Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13.

In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases.

Effect of early pregnancy following chemotherapy on disease relapse and fetal outcome in women treated for gestational trophoblastic neoplasia.

OBJECTIVE: To examine the effects of early pregnancy (< 12 months following chemotherapy) on a recent cohort of women treated with modern therapies for gestational trophoblastic neoplasia (GTN). STUDY DESIGN: The Charing Cross GTN database was screened between 1998-2012 to identify 1,204 patients treated with either single-agent (61.9%) or multiagent (38.1%) chemotherapy. RESULTS: A total of 23% of single-agent and 15.4% of the multiagent treatment groups conceived within 12 months of chemotherapy, resulting in 255 early pregnancies, with 73.3% resulting in live births. There was no significant increased risk of miscarriage, ectopic pregnancy, second molar pregnancy or stillbirth as compared to the general U.K. population. Intriguingly, the incidence of relapse was only 1.7% in the early pregnancy group as compared to 5.2% in the 963 patients who did not conceive early. CONCLUSION: Women who become pregnant within 12 months postchemotherapy for GTN can be reassured of a likely favorable outcome, although the safest option is still to delay pregnancy for a year.

The demographics of molar pregnancies in England and Wales from 2000-2009.

OBJECTIVE: To analyze the overall incidence of molar pregnancies and that of complete and partial molar pregnancies across the reproductive age range for England and Wales for the period 2000-2009. STUDY DESIGN: The cases of all patients with molar pregnancies registered with the UK Trophoblast disease service from England and Wales were identified. The overall number of molar pregnancies registered from 1998-2007 was compared to the number of maternities (live births and still births) and total viable conceptions for each year. For the series 2000-2009 the number of complete and partial molar pregnancies were compared to the number of maternities and terminations occurring for women across the age range < 14 to 50+ years, allowing an accurate estimate of the risk of molar pregnancy for women conceiving at any age. RESULTS: The results indicate that for the period 1998-2007 the overall incidence of molar pregnancies was 1 case per 591 viable conceptions. The incidence increased from 1:611 in 1997 to 1:528 in 2008. The age-specific data for the period 2000-2009 confirms a risk level of < 0.2%for women aged 18 {N dash} 39 years, with a modest excess risk for young teenagers but a much more significant increase for women > 40, where the risk is 1% at 45 and 17% at > or = 50. CONCLUSION: This study provides detailed data regarding the risk of partial and complete molar pregnancies with increasing maternal age. It confirms that the risk of partial molar pregnancy varies relatively little with age, with complete molar pregnancies contributing the main component of the overall increase with age.

Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet.

AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. We identified a mutation in the γ1 subunit (γ1D316A) that leads to activation of AMPK. We generated mice with this mutation to study the effect of chronic liver-specific activation of AMPK in vivo. Primary hepatocytes isolated from these mice have reduced gluconeogenesis and fatty acid synthesis, but there is no effect on fatty acid oxidation compared to cells from wild-type mice. Liver-specific activation of AMPK decreases lipogenesis in vivo and completely protects against hepatic steatosis when mice are fed a high-fructose diet. Our findings demonstrate that liver-specific activation of AMPK is sufficient to protect against hepatic triglyceride accumulation, a hallmark of non-alcoholic fatty liver disease (NAFLD). These results emphasize the clinical relevance of activating AMPK in the liver to combat NAFLD and potentially other associated complications (e.g., cirrhosis and hepatocellular carcinoma).

Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution.

Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.