Genes essential for cell viability that are linked to tumor suppressor genes play a role in cancer susceptibility

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Loss of heterozygosity (LOH) is one of the most important genetic mechanisms in tumorigenesis and leads to the inactivation of “so called” tumor suppressor genes that regulate growth and differentiation. In a recent study,¹ we discovered in a new mouse tumor model that genes that are essential for cell viability (cell essential genes) can profoundly modify the genetic mechanism of tumorigenesis by impacting LOH at genetically linked tumor suppressor loci. Specifically, we observed that a missense mutation in Rpa1, which is incompatible with cell survival in homozygous mutant cells, prevents LOH at the nearby Trp53 gene locus when it is linked to a mutant Trp53 allele (cis configuration). As a result, the cis-linkage caused selection against Trp53-dependent tumorigenesis by LOH. In contrast to the protective effect that was mediated in cis, when the Rpa1 mutation was located on the opposite chromosome (trans configuration), it enhanced LOH and tumorigenesis. This enhancement was due to the increased genomic instability that is caused by the Rpa1 dominant mutation in the heterozygous state. Our study suggests that these results represent a novel intrinsic genetic mechanism of tumor suppression. Therefore, we propose that a similar mechanism exists in humans, and that specific genetic linkages between functional variants in cell essential genes and mutations in tumor suppressor genes may alter cancer phenotypes based on their allelic configuration. Furthermore, this mechanism may be relevant in other diseases that arise due to LOH.

To date, more than 350 of the 22,000 protein-coding genes in the human genome have been shown to carry recurrent somatic mutations in cancer. In mice, more than 2,000 genes are known to potentially contribute to cancer development.⁴ More than 1 million single nucleotide polymorphisms (SNPs) have been identified across the human genome, and recent studies have shown that individual human genomes contain a significant number of copy number variants (CNVs) that include deletions and duplications of tens to thousands of kilobases.^2,10,11 There is also growing interest in large scale sequencing and DNA copy number analysis of human cancer genomes.^2-9 These efforts, which include the Cancer Genome Atlas (cancergenome.nih.gov), have uncovered a large number of genetic variants and CNVs throughout cancer genomes. Importantly, this information can now be used in genome-wide association studies (GWAS) to identify associations with common diseases such as cancer, and some of the pilot projects have already begun to provide exciting new insights into cancer genetics.^2-4,11 However, there is very little known about how linkage between cell essential genes and tumor suppressor genes impacts cancer phenotypes. Furthermore, the allelic configurations of disease relevant genes, such as mutated tumor suppressor genes and potential loss of function variants in linked cell essential genes, as well as variants that reduce cell proliferation rates, have not been previously considered in the study of LOH. Our data¹ suggest that in addition to association analysis between SNPs/CNVs and disease phenotypes, such as cancer susceptibility, it will be important to consider the status of essential genes linked to tumor suppressor genes.

Although it is currently unknown how frequent functional SNPs/CNVs occur in cell essential genes, it should not be uncommon given the high prevalence of SNPs/CNVs present throughout the human genome. Since LOH may involve whole chromosomes through the correction of a trisomy that occurs from mitotic non-disjunction or chromosome segments through somatic recombination, lethal mutations in cell essential genes need only be located on the same chromosome to exert a protective effect against a mutation acquired in a tumor suppressor. Therefore, a genome-wide analysis of SNPs/CNVs of cell essential genes and their linkages with tumor suppressor genes may shed new light on an important genetic mechanism in human cancer. A schematic diagram illustrating possible associations between cell essential genes and tumor suppressor genes is depicted in Figure 1. Importantly, this mechanism may be relevant in both familial cancer syndromes, where affected individuals carry a tumor suppressor mutation in every cell, as well as in sporadic cancers, where mutations are somatically acquired, both of which require a second hit that is often the result of LOH. Finally, the study of phenotypic variability between individuals that carry the same familial mutation will help to establish whether this mechanism of cancer attenuation due to cis-linkage between mutations in cell essential genes and tumor suppressor genes is relevant in human disease.

Figure 1. Proposed model for the effect of genetic variants and linkage in disease phenotype. Locations of essential gene (EG) and tumor suppressor gene (TSG) on the chromosomes are representative. The actual linked mapping positions of EG and TSG can be distributed elsewhere along the chromosomes. EG^m, mutant cell essential gene; TSG^m, mutant tumor suppressor gene. “+” represents wild type EG (red) or wild type TSG (blue). Chromosomes: Green denotes paternal (or maternal) origin and red denotes maternal (or paternal) origin of the chromosome. Cis, EG^m and TSG^m are on the same chromosome. Trans, EG^m and TSG^m are on opposite chromosomes. This simplified model assumes whole chromosome loss and gain. However, in reality, the chromosomal changes may be segmental involving fragments of the chromosome. In this case, the EG and TSG segregate within the chromosomal fragment by linkage disequilibrium. This model also assumes LOH is required for tumor formation. However, some mutant tumor suppressor genes may drive tumorigenesis via haploinsufficiency, which is not depicted in the diagram.