Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma.

We performed fluorescent in situ hybridization (FISH) for 16q23 abnormalities in 861 patients with newly diagnosed multiple myeloma and identified deletion of 16q [del(16q)] in 19.5%. In 467 cases in which demographic and survival data were available, del(16q) was associated with a worse overall survival (OS). It was an independent prognostic marker and conferred additional adverse survival impact in cases with the known poor-risk cytogenetic factors t(4;14) and del(17p). Gene expression profiling and gene mapping using 500K single-nucleotide polymorphism (SNP) mapping arrays revealed loss of heterozygosity (LOH) involving 3 regions: the whole of 16q, a region centered on 16q12 (the location of CYLD), and a region centered on 16q23 (the location of the WW domain-containing oxidoreductase gene WWOX). CYLD is a negative regulator of the NF-kappaB pathway, and cases with low expression of CYLD were used to define a "low-CYLD signature." Cases with 16q LOH or t(14;16) had significantly reduced WWOX expression. WWOX, the site of the translocation breakpoint in t(14;16) cases, is a known tumor suppressor gene involved in apoptosis, and we were able to generate a "low-WWOX signature" defined by WWOX expression. These 2 genes and their corresponding pathways provide an important insight into the potential mechanisms by which 16q LOH confers poor prognosis.

Human capital and the quantity–quality trade-off during the demographic transition

This paper provides an empirical test of the child quantity–quality (QQ) trade-off predicted by unified growth theory. Using individual census returns from the 1911 Irish census, we examine whether children who attended school were from smaller families—as predicted by a standard QQ model. To measure causal effects, we use a selection of models robust to endogeneity concerns which we validate for this application using an Empirical Monte Carlo analysis. Our results show that a child remaining in school between the ages of 14 and 16 caused up to a 27 % reduction in fertility. Our results are robust to alternative estimation techniques with different modeling assumptions, sample selection, and alternative definitions of fertility. These findings highlight the importance of the demographic transition as a mechanism which underpinned the expansion in human capital witnessed in Western economies during the twentieth century.