Xiaowei Chen, PhD
Office Phone: 215-214-4286
Global DASE analysis to identify novel coding or no-coding genetic factors for breast tumorigenesis
We hypothesize that DASE is a functional index for cis-acting variants and pathogenic mutations, and global profiling of DASE in breast cancer precursor tissues can be used to identify novel causative alleles for breast cancer susceptibility. We employed the Illumina® Beadchip for genome-wide allele-specific expression (GWASE) measurements in a set of normal HMEC established from breast cancer patients. We developed two statistical methods, SNP- and gene-based approaches, which allow us to identify 90 and 143 genes with significant DASE>2 (P ≤ 0.01, FDR ≤ 0.05), respectively. Importantly, 34 coding and 26 non-coding candidate loci are identified by both approaches. Ingenuity Pathway Analysis revealed two major interaction networks, which involve a variety of biological functions, including cell death and cell-to-cell signaling. Our study demonstrated that global DASE profiling could be a powerful new approach to identify breast cancer risk alleles. We are currently collaborating with Dr. Richard Katz (CE member) to use BioID system to characterize the roles of these DASE genes in breast cancer development.
Identification of breast cancer-associated lincRNA candidates using high-dense SNP arrays
The intergenic portion of the human genome is pervasively transcribed to produce large numbers of long intergenic non-coding RNAs (lincRNAs), which have recently been suggested to regulate a wide array of transcriptional and posttranscriptional processes in both physiological and disease conditions. Results from our previous studies showed that lincRNA genes appear to be less susceptible to copy number variations (CNV) in comparison to coding and other intergenic regions, indicating lincRNAs may be essential for maintaining cell survival. Here, we established a novel genome-wide approach, employing high-density arrays, to globally identifying lincRNA genes whose expression is altered in breast cancers. We hypothesize that the lincRNAs whose expression is frequently altered during malignant transformation likely influence breast tumor progression and thus are new breast cancer candidate genes.
Intra-individual heterogeneity among pre-malignant/pre-invasive lesions
The heterogeneity among multiple DCIS lesions within the same patient, also diagnosed with invasive IDC, has not been well evaluated, leaving clinical and research implications of this intra-individual heterogeneity of DCIS yet to be explored. In our recent study, we have clearly demonstrated that intra-individual heterogeneity in multi-lesional DCIS is very common in patients with concurrent diagnoses of IDC. Our results showed that seventy-two percent of the individuals had heterogeneous expression in at least 2 out of 6 IHC markers tested. Furthermore, a subpopulation of DCIS lesions (Subgroup IIb) had a higher Ki-67 index and positive p53 expression, but lower p16 staining intensity, than those in DCIS lesions (Subgroup I) with different molecular subtypes from the adjacent IDC. In comparison to other DCIS subgroups (I or IIa), type IIb DCIS lesions had the same molecular subtypes as the adjacent IDC but not the same subtypes as the adjacent normal terminal duct lobular units (TDLU). Our findings suggested the existence of DCIS subgroups with different degrees of “aggressiveness” (i.e. Subgroup I, indolent DCIS; Subgroup IIb, invasion-prone DCIS). Supported by these novel findings, we hypothesize that the “aggressive” DCIS subgroups which give rise to IDC share the same gene signatures as adjacent IDC, and these gene signatures will not only serve as risk markers to differentiate “indolent” or “invasion-prone” DCIS subpopulations but will also play a role in the DCIS initiation and progression. We are currently collaborating with Dr. Mary Daly (CPC member) to characterize the high-risk DCIS subgroup.