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Region Hovedstaden - en del af Københavns Universitetshospital

Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents

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  • Sahra Bodo
  • Chrystelle Colas
  • Olivier Buhard
  • Ada Collura
  • Julie Tinat
  • Noémie Lavoine
  • Agathe Guilloux
  • Alexandra Chalastanis
  • Philippe Lafitte
  • Florence Coulet
  • Marie-Pierre Buisine
  • Denisa Ilencikova
  • Clara Ruiz-Ponte
  • Miriam Kinzel
  • Sophie Grandjouan
  • Hilde Brems
  • Sophie Lejeune
  • Hélène Blanché
  • Qing Wang
  • Olivier Caron
  • Odile Cabaret
  • Magali Svrcek
  • Dominique Vidaud
  • Béatrice Parfait
  • Alain Verloes
  • Ulrich Knappe
  • Florent Soubrier
  • Isabelle Mortemousque
  • Alexander Leis
  • Jessie Auclair-Perrossier
  • Thierry Frébourg
  • Jean-François Fléjou
  • Natacha Entz-Werle
  • Julie Leclerc
  • David Malka
  • Odile Cohen-Haguenauer
  • Yael Goldberg
  • Anne-Marie Gerdes
  • Faten Fedhila
  • Michèle Mathieu-Dramard
  • Richard Hamelin
  • Badre Wafaa
  • Marion Gauthier-Villars
  • Franck Bourdeaut
  • Eamonn Sheridan
  • Hans Vasen
  • Laurence Brugières
  • Katharina Wimmer
  • Martine Muleris
  • Alex Duval
  • European Consortium “Care for CMMRD”
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BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD.

METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD.

RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features.

CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.

Udgave nummer4
Sider (fra-til)1017-1029.e3
StatusUdgivet - okt. 2015

ID: 45842923