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Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709

A large patient cohort of 759 gastric carcinomas was categorized in four molecular subtypes based on The Cancer Genome Atlas (TCGA) classification and the prognostic and predictive implications of these subgroups were analyzed in the context of preoperative chemotherapy. Novel modified molecular subgroups with high prognostic and therapeutic impact were identified by microsatellite based multiplex PCR assays. Mutation profiling using massive parallel sequencing detected one distinct subgroup with frequent mutations in TP53 and in the PI3K/AKT signaling pathway., Eine umfangreiche Patientenkohorte mit 759 Magenkarzinomen wurde in vier molekulare Subgruppen basierend auf der Cancer Genome Atlas (TCGA) Klassifikation eingeteilt und die prognostische und prädiktive Relevanz dieser Subgruppen wurde im Kontext einer präoperativen Chemotherapie untersucht. Neue modifizierte Subtypen, die eine ausgeprägte prognostische und therapeutische Signifikanz zeigten, wurden mit einer Mikrosatelliten basierten multiplex-PCR identifiziert. Mit massiver paralleler Gensequenzierung konnte zusätzlich eine eindeutige Subgruppe mit häufigen Mutationen in TP53 und der PI3K/AKT Signalkette identifiziert werden.

Das Ziel der Arbeit war die Bestimmung der prädiktiven, prognostischen und klinisch-pathologischen Relevanz der molekularen ACRG-Klassifikation sowie einer modifizierten Variante im Kontext präoperativer Chemotherapie. Die Subgruppen wurden an 699 Magenkarzinomen mit und ohne neoadjuvante Chemotherapie auf mRNA- und Proteinebene evaluiert. Es konnte eine prognostische Relevanz der Subgruppen und deren Assoziation mit bestimmten klinisch-pathologischen Charakteristika gezeigt werden., The aim of the study was the determination of the predictive, prognostic and clinico-pathological relevance of the molecular ACRG classification and of a modified variant in the context of preoperative chemotherapy. The subgroups were analyzed on mRNA and protein level in 699 gastric adenocarcinomas with and without chemotherapy. A prognostic relevance of the subgroups and an association with distinct clinico-pathological subtypes was found.

Tumour budding (TB) has been associated with adverse clinicopathological factors and poor survival in a plethora of therapy-naive carcinoma entities including gastric adenocarcinoma (GC). As conventional histopathological grading is usually omitted in the post-neoadjuvant setting of GC, our study aimed to investigate the prognostic impact of TB in GCs resected after neoadjuvant therapy. We evaluated TB according to the criteria from the International Tumour Budding Consensus Conference (ITBCC) in 167 post-neoadjuvant resections of intestinaltype GC and correlated the results with overall survival (OS) and clinicopathological parameters. GCs were categorised into Bd1 (0-4 buds, low TB), Bd2 (5-9 buds, intermediate TB), and Bd3 (>= 10 buds, high TB). Carcinomas with intermediate and high TB were significantly enriched in higher ypTNM stages and strongly associated with reduced 5-year OS in univariable analyses (p < 0.001). In multivariable analyses including sex, age, resection status, UICC stage, and tumour regression grading, TB remained a stage-independent predictor of survival (p < 0.001, hazard ratio Bd2: 2.60, Bd3: 4.74). The assessment of TB according to the ITBCC criteria provides valuable prognostic information in the post-neoadjuvant setting of intestinal-type GC and may be a considerable substitute for the conventional grading system in GCs after neoadjuvant therapy.

We investigated the clinical impact of elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in the context of neoadjuvant chemotherapy (CTx) in gastric/gastro-oesophageal adenocarcinomas. We analysed 583 resected tumours (272 without and 311 after CTx) and 142 tumour biopsies before CTx. If at least two or three of the five tetranucleotide repeat markers tested showed instability, the tumours were defined as EMAST (2+) or EMAST (3+), respectively. Expression of mismatch repair proteins including MSH3 was analysed using immunohistochemistry. Microsatellite instability (MSI) and Epstein-Barr virus (EBV) positivity were determined using standard assays. EMAST (2+) and (3+) were detected in 17.8 and 11.5% of the tumours, respectively. The frequency of EMAST (2+) or (3+) in MSI-high (MSI-H) tumours was 96.2 or 92.5%, respectively, demonstrating a high overlap with this molecular subtype, and the association of EMAST and MSI status was significant (each overall p < 0.001). EMAST (2+ or 3+) alone in MSI-H and EBV-negative tumours demonstrated only a statistically significant association of EMAST (2+) positivity and negative lymph node status (42.3% in EMAST (2+) and 28.8% in EMAST negative, p = 0.045). EMAST alone by neither definition was significantly associated with overall survival (OS) of the patients. The median OS for EMAST (2+) patients was 40.0 months (95% confidence interval [CI] 16.4-63.6) compared with 38.7 months (95% CI 26.3-51.1) for the EMAST-negative group (p = 0.880). The median OS for EMAST (3+) patients was 46.7 months (95% CI 18.2-75.2) and 38.7 months (95% CI 26.2-51.2) for the negative group (p = 0.879). No statistically significant association with response to neoadjuvant CTx was observed (p = 0.992 and p = 0.433 for EMAST (2+) and (3+), respectively). In conclusion, our results demonstrate a nearly complete intersection between MSI-H and EMAST and they indicate that EMAST alone is not a distinct instability type associate

