.) (Bolser et al 2012). The results obtained will be statistically analysed. The results of RT-PCR shall be normalized to expression of GAPDH using the formula 2∆ CT. One-way ANOVA shall be used for comparing treatment with the combination of anacardic acid and olaparib to the untreated control. A P value less than 0.05 will be considered statistically significant.

scholarly journals High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

2021 ◽  
Author(s):  
Marta Palafox ◽  
Laia Monserrat ◽  
Meritxell Bellet ◽  
Guillermo Villacampa ◽  
Abel Gonzalez-Perez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
De Novo ◽  
Acquired Resistance ◽  
Poor Clinical Outcome ◽  
Cyclin Dependent Kinases ◽  
Estrogen Receptor Positive ◽  
Inhibitor Resistance ◽  
P16 Expression ◽  
P16 Overexpression

Abstract Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), combined with endocrine therapy (ET), have demonstrated higher antitumor activity than ET alone for the treatment of advanced estrogen receptor-positive (ER+) breast cancer (BC). Some ER+ BC are de novo resistant to CDK4/6i and others develop acquired resistance. Therapies for tumors after progression are needed. Here, we demonstrate that p16 overexpression is associated with reduced antitumor activity of CDK4/6i in patient-derived xenografts (PDX; n=37) and ER+ BC cell lines, and reduced response of early/advanced ER+HER2- BC patients (n=49) to CDK4/6i. We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome in ER+, CDK4/6i-treated BC PDX and patients. Combination of CDK4/6i ribociclib with PI3K inhibitor (PI3Ki) alpelisib showed antitumor activity in ER+ non-basal-like BC PDX, independently of PIK3CA or RB1 mutation (n=25). Our results offer new insights into predicting primary and acquired resistance to CDK4/6i and post-progression therapeutic strategies.

scholarly journals HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

2019 ◽  
Vol 11 ◽  
pp. 175883591983351 ◽  
Author(s):  
Sonia Pernas ◽  
Sara M. Tolaney
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Mtor Inhibitors ◽  
Therapy Resistance ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody–drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.

scholarly journals Identification and Analysis of Estrogen Receptor α Promoting Tamoxifen Resistance-Related lncRNAs

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Xiulei Zhang ◽  
Shanjun Gao ◽  
Zhen Li ◽  
Wei Wang ◽  
Guangzhi Liu
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Estrogen Receptor Alpha ◽  
Acquired Resistance ◽  
Tamoxifen Resistance ◽  
Estrogen Receptor Α ◽  
Rna Seq ◽  
Breast Cancer Patients ◽  
Mcf 7

70-75% breast cancer patients are estrogen receptor alpha positive (ERα+), and the antiestrogen drug tamoxifen has been used for the past three decades. However, in 20-30% of these patients, tamoxifen therapy fails due to intrinsic or acquired resistance. A previous study has showed ERα signaling still exerts significant roles in the development of tamoxifen resistance and several lncRNAs have been demonstrated important roles in tamoxifen resistance. But ERα directly regulated and tamoxifen resistance related lncRNAs remain to be discovered. We reanalyze the published ERα chromatin immunoprecipitation-seq (ChIP-seq) and RNA-seq data of tamoxifen-sensitive (MCF-7/WT) and tamoxifen-resistant (MCF-7/TamR) breast cancer cells. We demonstrate that there are differential ERα recruitment events and the differentials may alert the expression profile in MCF-7/WT and MCF-7/TamR cells. Furthermore, we make an overlap of the ERα binding lncRNAs and differentially expressed lncRNAs and get 49 ERα positively regulated lncRNAs. Among these lncRNAs, the expression levels of AC117383.1, AC144450.1, RP11-15H20.6, and ATXN1-AS1 are negatively correlated with the survival probability of breast cancer patients and ELOVL2-AS1, PCOLCE-AS1, ITGA9-AS1, and FLNB-AS1 are positively correlated. These lncRNAs may be potential diagnosis or prognosis markers of tamoxifen resistance.

Results of a fifty-gene breast cancer RNA subtype classifier applied to 167 colorectal cancer (CRC) patients.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 20-20
Author(s):  
Sandeep K. Reddy ◽  
Tara Elisabeth Seery ◽  
Christopher Szeto
Keyword(s):  
Breast Cancer ◽  
Molecular Subtype ◽  
Published Data ◽  
Breast Cancers ◽  
Rna Seq ◽  
Luminal A ◽  
Luminal B ◽  
Over Expression ◽  
Whole Exome ◽  
Transcriptomic Sequencing

20 Background: ERBB2 (HER2) is thought to be a target in <10% of CRC patients versus 20% of breast cancers, 15% of gastroesophageal cancers, and 10% of biliary cancers, based on FISH or IHC. Intrinsic molecular subtype is used to classify cancers into distinct biologic subtypes (eg. CMS 1-4 in CRC). A 50-gene qPCR assay (PAM50) identifies 5 intrinsic biological subtypes: luminal A, luminal B, HER2-enriched, basal-like, and normal-like in breast cancer. The HERACLES trial (trastuzumab plus lapatinib) resulted a 32% ORR and median TTP of 5.5 months in heavily pre-pretreated HER2+ CRC patients. We determined molecular subtypes using the 50-gene breast cancer classifier to identify an expanded CRC patient population eligible for HER2 therapy. Methods: Retrospective analysis on Whole exome (WES) DNA tumor and paired germline and matched deep whole transcriptomic sequencing (RNA-Seq) (∼200x106 reads per tumor) data from NantHealth was performed. Breast Cancer Intrinsic Subtypes based on RNAseq was used to classify CRC into 5 BC subtypes. Results: 167 CRC patients were classified using the Nant50 Breast Cancer classifier: 15.0% as Luminal B, 13.1% as Luminal A, and 1.8% as Basal-like. Surprisingly, 117/167 (70%) classified as HER2-enriched (HER-E). 15/167 (9.0%) had over-expression of ERBB2 by RNAseq or CN gain, which is consistent with published data of HER2+ CRC. ERBB2 is very significantly differentially expressed in HER2-E subtyped CRC (p=<0.001), more than ERBB2 CN gain, suggesting that HER2-E may be more HER2 driven. Across subtypes APC and TP53 were the most commonly mutated genes at 65.3% and 52.6% respectively, however both were more enriched in HER2-E CRC (APC OR=3.3, p=0.001, TP53 OR=2.6, p=0.007). Other known drivers of CRC such as PIK3CA, KRAS, and BRAF, were not differentially mutated in HER2-E CRC, however NRAS mutants were significantly more enriched in non-HER2-E CRC (OR=4.6, p=0.02). Conclusions: Even after excluding known HER2 over-expression and CN gain, PAM50-like gene classifier identifies a far higher than expected percentage of HER-E subtype CRC (99/167 = 59%) which may represent an under appreciated population for HER2 directed therapy and clinical trials.

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