Breast Cancer Clinical Trial of Chemotherapy and Trastuzumab: Potential Tool to Identify Cardiac Modifying Variants of Dilated Cardiomyopathy

Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy

A NSGA-II based memetic algorithm for multiobjective parallel flowshop scheduling problem

Additional file 6: Table S4. Gene ontology enrichment analysis of lapatinib induced differentially expressed genes in iPSC dervied cardiomyocytes

Assessment of Tumor Heterogeneity, as Evidenced by Gene Expression Profiles, Pathway Activation, and Gene Copy Number, in Patients with Multifocal Invasive Lobular Breast Tumors

<div><p>Background</p><p>Invasive lobular carcinoma (ILC) comprises approximately ~10–20% of breast cancers. In general, multifocal/multicentric (MF/MC) breast cancer has been associated with an increased rate of regional lymph node metastases. Tumor heterogeneity between foci represents a largely unstudied source of genomic variation in those rare patients with MF/MC ILC.</p><p>Methods</p><p>We characterized gene expression and copy number in 2 or more foci from 11 patients with MF/MC ILC (all ER+, HER2-) and adjacent normal tissue. RNA and DNA were extracted from 3x1.5mm cores from all foci. Gene expression (730 genes) and copy number (80 genes) were measured using Nanostring PanCancer and Cancer CNV panels. Linear mixed models were employed to compare expression in tumor versus normal samples from the same patient, and to assess heterogeneity (variability) in expression among multiple ILC within an individual.</p><p>Results</p><p>35 and 34 genes were upregulated (FC>2) and down-regulated (FC<0.5) respectively in ILC tumor relative to adjacent normal tissue, q<0.05. 9/34 down-regulated genes (<i>FIGF</i>, <i>RELN</i>, <i>PROM1</i>, <i>SFRP1</i>, <i>MMP7</i>, <i>NTRK2</i>, <i>LAMB3</i>, <i>SPRY2</i>, <i>KIT</i>) had changes larger than <i>CDH1</i>, a hallmark of ILC. Copy number changes in these patients were relatively few but consistent across foci within each patient. Amplification of three genes (<i>CCND1</i>, <i>FADD</i>, <i>ORAOV1</i>) at 11q13.3 was present in 2/11 patients in both foci. We observed significant evidence of within-patient between-foci variability (heterogeneity) in gene expression for 466 genes (p<0.05 with FDR 8%), including <i>CDH1</i>, <i>FIGF</i>, <i>RELN</i>, <i>SFRP1</i>, <i>MMP7</i>, <i>NTRK2</i>, <i>LAMB3</i>, <i>SPRY2</i> and <i>KIT</i>.</p><p>Conclusions</p><p>There was substantial variation in gene expression between ILC foci within patients, including known markers of ILC, suggesting an additional level of complexity that should be addressed.</p></div

<i>CCND1</i> gene expression and gene copy number in 11 MF ILC patients.

<p>Patient 8 (blue) deletion; Patient 1 (orange/brown) moderate copy number gain; Patient 11 (red/pink) high copy number gain.</p

<i>CDH1</i> gene expression in 11 ILC patients with multiple foci.

<p>Log2 gene expression is plotted for three punches from each foci in each patient. For each patient, foci are shown in order of size with punches from the largest focus always displayed to the left and punches from the smallest focus (for which tissue is available) to the right, in the same order as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153411#pone.0153411.t001" target="_blank">Table 1</a>.</p

11q13.3 gene copy number in 11 MF ILC patients.

<p>Gene copy number was measured in three punches from each focus and a single punch from matched adjacent normal tissue where available. Ends of each box are minimum and maximum copy number and floating bar shows mean copy number. Copy number was measured by Nanostring and qPCR platforms. Patients are labelled p1-11 and foci are labelled t1, t2 and t3 in order of size, hence p1_t1 = patient 1, focus 1. Amplifications are highlighted in red and deletions in blue. A. <i>CCND1</i> copy number by Nanostring; B. <i>CCND1</i> copy number by qPCR; C. <i>FADD</i> copy number by Nanostring; D. <i>ORAOV1</i> copy number by Nanostring.</p

Patient material and clinical characteristics.

<p>Patient material and clinical characteristics.</p

Differential gene expression between MF ILC and adjacent normal tissue.

<p>Differential gene expression between MF ILC and adjacent normal tissue.</p

Sources of heterogeneity in MF ILC differentially expressed genes.

<p>Sources of heterogeneity in MF ILC differentially expressed genes.</p