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German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Overview
Motivation:

The aim of the GC-HNPCC is to improve the cinical care of patients with Lynch syndrome in Germany through a network of specialised university centers providing structured interdisciplinary care. Furthermore, GC-HNPCC collects comprehensive data on patients and families in a standardized manner, in order to promote research on Lynch syndrome.

Description:

The German Consortium for Hereditary Non-Polyposis Colorectal Cancer (GC-HNPCC) has been founded in 1999 by the German Cancer Aid and has been funded by the German Cancer Aid until recently. GC-HNPCC currently comprises 6 university centers providing genetic counseling, histopathological and molecular tissue analysis, genetic testing, and specific structured surveillance programs for early cancer detection at each clinical unit, all based on defined standard operating procedures.

Programme: Epidemiology

LHA-ID: 7Q0CEYUJ25-4

Public web page: https://www.imise.uni-leipzig.de/institut/Projekte/Verbundprojekt-Familiaerer-Darmkrebs

Human Diseases: Hereditary breast ovarian cancer syndrome

Leipzig Health Atlas PALs: Christoph Engel

Project Coordinators: No Project coordinators for this Project

Project start date: 1st Jan 1999

Project Hierarchy

Related items

Christoph Engel palproject_administrator

Projects: LIFE Adult, LIFE- Leipzig Research Center for Civilization Diseases, German Consortium for Hereditary Breast and Ovarian Cancer, German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Institutions: Institute for Medical Informatics, Statistics and Epidemiology

https://orcid.org/0000-0002-7247-282X
René Hänsel adminproject_administratorasset_housekeeperasset_gatekeeperprogramme_administrator

Projects: Leipzig Health Atlas, LIFE Adult, LIFE- Leipzig Research Center for Civilization Diseases, LIFE Head and Neck Cancer Group, LIFE Heart, Molecular mechanisms in malignant lymphoma, German Lymphoma Alliance (GLA), Molecular Mechanisms in Malignant Lymphomas - Demonstrators of Personalized Medicine, Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles, German Consortium for Hereditary Breast and Ovarian Cancer, German Consortium for Hereditary Non-Polyposis Colorectal Cancer, MMML-MYC-SYS, Natural Language Processing for Clinical Research, Genetical Statistics and Systems Biology, German Competence Network Sepsis (SepNet), LIFE Child, Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome, Footprints of Sepsis Framed Within Community Acquired Pneumonia in the Blood Transcriptome, ProstataCA

Institutions: Institute for Medical Informatics, Statistics and Epidemiology

https://orcid.org/0000-0001-8344-0658
Silke Zachariae asset_housekeeperasset_gatekeeper

Projects: LIFE Adult, LIFE- Leipzig Research Center for Civilization Diseases, LIFE Heart, German Consortium for Hereditary Breast and Ovarian Cancer, German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Institutions: Institute for Medical Informatics, Statistics and Epidemiology

https://orcid.org/0000-0003-1614-8790
MMRpredict
German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Depending on the calculated mutation probability genetic counsellors can decide whether patients should undergo further analysis of microsatellite instability and immunohistochemistry. The model is recommended for patients with an age at colorectal cancer diagnosis of 55 or younger.

"MMRpredict" is a risk prediction model for patients with colorectal cancer (Barnetson et al. 2006). It calculates the risk of having a mutation in the mismatch repair genes MLH1, MSH2 and MSH6 (overall probability)
...

Creators: Silke Zachariae, Christoph Engel

Contributor: Silke Zachariae

PREMM1,2,6
German Consortium for Hereditary Non-Polyposis Colorectal Cancer

The PREMM1,2,6 has been developed as a pretest to decide whether patients suspected of having Lynch syndrome should be tested for germline mismatch repair gene mutations.
"PREMM1,2,6" is a logistic regression model. It calculates the risk of having a mutation in the mismatch repair genes MLH1, MSH2 and MSH6 (for single genes and overall) based on the personal and familial cancer history of the proband (colorectal, endometrial, and other Lynch syndrome related cancers).

Creators: Christoph Engel, Silke Zachariae, Kastrinos et al.

Contributor: Silke Zachariae

PREMM5
German Consortium for Hereditary Non-Polyposis Colorectal Cancer

The PREMM5 has been developed as a pretest to decide whether patients suspected of having Lynch syndrome should be tested for germline mismatch repair gene mutations. In contrast to "PREMM1,2,6" it can be used to predict mutation probabilities in unaffected index patients.
"PREMM5" is a logistic regression model. It calculates the risk of having a mutation in the mismatch repair genes MLH1, MSH2/EPCAM, MSH6 and PMS2 (for single genes and overall) based on the personal and familial cancer history
...

Creators: Christoph Engel, Silke Zachariae, Kastrinos et al.

