Healthcare rationing---are additional criteria needed for assessing evidence based clinical practice guidelines?

ABSTRACT Alternative polyadenylation (APA) is a post-transcriptional mechanism that regulates gene expression. In human cancer, shortening of the 3ʹ-untranslated region (3ʹ-UTR) through APA is widespread affecting thousands of genes1. We previously identified that 3ʹ-UTR shortening (3ʹUS) disrupts the competing-endogenous RNA (ceRNA) network (3ʹUS-ceRNA effect) to promote breast cancer2. As different breast cancer subtypes are associated with different molecular mechanisms3, we identified distinct 3ʹUS profiles of different breast cancer subtypes in this work, calling for the characterization of subtype-specific 3ʹUS-ceRNA effect in the ceRNA network. A quantitative challenge is that different sample sizes available for the different breast cancer subtypes can result in a systematic bias on size and topology of the constructed ceRNA networks. We addressed the bias by normalizing the networks in two-way, first between and second within the subtypes. Using the two-way network normalization, we built comparable ceRNA networks for estrogen receptor negative (ER-) and positive (ER+) subtype breast tumor samples of different size. Functional enrichment analyses associated subtype-specific 3ʹUS-ceRNA effect with ER-’s aggressive phenotype4 and unique growth mechanism5. Especially, for ER-specific growth mechanism, subtype-specific 3ʹUS-ceRNA effect disrupts ceRNA crosstalk of housekeeping genes, which help maintain similar ceRNA network topology for ER- and ER+ normal samples. As ER-specific 3ʹUS-ceRNA effect is associated with ER-’s pathological features, aggressive phenotype and unique growth mechanism, our study provides new insights into the interactive mechanism of 3ʹUS and ceRNA for ER-specific cancer progression.