A systematic SNP selection approach to identify mechanisms underlying disease aetiology: Linking height to post-menopausal breast and colorectal cancer risk

Data from GWAS suggest that SNPs associated with complex diseases or traits tend to co-segregate in regions of low recombination, harbouring functionally linked gene clusters. This phenomenon allows for selecting a limited number of SNPs from GWAS repositories for large-scale studies investigating shared mechanisms between diseases. For example, we were interested in shared mechanisms between adult-attained height and post-menopausal breast cancer (BC) and colorectal cancer (CRC) risk, because height is a risk factor for these cancers, though likely not a causal factor. Using SNPs from public GWAS repositories at p-values < 1 × 10-5 and a genomic sliding window of 1 mega base pair, we identified SNP clusters including at least one SNP associated with height and one SNP associated with either post-menopausal BC or CRC risk (or both). SNPs were annotated to genes using HapMap and GRAIL and analysed for significantly overrepresented pathways using ConsensuspathDB. Twelve clusters including 56 SNPs annotated to 26 genes were prioritised because these included at least one height- and one BC risk- or CRC risk-associated SNP annotated to the same gene. Annotated genes were involved in Indian hedgehog signalling (p-value = 7.78 × 10-7) and several cancer site-specific pathways. This systematic approach identified a limited number of clustered SNPs, which pinpoint potential shared mechanisms linking together the complex phenotypes height, post-menopausal BC and CRC

Esophagectomy : outcomes and perioperative course of esophageal cancer surgery

The incidence of esophageal cancer is still rising steadily. Surgery with neoadjuvant chemo(radio)therapy constitutes the mainstay of therapy. Still associated with high morbidity and mortality rates, it is essential to further improve medical and surgical therapy strategies. The studies presented in this thesis focus on perioperative morbidity and prognosis associated with esophagectomy. In a comparative study, it was found that patients who were treated with perioperative chemotherapy experienced an almost 4-fold higher risk of developing thrombosis during their treatment period compared to patients who were treated with surgery alone. Whilst all TEEs were adequately treated, risk of a postoperative TEE was not increased, nor did it affect the duration of postoperative hospital stay. However, when left untreated, the preoperative development of subclinical thrombosis could seriously affect postoperative outcome of esophagectomy in patients who are treated with neoadjuvant therapy. In an experimental study, the randomized application to hand-sewn esophagogastric anastomoses in a rat model showed increased anastomotic strength during early postoperative recovery. This indicates that sealing of the anastomosis has the potential to prevent leakage and consequent morbidity after esophagectomy in humans. Esophageal surgery and prolonged single lung ventilation cause increased release of pro- and anti-inflammatory mediators, which are associated with development of postoperative pneumonia. In a randomized clinical trial, the immunological response to single lung ventilation was evaluated in combination with continuous positive airway pressure (CPAP) on the collapsed lung. CPAP was associated with a reduced local inflammatory response in the collapsed lung. Pneumonia is a common postoperative complication after esophagectomy and is often used as a clinical endpoint in literature. Underreporting of pneumonia rates seems to occur due to the use of varying definitions for pneumonia. Multivariate analysis of diagnostic determinants for pneumonia among a large series of esophagectomy patients showed that pulmonary radiography findings, temperature recordings and leukocyte count are most often used. Sputum culture did not affect the decision to treat pneumonia. A simple scoring system was developed that has the potential to aid diagnosis of pneumonia after esophagectomy at the hospital ward. COX-2 and VEGF play an important role in carcinogenesis, tumor progression and angiogenesis. The expression profiles of COX-2 and VEGF were evaluated in esophageal adenocarcinoma using a tissue micro array. Both markers were associated with poor prognosis and COX-2 was an independent prognostic marker for survival. Specific inhibition of the pathways in which COX-2 and/or VEGF are involved may affect treatment outcomes and prognosis. These findings support the use of COX-2 and VEGF inhibitors in future clinical studies. Another important prognostic indicator after esophageal cancer surgery is the circumferential resection margin (CRM). However, there is a lack of consensus regarding the criteria of positive/negative CRM, which has led to the use of different definitions in literature and clinical practice. The prognostic values of two commonly used definitions were analyzed. The results showed significantly reduced survival when tumor cells were found at the circumferential margin of the resected specimen. No influence on survival was noticed when tumor reached within 1 millimeter of the margi