Whole Genome Pathway Analysis Identifies an Association of Cadmium Response Gene Loss with Copy Number Variation in Mutant p53 Bearing Uterine Endometrial Carcinomas

• Published in: PloS one 2016-07, Vol.11 (7), p.e0159114
• Main Authors: Delaney, Joe Ryan, Stupack, Dwayne G
• Format: Article
• Language: English
• Subjects: Algorithms; Aneuploidy; Autophagy; Biology and Life Sciences; Cadmium; Cadmium - toxicity; Cancer; Carcinoma; Cell adhesion; Cell Adhesion - genetics; Cell Adhesion - physiology; Chromosome aberrations; Clonal deletion; Comparative Genomic Hybridization; Consortia; Copy number; Development and progression; DNA Copy Number Variations - genetics; Endometrial cancer; Endometrial Neoplasms - chemically induced; Endometrial Neoplasms - genetics; Endometrial Neoplasms - metabolism; Endometrium; Female; Genes; Genetic aspects; Genetic variation; Genome-Wide Association Study; Genomes; Genomics; Heavy metals; Humans; Immunology; Incidence; Medicine and Health Sciences; Metabolic pathways; Metallothionein; Metallothionein - genetics; Metallothionein - metabolism; Metallothioneins; Mutation; Mutation - genetics; Ontology; p53 Protein; Pathways; Physical Sciences; Physiological aspects; Reproductive health; Tumor Suppressor Protein p53 - genetics; Tumorigenesis; Tumors; Uterine cancer; Uterus
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0159114

Massive chromosomal aberrations are a signature of advanced cancer, although the factors promoting the pervasive incidence of these copy number alterations (CNAs) are poorly understood. Gatekeeper mutations, such as p53, contribute to aneuploidy, yet p53 mutant tumors do not always display CNAs. Uterine Corpus Endometrial Carcinoma (UCEC) offers a unique system to begin to evaluate why some cancers acquire high CNAs while others evolve another route to oncogenesis, since about half of p53 mutant UCEC tumors have a relatively flat CNA landscape and half have 20-90% of their genome altered in copy number. We extracted copy number information from 68 UCEC genomes mutant in p53 by the GISTIC2 algorithm. GO term pathway analysis, via GOrilla, was used to identify suppressed pathways. Genes within these pathways were mapped for focal or wide distribution. Deletion hotspots were evaluated for temporal incidence. Multiple pathways contributed to the development of pervasive CNAs, including developmental, metabolic, immunological, cell adhesion and cadmium response pathways. Surprisingly, cadmium response pathway genes are predicted as the earliest loss events within these tumors: in particular, the metallothionein genes involved in heavy metal sequestration. Loss of cadmium response genes were associated with copy number changes and poorer prognosis, contrasting with 'copy number flat' tumors which instead exhibited substantive mutation. Metallothioneins are lost early in the development of high CNA endometrial cancer, providing a potential mechanism and biological rationale for increased incidence of endometrial cancer with cadmium exposure. Developmental and metabolic pathways are altered later in tumor progression.