Contributor: Silke Zachariae

Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer.
German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Abstract (Expand)

OBJECTIVE: Microsatellite instability (MSI) is detected in approximately 15% of all colorectal cancers (CRC) and virtually in all cases with Lynch syndrome. The MSI phenotype is caused by dysfunctional … mismatch repair (MMR) and leads to accumulation of DNA replication errors. Sporadic MSI CRC often harbours BRAF(V600E); however, no consistent data exist regarding targeted treatment approaches in BRAF(wt) MSI CRC. DESIGN: Mutations and quantitative MSI were analysed by deep sequencing in 196 formalin fixed paraffin embedded (FFPE) specimens comprising Lynch and Lynch-like CRCs from the German Hereditary Nonpolyposis Colorectal Cancer registry. Functional relevance of recurrent ERBB2/HER2 mutations was investigated in CRC cell lines using reversible and irreversible HER-targeting inhibitors, EGFR-directed antibody cetuximab, HER2-directed antibody trastuzumab and siRNA-mediated ERBB2/HER2 knockdown. RESULTS: Quantification of nucleotide loss in non-coding mononucleotide repeats distinguished microsatellite status with very high accuracy (area under curve=0.9998) and demonstrated progressive losses with deeper invasion of MMR-deficient colorectal neoplasms (p=0.008). Characterisation of BRAF(wt) MSI CRC revealed hot-spot mutations in well-known oncogenic drivers, including KRAS (38.7%), PIK3CA (36.5%), and ERBB2 (15.0%). L755S and V842I substitutions in ERBB2 were highly recurrent. Functional analyses in ERBB2-mutated MSI CRC cell lines revealed a differential response to HER-targeting compounds and superiority of irreversible pan-HER inhibitors. CONCLUSIONS: We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC.

Authors: M. Kloth, V. Ruesseler, Christoph Engel, K. Koenig, M. Peifer, E. Mariotti, H. Kuenstlinger, A. Florin, U. Rommerscheidt-Fuss, U. Koitzsch, C. Wodtke, F. Ueckeroth, S. Holzapfel, S. Aretz, P. Propping, Markus Löffler, S. Merkelbach-Bruse, M. Odenthal, N. Friedrichs, L. C. Heukamp, T. Zander, R. Buettner

Date Published: 24th May 2015

Journal: Gut

Human Diseases: colorectal cancer

Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: a comprehensive analysis of 3,671 families.
German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Abstract (Expand)

Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for colorectal and endometrial cancers, as well as other malignancies. As mutation analysis to detect these patients is expensive … and time-consuming, clinical criteria and tumor-tissue analysis are widely used as pre-screening methods. The aim of our study was to evaluate the performance of commonly applied clinical criteria (the Amsterdam I and II Criteria, and the original and revised Bethesda Guidelines) and the results of tumor-tissue analysis in predicting MMR gene mutations. We analyzed 3,671 families from the German HNPCC Registry and divided them into nine mutually exclusive groups with different clinical criteria. A total of 680 families (18.5%) were found to have a pathogenic MMR gene mutation. Among all 1,284 families with microsatellite instability-high (MSI-H) colorectal cancer, the overall mutation detection rate was 53.0%. Mutation frequencies and their distribution between the four MMR genes differed significantly between clinical groups (p < 0.001). The highest frequencies were found in families fulfilling the Amsterdam Criteria (46.4%). Families with loss of MSH2 expression had higher mutation detection rates (69.5%) than families with loss of MLH1 expression (43.1%). MMR mutations were found significantly more often in families with at least one MSI-H small-bowel cancer (p < 0.001). No MMR mutations were found among patients under 40-years-old with only colorectal adenoma. Familial clustering of Lynch syndrome-related tumors, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome.

Authors: V. Steinke, S. Holzapfel, Markus Löffler, E. Holinski-Feder, M. Morak, H. K. Schackert, H. Gorgens, C. Pox, B. Royer-Pokora, M. von Knebel-Doeberitz, R. Buttner, P. Propping, Christoph Engel

Date Published: 1st Jul 2014

Journal: Int J Cancer

Human Diseases: colon cancer

Risks of less common cancers in proven mutation carriers with lynch syndrome.
German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Abstract (Expand)

PURPOSE: Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was … to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. PATIENTS AND METHODS: Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. RESULTS: The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. CONCLUSION: The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.

Authors: Christoph Engel, Markus Löffler, V. Steinke, N. Rahner, E. Holinski-Feder, W. Dietmaier, H. K. Schackert, H. Goergens, M. von Knebel Doeberitz, T. O. Goecke, W. Schmiegel, R. Buettner, G. Moeslein, T. G. Letteboer, E. Gomez Garcia, F. J. Hes, N. Hoogerbrugge, F. H. Menko, T. A. van Os, R. H. Sijmons, A. Wagner, I. Kluijt, P. Propping, H. F. Vasen

Date Published: 10th Dec 2012

Journal: J Clin Oncol

Human Diseases: colon cancer

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