Reproducibility in Cancer

M elanoma is associated with DNA damage and genomic alterations caused by ultraviolet light. In 2012, as part of efforts to better understand the causes of melanoma, researchers at the Broad Institute, the Dana-Farber Cancer Institute and a number of other institutes reported the results of whole genome sequencing of 25 human metastatic melanomas (Berger et al., 2012). This analysis discovered an average of 97 structural rearrangements of the genome per tumor, and some 9,653 mutations of various types in 5,712 genes. A number of known melanoma oncogenes were identified, including BRAF (in 64% of tumors) and mutated NRAS (36%). The analysis also found that a significant fraction of tumors contained rearrangements and mutations of a gene called PREX2, and experiments confirmed that cancer-associated mutations of PREX2 promoted the growth of human melanoma cells in mice. It has been known for a number of years that PREX2 is a GTP/GDP exchange factor that inhibits a tumor suppressor protein called PTEN, and that this process can promote tumorigenesis by activating the PI3K signaling pathway (Fine et al., 2009; Hodakoski et al., 2014; Figure 1A). More recently it has been shown that PTEN can inhibit PREX2, and that this can stop tumor cells invading tissue by preventing the activation of an enzyme called RAC (Mense et al., 2015). Moreover, cancer-associated mutations in PREX2 disrupt these mutual inhibition processes: mutated PREX2 can still inhibit PTEN, but PTEN cannot inhibit mutated PREX2 (Mense et al., 2015; Figure 1B). All this work supports the conclusion that the overexpression of PREX2 can increase PI3K-dependent tumor growth (Fine et al., 2009), and that mutated PREX2 promotes tumorigenesis by increasing RAC-dependent invasiveness (Mense et al., 2015). As part of the Reproducibility Project: Cancer Biology, Chroscinski et al. published a Registered Report which explained in detail how they would seek to replicate selected experiments from Berger et al. (Chroscinski et al., 2014). The results of these experiments have now been published as a Replication Study (Horrigan et al., 2017). The original paper by Berger et al. contained two major conclusions. First, PREX2 was identified as a frequently mutated gene in human melanoma. The Reproducibility Project did not attempt to replicate this finding, but subsequent studies have reported the frequency of PREX2 mutations in human melanoma (Hodis et al., 2012; Krauthammer et al., 2012; Marzese et al., 2014; Ni et al., 2013; Copyright Davis. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Related research articles Horrigan SK,