Search

Introduction: Chronic sympathetic nervous system (SNS) activation following exposure to psychosocial stressors may influence cancer risk through dysregulation of immune function or adrenergic signaling pathways. Prior research out of the Black Women’s Health Study (BWHS) reported associations between psychosocial stressors and breast cancer risk. We hypothesized that women with greater exposure to psychosocial stressors before their breast cancer diagnosis have higher tumor gene expression of immune-related and adrenergic signaling pathways. Methods: The BWHS is a large, prospective cohort study that has collected health and lifestyle information biennially since 1995. We included data from 417 BWHS breast cancer cases with RNA sequencing data and information on early-life trauma and neighborhood disadvantage. We used the R package DESeq2 to conduct age-adjusted differential gene expression analyses by levels of each stress exposure and described the top differentially expressed pathways using the Molecular Signature Database REACTOME subset of canonical pathways. Targeted analyses of immune-related pathways used CIBERSORT to quantify the proportions of infiltrating immune cells and the R package GSVA for single-sample gene set enrichment analysis (ssGSEA) of genes comprising a T cell exhaustion signature. We also used ssGSEA to evaluate a set of genes involved in adrenergic signaling. Given the variability in gene expression for ER+ versus ER- breast cancers, all analyses were run separately for ER+ (n=299) and ER- (n=118) tumors. Results: Pathways related to nervous system development and the metabolism of RNA were differentially expressed by levels of stress exposures among ER+ and ER- cases, while pathways related to immune function and adrenergic signaling were differentially expressed only among ER- cases, and only when evaluating differential gene expression by levels of neighborhood disadvantage. Targeted analyses of tumor immune infiltration showed significantly higher B cell fractions among ER+ cases without exposure to early trauma compared to those with early trauma. The relative fractions of other immune cells did not differ by stress exposure for ER+ or ER- tumors. Findings from ssGSEA gene set analyses indicated similar expression of genes involved in T cell exhaustion and adrenergic signaling pathways by stress exposure levels for both ER+ and ER- breast cancers. Conclusions: Our findings provide evidence of differential gene expression by levels of stress exposure; however, the differential expression may be driven by multiple pathways and not just the hypothesized immune-related and adrenergic signaling pathways. Additional studies are needed to describe mechanisms by which psychosocial stressors may influence breast cancer risk, both overall and by gene expression profile. Citation Format: Mollie E. Barnard, Xutao Wang, Jessica L. Petrick, W. Evan Johnson, Julie R. Palmer. Psychosocial stressors and breast cancer gene expression in the Black Women's Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3007.

Several approaches are now available for subclonal reconstruction of heterogeneous tumor biopsies from somatic variant allele frequencies measured in bulk DNA sequencing datasets, including our own SubcloneSeeker program. However, to understand how chemoresistance, relapse, or metastasis evolves at a subclonal level, we also need to study the molecular phenotype corresponding to each subclone. Single-cell RNAseq technologies now allow one to study the transcriptomic characteristics and phenotypic behaviors of individual cells, but new algorithms are needed to link these cells to the genomically defined tumor subclones they represent. Here we present a computational approach to make such cell assignments, using a combination of bulk DNA sequencing data (WGS or WES), and single cell RNA sequencing (scRNAseq) collected from the same tissues. Subclones constructed from bulk DNA sequencing data are defined by specific combinations of somatic mutations (SNVs and CNVs). Our algorithm uses the scRNA-seq reads to assess which of these subclone-defining mutations are present in each individual cell, then utilizes a Bayesian probabilistic framework for making the cell-to-subclone assignment. This framework overcomes the challenges of sparse scRNA-seq read coverage, and maximizes the accuracy and efficiency of cell assignment. We have successfully applied this method to multiple longitudinal and metastatic cancer patient datasets, representing both WES and WGS bulk DNA sequencing, as well as datasets collected using the 10X Chromium and Fluidigm C1 technologies. Our algorithm uses both somatically acquired CNV and SNV events in the tumor for cell assignment. Using our approach, as many of 80% of tumor cells could be assigned to specific subclones, enabling comparative gene expression and pathway analysis across subclones. Citation Format: Yi Qiao, Xiaomeng Huang, Samuel Brady, Andrea Bild, David Bowtell, William Johnson, Gabor Marth. Subclone-specific evolution of tumor phenotypes – A framework to study subclone-specific gene expression from a combination of bulk DNA and single cell RNA sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4689.

