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

被引：82

作者：

Bodo, Sahra ^{[1
,2
]}

Colas, Chrystelle ^{[1
,2
,3
]}

Buhard, Olivier ^{[1
,2
]}

Collura, Ada ^{[1
,2
]}

Tinat, Julie ^{[4
]}

Lavoine, Noernie ^{[5
]}

Guilloux, Agathe ^{[1
,2
]}

Chalastanis, Alexandra ^{[1
,2
]}

Lafitte, Philippe ^{[1
,2
]}

Coulet, Florence ^{[2
,3
]}

Buisine, Marie-Pierre ^{[6
,7
,8
]}

Ilencikova, Denisa ^{[9
]}

Ruiz-Ponte, Clara ^{[10
]}

Kinzel, Miriam ^{[11
]}

Grandjouan, Sophie ^{[12
]}

Brems, Hi Ide ^{[13
]}

Lejeune, Sophie ^{[14
]}

Blanche, Helene ^{[15
]}

Wang, Qing ^{[16
]}

Caron, Olivier ^{[17
]}

Cabaret, Odile ^{[18
]}

Syrcek, Maga Li ^{[1
,2
,19
]}

Vidaud, Dominique ^{[20
]}

Parfait, Beatrice ^{[20
]}

Verloes, Alain ^{[21
,22
]}

Knappe, Ulrich J. ^{[23
]}

Soubrier, Florent ^{[24
]}

Mortemousque, Isabelle ^{[25
]}

Leis, Alexander ^{[26
]}

Auclair-Perrossier, Jessie ^{[16
]}

Frebourg, Thierry ^{[4
]}

Flejou, Jean-Francois ^{[1
,2
,19
]}

Entz-Werle, Natacha ^{[27
]}

Leclerc, Julie ^{[6
,7
,8
]}

Malka, David ^{[28
]}

Cohen-Haguenauer, Odile ^{[29
]}

Goldberg, Yael ^{[30
]}

Gerdes, Anne-Marie ^{[31
]}

Fedhila, Faten ^{[32
]}

Mathieu-Dramard, Michele ^{[33
]}

Lin, Richard Hame ^{[1
,2
]}

Wafaa, Badre ^{[34
]}

Gauthier-Villars, Marion ^{[35
]}

Bourdeaut, Franck ^{[36
,37
]}

Sheridan, Eamonn ^{[38
]}

Vasen, Hans ^{[39
]}

Brugieres, Laurence ^{[5
]}

Wimmer, Katharina ^{[40
]}

Muleris, Martine ^{[1
,2
]}

Duva, Alex ^{[1
,2
]}

机构：

[1] Ctr Rech St Antoine, INSERM, Equipe Instabilite Microsatellites & Canc, Equipe Labellisee Ligue Natl Canc,UMR S 938, Paris, France

[2] Univ Paris 06, Paris, France

[3] GH Pitie Salpetriere, AP HP, Lab Oncogenet & Angiogenet, Paris, France

[4] Hop Univ, Dept Genet, Rouen, France

[5] Gustave Roussy Canc Inst, Dept Children & Adolescents Oncol, Villejuif, France

[6] CHRU Lille, Inst Biochim & Biol Mol, Oncol & Genet Mol, F-59037 Lille, France

[7] INSERM, UMR837, F-59045 Lille, France

[8] Univ Lille, Lille, France

[9] Comenius Univ, Childrens Univ Hosp, Dept Pediat 2, Bratislava, Slovakia

[10] Ctr Invest Biomed Red Enfermedades Raras CIBERer, Grp Med Xenom, IDIS, FPGMX SERGAS, Santiago De Compostela, Spain

[11] Praxis Med Genet, Berlin, Germany

[12] CHU Cochin, Fac Rene Descartes Paris 5, Paris, France

[13] Katholieke Univ Leuven, Dept Human Genet, Leuven, Belgium

[14] CHRU Lille, Serv Genet Clin, F-59037 Lille, France

[15] CEPH, Fdn Jean Dausset, Inst Genet Mol, Paris, France

[16] Ctr Leon Berard, Plateforme Genet Constitut HCL CLB, Lab Rech Translat, F-69373 Lyon, France

[17] Gustave Roussy Canc Inst, Dept Med Oncol, Villejuif, France

[18] Inst Gustave Roussy, Dept Biol & Pathol Med, Serv Genet, Villejuif, France

[19] Hop St Antoine, AP HP, Serv Anat & Cytol Pathol, F-75571 Paris, France

[20] Univ Paris 05, INSERM, Fac Sci Pharmaceut & Biol, UMR745, Paris, France

[21] Hop Robert Debre, AP HP, Dept Genet, F-75019 Paris, France

[22] Hop Robert Debre, INSERM, PROTECT, UMR 1141, F-75019 Paris, France

[23] Johannes Westing Klinikum, Dept Neurosurg, Minden, Germany

[24] GH Pitie Salpetriere, AP HP, Dept Genet, Paris, France

[25] CHRU Tours, Serv Genet, Tours, France

[26] French Med Inst Children, Kabul, Afghanistan

[27] UdS EA, CHRU Hautepierre, Pediat Oncohematol Pediat, Strasbourg, France

[28] Gustave Roussy, Dept Canc Med, Villejuif, France

[29] Hop St Louis, Med Oncol Serv, Paris, France

[30] Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel

[31] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, Copenhagen, Denmark

[32] Hop Enfants Tunis, Serv Med Infantile, Tunis, Tunisia

[33] Amiens Univ Hosp, Unit Med Genet, Amiens, France

[34] Hosp Univ Ctr, Ibn Rochd, Dept Hepatogastroenterol, Casablanca, Morocco

[35] Inst Curie, Serv Genet, Paris, France

[36] Inst Curie, Dept Pediat Oncol, Paris, France

[37] Inst Curie, INSERM, U830, Paris, France

[38] Univ Leeds, Dept Mol Med, Leeds, W Yorkshire, England

[39] Leiden Univ, Med Ctr, Dept Gastroenterol & Hepatol, Leiden, Netherlands

[40] Med Univ Innsbruck, Div Human Genet, A-6020 Innsbruck, Austria

来源：

GASTROENTEROLOGY | 2015年 / 149卷 / 04期

关键词：

Colon Cancer; Functional Tests; Predisposition; Tumor; NEUROFIBROMATOSIS TYPE-1; COLORECTAL-CANCER; BIALLELIC MUTATIONS; SOMATIC MUTATIONS; MSH6; MUTATIONS; GOLD STANDARD; PMS2; CELLS; HEREDITARY; SYSTEM;

D O I：

10.1053/j.gastro.2015.06.013

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：1017 / U752

页数：16

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