Prevalence, causes and impact of TP53-loss phenocopying events in human tumors.

BACKGROUND: TP53 is a master tumor suppressor gene, mutated in approximately half of all human cancers. Given the many regulatory roles of the corresponding p53 protein, it is possible to infer loss of p53 activity - which may occur due to alterations in trans - from gene expression patterns. Several such alterations that phenocopy p53 loss are known, however additional ones may exist, but their identity and prevalence among human tumors are not well characterized. RESULTS: We perform a large-scale statistical analysis on transcriptomes of ~ 7,000 tumors and ~ 1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines, respectively, phenocopy TP53 loss: they are likely deficient in the activity of the p53 pathway, while not bearing obvious TP53 inactivating mutations. While some of these cases are explained by amplifications in the known phenocopying genes MDM2, MDM4 and PPM1D, many are not. An association analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additional common TP53-loss phenocopying gene, USP28. Deletions in USP28 are associated with a TP53 functional impairment in 2.9-7.6% of breast, bladder, lung, liver and stomach tumors, and have comparable effect size to MDM4 amplifications. Additionally, in the known copy number alteration (CNA) segment harboring MDM2, we identify an additional co-amplified gene (CNOT2) that may cooperatively boost the TP53 functional inactivation effect of MDM2. An analysis of cancer cell line drug screens using phenocopy scores suggests that TP53 (in)activity commonly modulates associations between anticancer drug effects and various genetic markers, such as PIK3CA and PTEN mutations, and should thus be considered as a drug activity modifying factor in precision medicine. As a resource, we provide the drug-genetic marker associations that differ depending on TP53 functional status. CONCLUSIONS: Human tumors that do not bear obvious TP53 genetic alterations but that phenocopy p53 activity loss are common, and the USP28 gene deletions are one likely cause.

The power of geohistorical boundaries for modeling the genetic background of human populations: The case of the rural catalan Pyrenees.

The genetic variation of the European population at a macro-geographic scale follows genetic gradients which reflect main migration events. However, less is known about factors affecting mating patterns at a micro-geographic scale. In this study we have analyzed 726,718 autosomal single nucleotide variants in 435 individuals from the catalan Pyrenees covering around 200 km of a vast and abrupt region in the north of the Iberian Peninsula, for which we have information about the geographic origin of all grand-parents and parents. At a macro-geographic scale, our analyses recapitulate the genetic gradient observed in Spain. However, we also identified the presence of micro-population substructure among the sampled individuals. Such micro-population substructure does not correlate with geographic barriers such as the expected by the orography of the considered region, but by the bishoprics present in the covered geographic area. These results support that, on top of main human migrations, long ongoing socio-cultural factors have also shaped the genetic diversity observed at rural populations.

Fine-scale population structure in five rural populations from the Spanish Eastern Pyrenees using high-coverage whole-genome sequence data.

The area of the Spanish Pyrenees is particularly interesting for studying the demographic dynamics of European rural areas given its orography, the main traditional rural condition of its population and the reported higher patterns of consanguinity of the region. Previous genetic studies suggest a gradient of genetic continuity of the area in the West to East axis. However, it has been shown that micro-population substructure can be detected when considering high-quality NGS data and using spatial explicit methods. In this work, we have analyzed the genome of 30 individuals sequenced at 40× from five different valleys in the Spanish Eastern Pyrenees (SEP) separated by less than 140 km along a west to east axis. Using haplotype-based methods and spatial analyses, we have been able to detect micro-population substructure within SEP not seen in previous studies. Linkage disequilibrium and autozygosity analyses suggest that the SEP populations show diverse demographic histories. In agreement with these results, demographic modeling by means of ABC-DL identify heterogeneity in their effective population sizes despite of their close geographic proximity, and suggests that the population substructure within SEP could have appeared around 2500 years ago. Overall, these results suggest that each rural population of the Pyrenees could represent a unique entity.