Disentangling oncogenic amplicons in esophageal adenocarcinoma.

Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons' origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.

Does interpregnancy BMI change affect the risk of complications in the second pregnancy? Analysis of pooled data from Aberdeen, Finland and Malta.

OBJECTIVE: Weight management interventions during pregnancy have had limited success in reducing the risk of pregnancy complications. Focus has now shifted to pre-pregnancy counselling to optimise body weight before subsequent conception. We aimed to assess the effect of interpregnancy body mass index (BMI) change on the risk of perinatal complications in the second pregnancy. METHODS: A cohort study was performed using pooled maternity data from Aberdeen, Finland and Malta. Women with a BMI change of ±2 kg/m2 between their first and second pregnancies were compared with those who were BMI stable (remained within ±2 kg/m2). Outcomes assessed included pre-eclampsia (PE), intrauterine growth restriction (IUGR), preterm birth, birth weight, and stillbirth in the second pregnancy. We also assessed the effect of unit change in BMI for PE and IUGR. Logistic regression was used to calculate odds ratios with 95% confidence intervals. RESULTS: An increase of ≥2 kg/m2 between the first two pregnancies increased the risk of PE (1.66 (1.49-1.86)) and high birthweight (>4000 g) (1.06 (1.03-1.10)). A reduction of ≥2 kg/m2 increased the chance of IUGR (1.15 (1.01-1.31)) and preterm birth (1.14 (1.01-1.30)), while reducing the risk of instrumental delivery (0.75 (0.68-0.85)) and high birthweight (0.93 (0.87-0.98)). Reducing BMI did not significantly decrease PE risk in women with obesity or those with previous PE. A history of PE or IUGR in the first pregnancy was the strongest predictor of recurrence independent of interpregnancy BMI change (5.75 (5.30-6.24) and (7.44 (6.71-8.25), respectively). CONCLUSION: Changes in interpregnancy BMI have a modest impact on the risk of high birthweight, PE and IUGR in contrasting directions. However, a prior history of PE and IUGR is the dominant predictor of recurrence at second pregnancy.