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

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 J 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”

doi:10.1053/j.gastro.2015.06.013

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

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 CaronOdile Cabaret, Magali Svrcek, Dominique Vidaud, Béatrice Parfait, Alain Verloes, Ulrich J 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”

Institut for Klinisk Medicin

57 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Gastroenterology
Vol/bind	149
Udgave nummer	4
Sider (fra-til)	1017-29.e3
Antal sider	16
ISSN	0016-5085
DOI	https://doi.org/10.1053/j.gastro.2015.06.013
Status	Udgivet - 1 okt. 2015

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10.1053/j.gastro.2015.06.013

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Bodo, S., Colas, C., Buhard, O., Collura, A., Tinat, J., Lavoine, N., Guilloux, A., Chalastanis, A., Lafitte, P., Coulet, F., Buisine, M.-P., Ilencikova, D., Ruiz-Ponte, C., Kinzel, M., Grandjouan, S., Brems, H., Lejeune, S., Blanché, H., Wang, Q., ... European Consortium “Care for CMMRD” (2015). Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. Gastroenterology, 149(4), 1017-29.e3. https://doi.org/10.1053/j.gastro.2015.06.013

Bodo, S, Colas, C, Buhard, O, Collura, A, Tinat, J, Lavoine, N, Guilloux, A, Chalastanis, A, Lafitte, P, Coulet, F, Buisine, M-P, Ilencikova, D, Ruiz-Ponte, C, Kinzel, M, Grandjouan, S, Brems, H, Lejeune, S, Blanché, H, Wang, Q, Caron, O, Cabaret, O, Svrcek, M, Vidaud, D, Parfait, B, Verloes, A, Knappe, UJ, Soubrier, F, Mortemousque, I, Leis, A, Auclair-Perrossier, J, Frébourg, T, Fléjou, J-F, Entz-Werle, N, Leclerc, J, Malka, D, Cohen-Haguenauer, O, Goldberg, Y, Gerdes, A-M, Fedhila, F, Mathieu-Dramard, M, Hamelin, R, Wafaa, B, Gauthier-Villars, M, Bourdeaut, F, Sheridan, E, Vasen, H, Brugières, L, Wimmer, K, Muleris, M, Duval, A & European Consortium “Care for CMMRD” 2015, 'Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents', Gastroenterology, bind 149, nr. 4, s. 1017-29.e3. https://doi.org/10.1053/j.gastro.2015.06.013

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

abstract = "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.",

keywords = "Adaptor Proteins, Signal Transducing, Adenosine Triphosphatases, Adult, Antineoplastic Agents, Alkylating, Biomarkers, Tumor, Brain Neoplasms, Caco-2 Cells, Case-Control Studies, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, DNA Mutational Analysis, DNA Repair Enzymes, DNA-Binding Proteins, Drug Resistance, Neoplasm, Female, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, HCT116 Cells, Heredity, Humans, Lymphocytes, Male, Methylation, Microsatellite Instability, Multiplex Polymerase Chain Reaction, MutS Homolog 2 Protein, Neoplastic Syndromes, Hereditary, Nuclear Proteins, Phenotype, Predictive Value of Tests, Reproducibility of Results, Transfection, Young Adult",

author = "Sahra Bodo and Chrystelle Colas and Olivier Buhard and Ada Collura and Julie Tinat and No{\'e}mie Lavoine and Agathe Guilloux and Alexandra Chalastanis and Philippe Lafitte and Florence Coulet and Marie-Pierre Buisine and Denisa Ilencikova and Clara Ruiz-Ponte and Miriam Kinzel and Sophie Grandjouan and Hilde Brems and Sophie Lejeune and H{\'e}l{\`e}ne Blanch{\'e} and Qing Wang and Olivier Caron and Odile Cabaret and Magali Svrcek and Dominique Vidaud and B{\'e}atrice Parfait and Alain Verloes and Knappe, {Ulrich J} and Florent Soubrier and Isabelle Mortemousque and Alexander Leis and Jessie Auclair-Perrossier and Thierry Fr{\'e}bourg and Jean-Fran{\c c}ois Fl{\'e}jou and Natacha Entz-Werle and Julie Leclerc and David Malka and Odile Cohen-Haguenauer and Yael Goldberg and Anne-Marie Gerdes and Faten Fedhila and Mich{\`e}le Mathieu-Dramard and Richard Hamelin and Badre Wafaa and Marion Gauthier-Villars and Franck Bourdeaut and Eamonn Sheridan and Hans Vasen and Laurence Brugi{\`e}res and Katharina Wimmer and Martine Muleris and Alex Duval and {European Consortium “Care for CMMRD”}",

