title: Gene Coexpression Analyses Differentiate Networks Associated with Diverse Cancers Harboring TP53 Missense or Null Mutations.
abstract: In a variety of solid cancers, missense mutations in the well-established TP53 tumor suppressor gene may lead to the presence of a partially-functioning protein molecule, whereas mutations affecting the protein encoding reading frame, often referred to as null mutations, result in the absence of p53 protein. Both types of mutations have been observed in the same cancer type. As the resulting tumor biology may be quite different between these two groups, we used RNA-sequencing data from The Cancer Genome Atlas (TCGA) from four different cancers with poor prognosis, namely ovarian, breast, lung and skin cancers, to compare the patterns of coexpression of genes in tumors grouped according to their TP53 missense or null mutation status. We used Weighted Gene Coexpression Network analysis (WGCNA) and a new test statistic built on differences between groups in the measures of gene connectivity. For each cancer, our analysis identified a set of genes showing differential coexpression patterns between the TP53 missense- and null mutation-carrying groups that was robust to the choice of the tuning parameter in WGCNA. After comparing these sets of genes across the four cancers, one gene (KIR3DL2) consistently showed differential coexpression patterns between the null and missense groups. KIR3DL2 is known to play an important role in regulating the immune response, which is consistent with our observation that this gene's strongly-correlated partners implicated many immune-related pathways. Examining mutation-type-related changes in correlations between sets of genes may provide new insight into tumor biology.
authors.affiliation: Lady Davis Research Institute, Jewish General Hospital Montreal, QC, Canada.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Oros Klein
authors.affiliation: Département de Mathématiques, Université du Québec à Montréal Montreal, QC, Canada.
authors.forename: Karim
authors.initials: K
authors.lastname: Oualkacha
authors.affiliation: Département de Mathématiques, Université du Québec à Montréal Montreal, QC, Canada.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Lafond
authors.affiliation: Lady Davis Research Institute, Jewish General HospitalMontreal, QC, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill UniversityMontreal, QC, Canada.
authors.forename: Sahir
authors.initials: S
authors.lastname: Bhatnagar
authors.affiliation: Cancer Research Program, The Research Institute of the McGill University Health CentreMontreal, QC, Canada; Departments of Medicine and Human Genetics, McGill UniversityMontreal, QC, Canada.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Tonin
authors.affiliation: Lady Davis Research Institute, Jewish General HospitalMontreal, QC, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill UniversityMontreal, QC, Canada; Departments of Oncology and Human Genetics, McGill UniversityMontreal, QC, Canada.
authors.forename: Celia M T
authors.initials: CM
authors.lastname: Greenwood
keywords: KIR3DL2; TP53; breast cancer; immune pathways; lung cancer; melanoma; ovarian cancer; weighted gene expression network