Investigators from Sichuan University, Chengdu, China, published their recent research on cancer in Nature on March 16th. The title of the article is “Deletions linked to TP53 loss drive cancer through p53-independent mechanisms”.

This work was collaboration betweenSichuanUniversityand Memorial Sloan Kettering Cancer Center (MSKCC) inNew York,US. Drs. Yu Liu and Chong Chen inSichuanUniversitywere the co-first authors and Dr. Scott W. Lowe in MSKCC was the corresponding author.

In this study, Liu and her colleague provided direct evidence that large chromosome deletions could be cancer drivers and expounded the underlying mechanism that there were multiple cooperating tumor suppressors in the deleted chromosome regions. They also generated novel cancer animal models driven by these chromosome abnormalities. These models would help developing potential target therapies against these miserable diseases. This study sets an example of functional studies and translational researches of chromosome abnormalities frequently in many human diseases.

Extended reading

Mutations of tumor suppressor TP53 are the most frequent genetic event in human cancer and often include missense mutations on one allele and large chromosome deletions on the other allele, which is generally thought to be achieved through “two-hit” mechanism. According to “two-hit” hypothesis, the major function of large chromosome deletions is loss of hererozygosity of TP53. Though there are extensive studies on the gain-of-functions of missense TP53 mutations on tumorigenesis, it is unclear whether hundreds of genes in chromosome 17p co-deleted together with TP53 also participate in this process.

In the study “Deletions linked to TP53 loss drive cancer through p53-independent mechanisms”, the researchers showed that loss of chromosome 11B3 inmouse, a 4 Mb region synthetic to human chromosome 17p13.1, promoted lymphoma genesis and leukemogenesis more than Trp53 loss only. Mechanically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5aand Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease.

Liu et al. provide convincing evidence that chromosome 17p loss results additional effects beyond the effect of TP53 loss. Given the established gain-of-function roles of TP53 missense mutations, the study indicates the selective advantage by the most frequent somatic event in cancer is the combined impact of both TP53-dependent and independent effects. Therefore, cancer with TP53 abnormalities may contain the properties of both TP53 missense mutations and chromosome 17p large deletions, which might suggest distinct susceptibilities.

http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature17157.html