Bimodal gene expression patterns in breast cancer

Abstract

We identified a set of genes with an unexpected bimodal distribution among breast cancer patients in multiple studies. The property of bimodality seems to be common, as these genes were found on multiple microarray platforms and in studies with different end-points and patient cohorts. Bimodal genes tend to cluster into small groups of four to six genes with synchronised expression within the group (but not between the groups), which makes them good candidates for robust conditional descriptors. The groups tend to form concise network modules underlying their function in cancerogenesis of breast neoplasms.

Figure 1

Signal distribution of normal and "bimodal" genes in patient cohort. (A) Theoretical normal gene signal distribution for quantitative traits [18]. (B) Theoretical bimodal gene signal distribution

Figure 2

Bimodal genes. (A) Distribution of GRB7 expression among 295 patients (Sorlie295 dataset). The green line marks the threshold which separates the average of signals below threshold TGRB7≈0.0015. Red lines mark lGRB7≈1.74 and uGRB7≈1.77. (B) Distribution of GRB7 expression among 295 patients after normalization. The green line marks the threshold which separates the average of signals below threshold TGRB7 = 0. Red lines mark lGRB7≈-1 and uGRB7 = 1.

Figure 3

Ontology enrichment for the set of 866 bimodal genes.

Figure 4

Signal normalization for bimodal genes. (A) Expression profiles for genes FOXA1 and GATA3 in Sorlie295 and GSE1456 data sets before normalization. (B) Expression profiles for genes FOXA1 and GATA3 in Sorlie295 and GSE1456 data sets before normalization and after normalization.

Figure 5

Identification of "Close neighbours" co-expression groups. (A) Average ERBB2 group expression profile. (B) Average ERBB2 group expression profile divides cohort of breast cancer patients into two groups. (C) "Close neighbours" expression group ERBB2 forms a network, functional module.

Figure 6

Co-expression of bimodal genes in ESR1 group. Genes from ESR1 group are regulated by an estradiol/testosterone regulation system

Figure 7

Identification of the "close" groups of genes in the space of 295 samples (Sorlie295 data set). (A) No close group is found for HMGA1 as query gene. OX: relative distances from the query gene to all 10604 array genes. OY: the number of genes. (B) Clear close group around ERBB2/GRB7 (encircled). OX: relative distances from the query gene to all 10604 array genes. OY: the number of genes.