Background: Lung squamous cell carcinoma (SqCC) arises in the epithelial layer of the bronchial airway and is often preceded by the development of premalignant lesions. However, not all premalignant lesions progress to lung SqCC and many will regress spontaneously. Understanding the somatic alterations and molecular subtypes associated with progression will allow us to identify biomarkers for early detection and develop therapeutic strategies for disease prevention and interception. Methods: Biopsies were obtained from high-risk smokers undergoing lung cancer screening by auto-fluorescence bronchoscopy and CT at the Roswell Park Cancer Institute. For each subject, multiple sites were sampled repeatedly over time. One biopsy from each region was sent for pathological review while another biopsy was taken for molecular studies. Whole-exome sequencing (WES) was performed at Uniform Services University to 120x coverage and RNA-seq was performed at Boston University School of Medicine. Results: The median number of somatic mutations across all premalignant lesions that underwent DNA-seq (150 biopsies from 20 subjects) was 0.45 per megabase and displayed a modest association with histological grade (p=0.05). The most frequently mutated known lung cancer genes included NOTCH1 (14%), TP53 (6%), FAT1 (3%), PIK3CA (2%), KRAS ( Citation Format: Joshua D. Campbell, Xijun Zhang, Catalina Perdomo, Sarah Mazzilli, Yaron Geshalter, Samjot S. Dhillon, Gang Liu, Sherry Zhang, Hanqiao Liu, Jessica Vick, Christopher Moy, Stefano Monti, Evan Johnson, Matthew Meyerson, Matthew Wilkerson, Clifton Dalgard, Suso Platero, Chris Stevenson, Marc Lenburg, Mary Reid, Jennifer Beane, Avrum Spira. Genomic characterization of premalignant lung squamous cell carcinoma lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3248.

Background: Squamous cell carcinoma (SCC) of the lung is a leading cause of cancer mortality in the US due to late stage diagnosis and lack of effective treatments. Lung SCC arises in the epithelial layer of the bronchial airways and is often preceded by the development of premalignant lesions (PMLs). The molecular events involved in the progression of PMLs to lung SCC are not clearly understood, and not all PMLs go on to form carcinoma. By molecularly characterizing PMLs and non-lesion areas in the airway of individuals with PMLs, we hypothesize that we will be able to identify subgroups of PMLs that are more likely to progress. Methods: We used mRNA sequencing to profile biopsies obtained from high-risk smokers undergoing lung cancer screening by auto-fluorescence bronchoscopy and CT at the Roswell Park Cancer Institute in Buffalo, NY. For each subject (n=30), we sampled bronchial biopsies repeatedly over time (394 +/- 170 days) with serial bronchoscopies (6 +/- 5 biopsies/subject) as the biopsied area progressed towards or regressed away from frank malignancy. mRNA-Seq (n=197 biopsies) data was aligned to hg19 using STAR, and gene/transcript levels were summarized using RNA-Seq using RSEM and Ensembl 74 annotation. Immune, stromal, and epithelial cells content were inferred using the ESTIMATE algorithm and pathway activity of in vitro derived oncogenic signatures was estimated using GSVA for each sample. Molecular subtypes were derived using non-negative matrix factorization (NMF) and consensus clustering. Linear modeling was used to associate PML outcome metrics and pathway activity scores with subtype membership. Results: We identified six distinct molecular subtypes of bronchial biopsies using NMF across the 10% most variable genes (n=2,322 gene). One subtype contained samples with stable high-grade histology (p Conclusions: Molecular classification of premalignant lesions may lead to biomarkers of disease progression that could be used to stratify patients into prevention trials and to monitor efficacy of the treatment. Additionally, the results suggest that personalized interventions targeting specific cancer-related pathways or the immune system may be have potential therapeutic benefits. Citation Format: Jennifer E. Beane, Sarah Mazzilli, Joshua Campbell, Christopher Moy, Michael Schaffer, Catalina Perdomo, David Jenkins, Gang Liu, Sherry Zhang, Hanqiao Liu, Jessica Vick, Evan Johnson, Suso Platero, Marc Lenburg, Mary Reid, Samjot S. Dhillon, Avrum Spira. Premalignant squamous cell lung carcinoma lesions have distinct molecular subtypes associated with histologic progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5002. doi:10.1158/1538-7445.AM2017-5002