In der vorliegenden Arbeit wurde die Rolle einer Splicevariante des KAI1 im Ovarialkarzinom untersucht. KAI1 spielt eine wichtige Rolle bei der Zellmigration und wird den Tumorsuppressorgenen zugeordnet. In der Arbeit konnte die Splicevariante KAI1 Δex7 auch im Ovarialkarzinom nachgewiesen werden. Die Korrelation mit den Überlebenszeiten der Patientinnen lässt darauf schließen, dass durch die Verminderung der KAI1 Wildtyp Expression die Funktion als Metastasierungssuppressorgen verloren geht und so die Tumorzellen in ihrer Migration nicht gehemmt werden. So zeigte sich bei den Patientinnen mit einer hohen Expression der Splicevariante ein Nachteil in Bezug auf das Überleben nach Diagnosestellung., This dissertation analyses the role of a splice variant of KAI1 in ovarian cancer. KAI1 plays an important role during cell migration and is allocated to the tumor suppressor gene. The dissertation shows that splice variant KAI1 Δex7 was also proven to be present in ovarian cancer. We can conclude from the correlation of KAI1 Δex7 expression level with the survival times of the patients, that by decreasing the KAI1 wildtype expression, it loses its function as metastasis suppressor gene and therefore tumor cells are no more inhibited to migrate. Thus, patients with a high expression of the splice variant died sooner.

Simple summary: Intraductal tubulopapillary neoplasms (ITPN) have recently been described as rare precursor lesions of pancreatic ductal adenocarcinoma and cholangiocarcinoma. Despite a high number of associated invasive adenocarcinomas at the time of diagnosis, patients with ITPN tend to have a much better clinical outcome than those with classical pancreato-biliary adenocarcinoma. Furthermore, rare molecular studies of ITPN show an unexpected lack of hotspot mutations in common driver genes of pancreato-biliary adenocarcinoma, including KRAS. This article reports the first large comprehensive and comparative molecular study of pancreato-biliary ITPN. In the absence of KRAS mutations, we found a high genetic heterogeneity with enrichment in core signaling pathways, including putative actionable genomic targets in one-third of the cases. Whereas, pancreatic ITPN demonstrates a highly distinct genetic profile, differing from classical pancreatic carcinogenesis, biliary ITPN and classical cholangiocarcinoma share common alterations in key genes of the chromatin remodeling pathway, and therefore, appear more closely related than pancreatic ITPN and classical pancreatic ductal adenocarcinoma PDAC. The molecular carcinogenesis of intraductal tubulopapillary neoplasms (ITPN), recently described as rare neoplasms in the pancreato-biliary tract with a favorable prognosis despite a high incidence of associated pancreato-biliary adenocarcinoma, is still poorly understood. To identify driver genes, chromosomal gains and losses, mutational signatures, key signaling pathways, and potential therapeutic targets, the molecular profile of 11 biliary and 6 pancreatic ITPNs, associated with invasive adenocarcinoma in 14/17 cases, are studied by whole exome sequencing (WES). The WES of 17 ITPNs reveals common copy number variants (CNVs) broadly distributed across the genome, with recurrent chromosomal deletions primarily in 1p36 and 9p21 affecting the tumor suppressors CHD5 and CDKN2A

Background Response to immunotherapy in gastric cancer is associated with microsatellite instability (or mismatch repair deficiency) and Epstein-Barr virus (EBV) positivity. We therefore aimed to develop and validate deep learning based classifiers to detect microsatellite instability and EBV status from routine histology slides. Methods In this retrospective, multicentre study, we collected tissue samples from ten cohorts of patients with gastric cancer from seven countries (South Korea, Switzerland, Japan, Italy, Germany, the UK and the USA). We trained a deep learning-based classifier to detect microsatellite instability and EBV positivity from digitised, haematoxylin and eosin stained resection slides without annotating tumour containing regions. The performance of the classifier was assessed by within-cohort cross-validation in all ten cohorts and by external validation, for which we split the cohorts into a five-cohort training dataset and a five-cohort test dataset. We measured the area under the receiver operating curve (AUROC) for detection of microsatellite instability and EBV status. Microsatellite instability and EBV status were determined to be detectable if the lower bound of the 95% CI for the AUROC was above 0middot5. Findings Across the ten cohorts, our analysis included 2823 patients with known microsatellite instability status and 2685 patients with known EBV status. In the within-cohort cross-validation, the deep learning-based classifier could detect microsatellite instability status in nine of ten cohorts, with AUROCs ranging from 0middot597 (95% CI 0middot522-0middot737) to 0middot836 (0middot795-0middot880) and EBV status in five of eight cohorts, with AUROCs ranging from 0middot819 (0middot752-0middot841) to 0middot897 (0middot513-0middot966). Training a classifier on the pooled training dataset and testing it on the five remaining cohorts resulted in high classification performance with AUROCs ranging from 0middot723 (95% CI 0middot676-0mid