Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium

被引：166

作者：

Bakry, Doua ^{[1
,2
]}

Aronson, Melyssa ^{[3
,4
]}

Durno, Carol ^{[3
,4
,5
]}

Rimawi, Hala ^{[6
]}

Farah, Roula ^{[7
]}

Alharbi, Qasim Kholaif ^{[8
]}

Alharbi, Musa ^{[9
]}

Shamvil, Ashraf ^{[10
]}

Ben-Shachar, Shay ^{[11
]}

Mistry, Matthew ^{[12
]}

Constantini, Shlomi ^{[13
]}

Dvir, Rina ^{[14
]}

Qaddoumi, Ibrahim ^{[15
]}

Gallinger, Steven ^{[3
,4
]}

Lerner-Ellis, Jordan ^{[16
,17
,18
]}

Pollett, Aaron ^{[16
,17
]}

Stephens, Derek ^{[19
,20
]}

Kelies, Steve ^{[21
]}

Chao, Elizabeth ^{[21
]}

Malkin, David ^{[1
,2
]}

Bouffet, Eric ^{[1
,2
,22
]}

Hawkins, Cynthia ^{[2
,23
]}

Tabori, Uri ^{[1
,2
,22
]}

机构：

[1] Univ Toronto, Inst Med Sci, Hosp Sick Children, Div Hematol Oncol, Toronto, ON, Canada

[2] Univ Toronto, Dept Pediat, Toronto, ON, Canada

[3] Zane Cohen Ctr Digest Dis, Familial Gastrointestinal Canc Registry, Toronto, ON, Canada

[4] Mt Sinai Hosp, Dept Surg, Toronto, ON M5G 1X5, Canada

[5] Hosp Sick Children, Div Gastroenterol Nutr & Hepatol, Toronto, ON M5G 1X8, Canada

[6] Jordan Univ Sci & Technol, Fac Med, Irbid, Jordan

[7] St George Hosp Univ, Med Ctr, Beirut, Lebanon

[8] King Fahad Specialist Hosp, Dept Pediat Hematol Oncol & Stem Cell Transplant, Dammam, Saudi Arabia

[9] King Fahad City Ctr, Riyadh, Saudi Arabia

[10] Children Canc Hosp, Karachi, Pakistan

[11] Tel Aviv Med Ctr & Sch Med, Gilbert Israeli Neurofibromatosis Ctr GINFC, Tel Aviv, Israel

[12] Univ Toronto, Inst Med Sci, Genet & Genom Program, Toronto, ON, Canada

[13] Tel Aviv Med Ctr & Sch Med, Dana Childrens Hosp, Dept Pediat Neurosurg, IL-64239 Tel Aviv, Israel

[14] Tel Aviv Med Ctr & Sch Med, Pediat Hematooncol Dept, IL-64239 Tel Aviv, Israel

[15] St Jude Childrens Res Hosp, Memphis, TN 38105 USA

[16] Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON, Canada

[17] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[18] Genome Technol Platform, Ontario Inst Canc Res, Toronto, ON, Canada

[19] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5S 1A1, Canada

[20] Hosp Sick Children, Toronto, ON M5G 1X8, Canada

[21] Ambry Genet, Aliso Viejo, CA USA

[22] Arthur & Sonia Labbatt Brain Tumor Res Ctr, Toronto, ON, Canada

[23] Hosp Sick Children, Dept Pathol, Toronto, ON M5G 1X8, Canada

来源：

EUROPEAN JOURNAL OF CANCER | 2014年 / 50卷 / 05期

关键词：

Constitutional mismatch repair deficiency syndrome; MLH1; MSH2; PMS2; MSH6; Microsatellite instability; CUMULATIVE LIFETIME INCIDENCE; LYNCH-SYNDROME; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; PROVEN MUTATIONS; 121; FAMILIES; NEUROFIBROMATOSIS; IDENTIFICATION; PHENOTYPE;

D O I：

10.1016/j.ejca.2013.12.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. Methods: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. Results: Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p = 0.0007). All children with CMMRD had cafe-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p < 0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. Discussion: CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：987 / 996

页数：10

共 27 条

[1] Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations [J].

Barrow, E. ;

Alduaij, W. ;

Robinson, L. ;

Shenton, A. ;

Clancy, T. ;

Lalloo, F. ;

Hill, J. ;

Evans, D. G. .

CLINICAL GENETICS, 2008, 74 (03) :233-242

[2] Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations [J].

Barrow, E. ;

Robinson, L. ;

Alduaij, W. ;

Shenton, A. ;

Clancy, T. ;

Lalloo, F. ;

Hill, J. ;

Evans, D. G. .

CLINICAL GENETICS, 2009, 75 (02) :141-149

[3] Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis [J].

Chao, EC ;

Lipkin, SM .

NUCLEIC ACIDS RESEARCH, 2006, 34 (03) :840-852

[4] Microsatellite instability [J].

de la Chapelle, A .

NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (03) :209-210

[5]

Dietmaier W, 1997, CANCER RES, V57, P4749

[6] Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow-up of a kindred [J].

Durno, Carol A. ;

Aronson, Melyssa ;

Tabori, Uri ;

Malkin, David ;

Gallinger, Steven ;

Chan, Helen S. L. .

PEDIATRIC BLOOD & CANCER, 2012, 59 (04) :652-656

[7] The Gastrointestinal Phenotype of Germline Biallelic Mismatch Repair Gene Mutations [J].

Durno, Carol A. ;

Holter, Spring ;

Sherman, Philip M. ;

Gallinger, Steven .

AMERICAN JOURNAL OF GASTROENTEROLOGY, 2010, 105 (11) :2449-2456

[8] Constitutive deficiency in DNA mismatch repair [J].

Felton, K. E. A. ;

Gilchrist, D. M. ;

Andrew, S. E. .

CLINICAL GENETICS, 2007, 71 (06) :483-498

[9] Diagnostic approach and management of Lynch syndrome (Hereditary Nonpolyposis Colorectal Carcinoma):: A guide for clinicians [J].

Hendriks, Yvonne M. C. ;

de Jong, Andrea E. ;

Morreau, Hans ;

Tops, Carli M. J. ;

Vasen, Hans F. ;

Wijnen, Juul Th. ;

Breuning, Martijn H. ;

Brocker-Vriends, Annette H. J. T. .

CA-A CANCER JOURNAL FOR CLINICIANS, 2006, 56 (04) :213-225

[10] The multifaceted mismatch-repair system [J].

Jiricny, J .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2006, 7 (05) :335-346

← 1 2 3 →