[Morphomolecular characterization of colorectal neoplasms]. / Morphomolekulare Charakterisierung kolorektaler Neoplasien.

BACKGROUND: Besides the classical histopathological examination, molecular characterization approaches are moving more and more into the center of clinical pathology. The association of tumors with distinct morphological features with specific molecular alterations can either help to underline a certain histologic diagnosis or to identify alterations that may serve as potential molecular targets. OBJECTIVES: The aim of the presented studies was the morphomolecular characterization of colorectal neoplasias with either a distinct morphology or in specific clinical settings. MATERIALS AND METHODS: Targeted massive parallel sequencing (MPS) of various colorectal neoplasias was performed in all of the presented studies. RESULTS: Our studies showed the clinical utility of MPS for routine molecular diagnostics of colorectal carcinoma (CRC) in different clinical settings. In addition, we were able to demonstrate a close genetic relationship of colorectal adenoneuroendocrine carcinomas with classical CRC as well as a distinct genetic profile for appendiceal goblet cell neoplasias. CONCLUSIONS: Morphomolecular characterization approaches not only enable the identification of potentially therapeutically relevant alterations, but also allow for the specific identification of morphologically distinct subtypes of colorectal neoplasias, which may be of diagnostic usefulness.

A novel pretherapeutic gene expression-based risk score for treatment guidance in gastric cancer.

Background: Perioperative chemotherapy is an established treatment of advanced gastric cancer patients. Treatment selection is based on clinical staging (cT). We aimed to establish and validate a prognostic score including clinical and molecular factors, to optimize treatment decisions for these patients. Patients and methods: We analyzed 626 carcinomas of the stomach and of the gastro-esophageal junction from two academic centers including primarily resected and pre-/perioperatively treated patients. Patients were divided into a training (N = 269) and validation (N = 357) set. Expression of 11 target genes was measured by quantitative PCR in resected tumors. A risk score to predict overall survival (OS) was generated and validated. Intra-tumoral heterogeneity was assessed by analyzing 50 tumor areas from 10 patients. Results: A risk score including the expression of CCL5, CTNNB1, EXOSC3 and LZTR1 and the clinical parameters cT, tumor localization and histopathologic type suggested two groups with a significant difference in OS [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.17-0.52]. The risk score was successfully validated in an independent cohort (HR 0.32; 95% CI 0.21-0.51; P < 0.001) as well as in subgroups of primarily resected (HR 0.30; 95% CI 0.17-0.54; P < 0.001) and pre-/perioperatively treated patients (HR 0.37; 95% CI 0.17-0.81; P = 0.009). A significant difference in OS of high- and low-risk patients was also found in primarily resected patients with intestinal (HR 0.45; 95% CI 0.23-0.90; P = 0.020) and nonintestinal-type carcinomas (HR 0.1; 95% CI 0.02-0.42; P < 0.001). Intra-tumor heterogeneity analysis indicated a classification reliability of 95% for a supposed analysis of three biopsies. Conclusion: The identified risk score could substantially contribute to an improved management of gastric cancer patients in the context of perioperative chemotherapy.