Loss-of-function variants in ATM confer risk of gastric cancer.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageGastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1

Neoadjuvant Chemoradiotherapy and Surgery for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed: The Study Protocol for the Randomized Controlled NEEDS Trial

Background: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC. Methods: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04460352