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

Abstract

BackgroundMassive 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.MethodsWe 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.ResultsMultiple 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.ConclusionMetallothioneins 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.

Cadmium Exposure as a Putative Risk Factor for the Development of Pancreatic Cancer: Three Different Lines of Evidence

“…miRNA 146 is associated with nuclear factor kappa-B, with links to carcinogenesis and inflammatory response [ 88 ]. Recent work has examined the epigenetic role of Cd in the development of various cancers such as melanoma [ 89 ], gastrointestinal tract [ 90 ], and uterine-endometrial carcinomas [ 91 ]. Across each specific cancer, the key epigenetic events that transpired were increased DNA methylation, increased expression, and production of either pro- or antiapoptotic proteins, such as DNMTs, p53, p16, and other proinflammatory proteins [ 89 – 91 ].…”

Genomic Copy Number Alterations in Serous Ovarian Cancer

“…Not all p53 mutant tumors are high in SCNAs [38]. Nonetheless, tumors with higher than average SCNAs are much more likely to have a facilitating mutation in p53 [26,39,40]. This implies a basic premise: ovarian cancer tumors utilize the mutation in TP53 to enable the proliferation of SCNAs.…”

Single-cell analysis of copy-number alterations in serous ovarian cancer reveals substantial heterogeneity in both low- and high-grade tumors

“…Chromosome fluorescence in-situ hybridization (FISH) studies have used centromere painting to ascertain whole chromosome gains and losses [16]. A problem with centromeric FISH analysis is that individual chromosome arms may be gained or lost on the same chromosome [1,9,14,30,31]. A common antagonistically altered chromosome in ovarian cancer is chromosome 8 [5].…”

“…Loss of p53 function is significantly associated with aneuploidy (more than 100 log10 P-value units beyond any other gene) [2], due to a loss of programmed cell death in response to aneuploidy. In endometrial cancer, p53 mutant tumors with higher aneuploidy have worse prognosis [13,14]. Because of intra-tumor heterogeneity, however, high aneuploidy does not necessarily mean high CNA heterogeneity among tumor cells in the same patient.…”