Background: Lung squamous cell carcinoma (SqCC) arises in the epithelial layer of the bronchial airway and is often preceded by the development of premalignant lesions. However, not all premalignant lesions progress to lung SqCC and many regress without therapeutic intervention. Understanding the somatic alterations that contribute to progression of premalignant lesions in the airway will allow us to identify biomarkers for early detection and develop therapeutic strategies for early intervention. Methods: Airway biopsies were obtained from high-risk smokers undergoing lung cancer screening by auto-fluorescence bronchoscopy and chest CT at the Roswell Park Cancer Institute. For each subject (n=30), multiple premalignant lesions were sampled repeatedly over time (n=144 samples). One biopsy from each region was sent for pathological review while another biopsy was taken for molecular studies. DNA was also isolated from the blood or cytologically normal bronchial brushings to serve as a matched normal control. Exome capture was performed using the Illumina TruSeq Rapid Exome kit and sequenced to a mean depth of coverage of 120x at Uniform Services University and Walter Reed National Military Medical Center. Results: The median number of somatic mutations across all premalignant lesions was 0.73 per megabase (range: 0.10 - 9.8 per Mb) and displayed a modest association with histological grade (p=0.07). The most frequently mutated lung cancer genes included KMT2C (12%), NOTCH1 (11%), FAT1 (6%), TP53 (5%), and CDKN2A (7/Mb) were taken from adjacent sites over two time points in the same individual with a prior history of lung squamous cell carcinoma. These lesions had a significantly overlapping set of mutations including FAT1 indicating a common evolutionary ancestor. Conclusions: The somatic alterations observed in known cancer genes such as TP53, KMT2C, NOTCH1, and FAT1 may be among the earliest driver events in lung SqCC development and may be useful as biomarkers for early detection as well as targets for lung cancer interception. Citation Format: Joshua Campbell, Xijun Zhang, Samjot S. Dhillon, Catalina Perdomo, Sarah Mazzilli, Yaron Geshalter, Gang Liu, Sherry Zhang, Hanqiao Lin, Jessica Vick, Christopher Moy, Stefano Monti, Evan Johnson, Matthew Meyerson, Steven Dubinett, Suso Platero, Matthew Wilkerson, Clifton Dalgard, Marc Lenburg, Mary Reid, Jennifer Beane, Avrum Spira. The genomic landscape of premalignant lung squamous cell carcinoma lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3259. doi:10.1158/1538-7445.AM2017-3259

Background: Lung squamous cell carcinoma (SqCC) arises in the epithelial layer of the bronchial airways and is often preceded by the development of premalignant lesions. However, not all premalignant lesions will progress to lung SqCC and many of these lesions will regress without therapeutic intervention. Understanding the molecular events that contribute to progression of premalignant lesions in the airway will allow us to identify biomarkers for early detection and develop therapeutic strategies for early intervention. Methods: Bronchial brushings and biopsies were obtained from high-risk smokers undergoing lung cancer screening by auto-fluorescence bronchoscopy and CT at the Roswell Park Cancer Institute. For each subject (n = 30), both premalignant lesions (PMLs) and the cytologically normal mainstem bronchus were sampled repeatedly over time (n = 288 samples). DNA and RNA were isolated from a total of 197 bronchial biopsies of PML (average of 5 per subject) and 91 bronchial brushings. DNA was also isolated from the blood to serve as a matched normal. Exome capture was performed using the Agilent SureSelect Human All Exon+UTR 70MB kit and sequenced to a mean depth of coverage of 75x (n = 85 samples from 22 subjects). RNA libraries were prepared with Illumina TruSeq (mRNA-Seq: n = 288 samples from 30 subjects and miRNA-Seq: n = 183 samples from 26 subjects). Results: We identified gene and miRNA expression changes associated with histological grade as well as progressive/stable disease. The Hippo pathway, Wnt signaling, p53 signaling, and immune-related pathways are modulated with histological grade and disease progression. Genes associated with histological grade in the cytologically normal airway and in the biopsies were significantly concordantly enriched (FDR3/Mb) were taken from adjacent sites over two time points in the same individual with a history of lung squamous cell carcinoma. These lesions had a significantly overlapping set of mutations (p = 2.2 × 10−17) indicating a common evolutionary ancestor, and contained mutations in CREBBP and FAT1, suggesting they are at increased risk for progressing to frank malignancy. Conclusions: We performed genomic profiling of PMLs in the airways of high-risk smokers. The gene expression and somatic alterations that were observed in known cancer genes may be among the earliest events in cancer development. Citation Format: Joshua D. Campbell, Catalina Perdomo, Sarah Mazzilli, Yaron Geshalter, Samjot S. Dhillon, Gang Liu, Sherry Zhang, Hangqio Lin, Jessica Vick, Christopher Moy, Evan Johnson, Matthew Meyerson, Suso Platero, Marc Lenburg, Mary Reid, Avrum Spira, Jennifer Beane. Genomic characterization of premalignant lung squamous cell carcinoma lesions. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 895.

