Universität zu Köln

Engel, Christoph ORCID: 0000-0002-7247-282X, Ahadova, Aysel, Seppala, Toni T. ORCID: 0000-0002-4940-3498, Aretz, Stefan ORCID: 0000-0002-5228-1890, Bigirwamungu-Bargeman, Marloes, Blaeker, Hendrik, Bucksch, Karolin, Buettner, Reinhard, Cappel, Wouter T. De Vos Tot Nederveen, Endris, Volker, Holinski-Feder, Elke, Holzapfel, Stefanie, Hueneburg, Robert, Jacobs, Maarten A. J. M., Koornstra, Jan J., Langers, Alexandra M., Lepisto, Anna, Morak, Monika, Moeslein, Gabriela, Peltomaeki, Paivi, Pylvaenaeinen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Schulmann, Karsten, Steinke-Lange, Verena, Stenzinger, Albrecht, Strassburg, Christian P., van de Meeberg, Paul C., van Kouwen, Mariette, van Leerdam, Monique ORCID: 0000-0002-5719-3208, Vangala, Deepak B., Vecht, Juda, Verhulst, Marie-Louise, Doeberitz, Magnus von Knebel, Weitz, Juergen, Zachariae, Silke, Loeffler, Markus, Mecklin, Jukka-Pekka ORCID: 0000-0003-4895-2249, Kloor, Matthias and Vasen, Hans F. (2020). Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome. Gastroenterology, 158 (5). S. 1326 - 1334. PHILADELPHIA: W B SAUNDERS CO-ELSEVIER INC. ISSN 1528-0012

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Abstract

BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Engel, Christoph UNSPECIFIED orcid.org/0000-0002-7247-282X UNSPECIFIED Ahadova, Aysel UNSPECIFIED UNSPECIFIED UNSPECIFIED Seppala, Toni T. UNSPECIFIED orcid.org/0000-0002-4940-3498 UNSPECIFIED Aretz, Stefan UNSPECIFIED orcid.org/0000-0002-5228-1890 UNSPECIFIED Bigirwamungu-Bargeman, Marloes UNSPECIFIED UNSPECIFIED UNSPECIFIED Blaeker, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Bucksch, Karolin UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Cappel, Wouter T. De Vos Tot Nederveen UNSPECIFIED UNSPECIFIED UNSPECIFIED Endris, Volker UNSPECIFIED UNSPECIFIED UNSPECIFIED Holinski-Feder, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzapfel, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Hueneburg, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Jacobs, Maarten A. J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koornstra, Jan J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Langers, Alexandra M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lepisto, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Morak, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Moeslein, Gabriela UNSPECIFIED UNSPECIFIED UNSPECIFIED Peltomaeki, Paivi UNSPECIFIED UNSPECIFIED UNSPECIFIED Pylvaenaeinen, Kirsi UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahner, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Renkonen-Sinisalo, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulmann, Karsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinke-Lange, Verena UNSPECIFIED UNSPECIFIED UNSPECIFIED Stenzinger, Albrecht UNSPECIFIED UNSPECIFIED UNSPECIFIED Strassburg, Christian P. UNSPECIFIED UNSPECIFIED UNSPECIFIED van de Meeberg, Paul C. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Kouwen, Mariette UNSPECIFIED UNSPECIFIED UNSPECIFIED van Leerdam, Monique UNSPECIFIED orcid.org/0000-0002-5719-3208 UNSPECIFIED Vangala, Deepak B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vecht, Juda UNSPECIFIED UNSPECIFIED UNSPECIFIED Verhulst, Marie-Louise UNSPECIFIED UNSPECIFIED UNSPECIFIED Doeberitz, Magnus von Knebel UNSPECIFIED UNSPECIFIED UNSPECIFIED Weitz, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Zachariae, Silke UNSPECIFIED UNSPECIFIED UNSPECIFIED Loeffler, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Mecklin, Jukka-Pekka UNSPECIFIED orcid.org/0000-0003-4895-2249 UNSPECIFIED Kloor, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Vasen, Hans F. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-339585
DOI:	10.1053/j.gastro.2019.12.032
Journal or Publication Title:	Gastroenterology
Volume:	158
Number:	5
Page Range:	S. 1326 - 1334
Date:	2020
Publisher:	W B SAUNDERS CO-ELSEVIER INC
Place of Publication:	PHILADELPHIA
ISSN:	1528-0012
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CANCER; HEREDITARY; INSTABILITY; GUIDELINES; MANAGEMENT; DEFICIENCY; SOCIETY Multiple languages Gastroenterology & Hepatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33958