domingo, 19 de enero de 2020

Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With... - PubMed - NCBI

2020 Jan 8. pii: S0016-5085(20)30014-7. doi: 10.1053/j.gastro.2019.12.032. [Epub ahead of print]

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.

Engel C1, Ahadova A2, Seppälä T3, Aretz S4, Bigirwamungu-Bargeman M5, Bläker H6, Bucksch K7, Büttner R8, de Vos Tot Nederveen Cappel W9, Endris V10, Holinski-Feder E11, Holzapfel S4, Hüneburg R12, Jacobs MAJM13, Koornstra JJ14, Langers AM15, Lepistö A16, Morak M11, Möslein G17, Peltomäki P18, Pylvänäinen K19, Rahner N20, Renkonen-Sinisalo L16, Schulmann K21, Steinke-Lange V11, Stenzinger A10, Strassburg CP12, van de Meeberg PC22, van Kouwen M23, van Leerdam M13, Vangala DB24, Vecht J9, Verhulst ML25, von Knebel Doeberitz M2, Weitz J26, Zachariae S7, Loeffler M7, Mecklin JP27, Kloor M2, Vasen HF15; German HNPCC Consortium, the Dutch Lynch Syndrome Collaborative Group, and the Finnish Lynch Syndrome Registry.

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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 y 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 y (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.