Squamous cell cancer (SCC) of the lung is a leading cause of cancer mortality in the US, due to late stage diagnosis and lack of effective treatments. Lung SCC arises in the epithelial layer of the bronchial airways and is often preceded by the development of premalignant lesions (PMLs). The molecular events involved in the progression of PMLs to lung SCC are not clearly understood and not all PMLs go on to form carcinoma. By molecularly characterizing PMLs and non-lesion areas in the airway of individuals with PMLs we hypothesize that we will be able to identify early events in the process of lung carcinogenesis that lead to SCC. We used next-generation sequencing to profile bronchial brushings and biopsies obtained from high-risk smokers undergoing lung cancer screening by auto-fluorescence bronchoscopy and CT at the Roswell Park Cancer Institute in Buffalo, NY. For each subject (n = 26), we sampled the PML(s) and the mainstem bronchus repeatedly over time (394 +/- 170 days) with serial bronchoscopies (5 +/- 3 biopsies/subject) as the PML progressed towards or regressed away from frank malignancy. mRNA-Seq (n = 192) and miRNA-Seq (n = 183) were performed on the endobronchial biopsies and brushings and exome-Seq was performed on blood DNA from these subjects. RNA-seq data was aligned to the hg19 and gene/transcript levels were summarized using RSEM/Ensembl 74 or Bedtools/ mirBase 18. Single nucleotide variants were quantified using a modified PRADA pipeline and GATK. We identified gene and miRNA expression changes as well as pathways that are associated with biopsy histological grade as well as progressive/stable disease. H&E stains of PMLs clustering with lesions of dissimilar grades were examined to show that molecular classification provides complementary information to pathological grading. Genes altered in the normal airway in the presence of a PML were significantly concordantly enriched with genes identified in the biopsies demonstrating a strong relationship between the PMLs and the field of injury. In addition, cancer-associated missense and loss-of-function mutations were detected in PMLs. One individual had cancer-associated mutations at the initial time point in a single moderate dysplastic PML. Upon resampling ∼40 months later, the PML had progressed to an in situ carcinoma while gaining additional mutations. Furthermore, an adjacent PML at this second time point, also in situ carcinoma, had a significantly overlapping set of mutations with the original lesion suggesting that clonal expansion and invasion occurred between temporal samplings. The multiomic characterization of PMLs reveals gene and miRNA expression changes and somatic mutations that are associated with the lesion severity and progressive disease. These studies provide insights into the early molecular events in the process of lung carcinogenesis and may be predictors of lung cancer risk and lesion progression as well as novel candidates for targeted or preventive therapy. Citation Format: Jennifer E. Beane, Joshua Campbell, Christopher Moy, Catalina Perdomo, Michael Schaffer, Sarah Mazzilli, Yaron Geshalter, Jacob Kantrowitz, Liye Zhang, David Jenkins, Mary Beth Pine, Samjot Dhillon, Gang Liu, Hanqiao Liu, Sherry Zhang, Jessica Vick, Stefano Monti, Evan Johnson, Suso Platero, Marc Lenburg, Mary Reid, Avrum Spira. Development of the pre-cancer genome atlas (PCGA) for squamous cell lung carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2878. doi:10.1158/1538-7445.AM2015-2878