year = "2015",

month = oct,

day = "1",

doi = "10.1053/j.gastro.2015.06.013",

language = "English",

volume = "149",

pages = "1017--29.e3",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "Elsevier",

number = "4",

}

TY - JOUR

T1 - Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents

AU - Bodo, Sahra

AU - Colas, Chrystelle

AU - Buhard, Olivier

AU - Collura, Ada

AU - Tinat, Julie

AU - Lavoine, Noémie

AU - Guilloux, Agathe

AU - Chalastanis, Alexandra

AU - Lafitte, Philippe

AU - Coulet, Florence

AU - Buisine, Marie-Pierre

AU - Ilencikova, Denisa

AU - Ruiz-Ponte, Clara

AU - Kinzel, Miriam

AU - Grandjouan, Sophie

AU - Brems, Hilde

AU - Lejeune, Sophie

AU - Blanché, Hélène

AU - Wang, Qing

AU - Caron, Olivier

AU - Cabaret, Odile

AU - Svrcek, Magali

AU - Vidaud, Dominique

AU - Parfait, Béatrice

AU - Verloes, Alain

AU - Knappe, Ulrich J

AU - Soubrier, Florent

AU - Mortemousque, Isabelle

AU - Leis, Alexander

AU - Auclair-Perrossier, Jessie

AU - Frébourg, Thierry

AU - Fléjou, Jean-François

AU - Entz-Werle, Natacha

AU - Leclerc, Julie

AU - Malka, David

AU - Cohen-Haguenauer, Odile

AU - Goldberg, Yael

AU - Gerdes, Anne-Marie

AU - Fedhila, Faten

AU - Mathieu-Dramard, Michèle

AU - Hamelin, Richard

AU - Wafaa, Badre

AU - Gauthier-Villars, Marion

AU - Bourdeaut, Franck

AU - Sheridan, Eamonn

AU - Vasen, Hans

AU - Brugières, Laurence

AU - Wimmer, Katharina

AU - Muleris, Martine

AU - Duval, Alex

AU - European Consortium “Care for CMMRD”

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Adenosine Triphosphatases

KW - Adult

KW - Antineoplastic Agents, Alkylating

KW - Biomarkers, Tumor

KW - Brain Neoplasms

KW - Caco-2 Cells

KW - Case-Control Studies

KW - Colorectal Neoplasms

KW - Colorectal Neoplasms, Hereditary Nonpolyposis

KW - DNA Mutational Analysis

KW - DNA Repair Enzymes

KW - DNA-Binding Proteins

KW - Drug Resistance, Neoplasm

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Testing

KW - Germ-Line Mutation

KW - HCT116 Cells

KW - Heredity

KW - Humans

KW - Lymphocytes

KW - Male

KW - Methylation

KW - Microsatellite Instability

KW - Multiplex Polymerase Chain Reaction

KW - MutS Homolog 2 Protein

KW - Neoplastic Syndromes, Hereditary

KW - Nuclear Proteins

KW - Phenotype

KW - Predictive Value of Tests

KW - Reproducibility of Results

KW - Transfection

KW - Young Adult

U2 - 10.1053/j.gastro.2015.06.013

DO - 10.1053/j.gastro.2015.06.013

M3 - Journal article

C2 - 26116798

SN - 0016-5085

VL - 149

SP - 1017-29.e3

JO - Gastroenterology

JF - Gastroenterology

IS - 4

ER -

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

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