The ability of cancer cells to detach from their neighbors, invade through local tissues, and establish distant metastases is a major contributor to cancer mortality. Epithelial-mesenchymal transition (EMT) describes a developmental process by which cells break cell-cell adhesions and gain motility. The interaction between a cancer cell and the tumor microenvironment is emerging as a critical component of this process. EMT is triggered by a number of cellular signaling pathways that can be modulated by the properties of the surrounding extracellular matrix (ECM). Defining how genetic networks regulate cellular signaling in response to changes in ECM interactions would allow design of treatment strategies that target the tumor microenvironment in order to halt cell invasion. Transcriptome sequencing on MDCK cells, a tissue culture model system that undergoes EMT in response to HGF stimulation, can be used to define how changes in gene expression drive the cellular events of metastasis. Since these cells can be grown on different ECM substrates, how cellular signaling is altered by substrate composition can be determined. Through differential expression analysis of a time-series, a timeline for the transcriptional events that drive metastasis can be established. Comparing the timeline of transcriptional events on different substrates will determine the contribution of regulatory pathways associated with conditions where the ECM alters EMT. In short, differential expression analysis of HGF-stimulated MDCK cells will define, one, a timeline for the changes in gene expression that drive EMT and, two, the differences in gene expression between substrates that are responsible for their ability to affect EMT. Being a well-characterized model for EMT makes MDCK cells an attractive model for studying cancer metastasis. Validation of findings in this line will be confirmed in a panel of human cancer cell lines. This can be done by comparing phenotypic and molecular (transcriptional and protein level) changes associated with EMT in MDCK cells to those of EMT in HepG2 cells. The cell lines’ morphological changes and actin rearrangement can be compared using live cell imaging and fluorescence microscopy techniques. In addition, a panel of genes/proteins that are up- or down-regulated during EMT can be used to compare the two lines at the molecular level using qPCR and Western blotting. This has the additional advantage of further characterizing the MDCK model and demonstrating its utility for understanding transcriptional events in EMT more generally. Citation Format: Kevin Tuttle, Adam Grant, Ryan Barlow, Evan Johnson, Marc D. Hansen. Transcriptional control of epithelial-mesenchymal transition in the context of changing tumor microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 166. doi:10.1158/1538-7445.AM2014-166

In the majority of breast cancers, estrogen and its cellular receptor, estrogen receptor (ER), are involved in regulating tumor cell proliferation. ER is both a prognostic marker and a therapeutic target in the management of hormone-dependent tumors. Current research efforts and the paradigm of ER transcriptional regulatory functions in breast cancer have focused on the role of ER in activating target gene transcription. Microarray studies and whole-genome ER binding site mapping experiments indicate, however, that ER can alternatively directly repress the expression of a significant subset of target genes. We posit that transcriptional repression by ER likely involves interactions with other co-regulatory transcription factors found in the proximity of ER binding sites in the cis-regulatory regions of repressed target genes and have identified the runt-related transcription factor 1 (RUNX1), a key regulator of hematopoiesis and leukemogenesis, as a candidate co-regulatory factor involved in transcriptional repression by ER. Here, we demonstrate that RUNX1 interacts with ER, specifically the ligand-binding domain, and is involved in the repression of ER target genes and estrogen-dependent and -independent proliferation of breast cancer cells. We also show that putative ER-RUNX1 target genes are associated with disease outcome in breast cancer patients. These findings not only provide the first evidence for the involvement of RUNX1 in hormonal carcinogenesis and additional insights into mechanisms of transcriptional regulation by ER but may potentially lead to more effective strategies for targeting ER and estrogen signaling in the prevention and treatment of breast cancer. Citation Format: Ka Liu, Richard L. Smith, Trang Nguyen-Vu, Nicholes R. Candelaria, Colin M. Rogerson, W. Evan Johnson, Edwin Cheung, Boris R. Jankovic, Wail Ba alawi, Jinsong Zhang, Vladimir B. Bajic, Chin-Yo Lin. Runt-related transcription factor 1 (RUNX1) is involved in transcriptional repression by estrogen receptor and breast cancer cell proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3107. doi:10.1158/1538-7445.AM2013-3107

The ability of cancer cells to detach from their neighbors, invade through local tissues, and establish distant metastases is a major contributor to cancer mortality. Epithelial-mesenchymal transition (EMT) describes a developmental process by which cells break cell-cell adhesions and gain motility. Interestingly, cells generated by EMT also bear stem cell properties and are more resistant to chemotherapeutics. EMT is triggered by a number of cellular signaling pathways, including via hepatocyte growth factor. Inappropriate signaling in epithelial tumors is thought to drive EMT, facilitating cancer metastasis. A common feature is the activation of a number of transcriptional programs. Here we report the results of transcriptomic studies that are designed to characterize transcriptional changes in cells undergoing EMT in response to HGF stimulation. MDCK cells, a normal epithelial cell line, were stimulated with HGF for different amounts of time under otherwise identical culture conditions. Since cell substrate composition affects the robustness of the HGF response, we performed this experiment on cells grown on different extracellular matrices in an attempt to better understand how cellular substrates provide context to HGF signaling. Triplicate samples of mRNA were generated from these cultures for transcriptomic sequencing and analysis. Each sample generated 20-40 million sequence reads that were assembled into known and de novo (novel) transcripts using Tuxedo Suite, allowing detection of differential transcript expression by cummeRbund and edgeR. Many of the differentially expressed genes correlated well to known cancer pathways. HGF signaling is widely accepted to play an important role in cancer progression and to be an important target for development of novel therapeutics. We previously identified a series of novel HGF pathway inhibitors using a phenotypic screening approach. Compounds were subjected to analysis of their structure-activity relationship, in vivo toxicity, and pharmacokinetic profiles. Compounds that block EMT without affecting proliferation were applied to MDCK cells prior to HGF stimulation and mRNA samples generated from these cultures. We report how these inhibitors alter the transcriptional response of MDCK cells to HGF stimulation, providing a molecular basis for how these inhibitors prevent EMT. Citation Format: Kevin J. Tuttle, Jason Burton, W Evan Johnson, Marc DH Hansen. Characterization of HGF-mediated EMT and its inhibition with novel HGF pathway inhibitors using transcriptomic analysis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C54.

BackgroundFamily history is an important factor contributing to a woman's risk of breast cancer development. This increased risk reflects the participation of inherited genetic components such as breast cancer susceptibility genes. However, many of the genetic components contributing to breast cancer remain unknown, and a number of women with a family history of breast cancer never develop breast cancer despite their high-risk status, while other high-risk woman go on to develop breast cancer. Thus, it is clear that we lack crucial pieces of information to help define a person's true risk of developing breast cancer.Methods and FindingsWe hypothesize that there are many undiscovered germline variations in genes that lead to altered gene expression patterns predictive of breast cancer development in high-risk women. We have developed a genomic model capable of predicting which high-risk women, both BRCA1/2 mutation carriers and BRCAX women, will actually develop breast cancer. Specifically, we use exon-level genome-wide expression profiling of peripheral blood mononuclear cells (PBMCs) to develop a model of disease risk (n=118 samples of either control or high-risk women). From this data, we generate a biomarker consisting of genes that most correlate to cancer development in women with strong family histories of breast cancer. Using an internal independent dataset, our biomarker can predict the high-risk women who will or will not develop cancer with over 85% accuracy. Further, we have validated this model on an independent external cohort (n=36) which was obtained and processed at sites unique to our training dataset. Our genomic biomarker can accurately predict breast cancer development in high-risk women with over 78% accuracy using this external dataset. Therefore, from our analyses, we can calculate with high accuracy an individual woman's true risk of developing breast cancer. This method provides a personalized approach to hereditary breast cancer risk assessment that is not currently available. This personalized risk assessment will aide clinicians in counseling their patients regarding specific management options based on a patient's individual risk of breast cancer. Lastly, these studies have also identified novel genes associated with breast cancer risk, which may provide a basis for targeted therapies that may help modify the risk of breast cancer development in high risk patients.ConclusionsTogether, these studies deliver both a non-invasive biomarker for hereditary breast cancer risk and a characterization of genes that contribute to breast cancer development. Overall, we expect these experiments to identify the genetic changes that underlie breast cancer predisposition, and assist clinicians and patients in determining the appropriate preventative measures based on their personal risk of developing breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4059.