JCT  Vol.4 No.5 , July 2013
Constitutional Mismatch Repair-Deficiency Syndrome Is a Rare Cause of Cancer Even in a Highly Consanguineous Population
ABSTRACT

Biallelic germline mutations in the mismatch repair genes, including MLH1, MSH2, MSH6 or PMS2, lead to a recessive constitutional mismatch repair-deficiency (CMMR-D) syndrome characterized by early onset malignancies in children and young adults. Because consanguinity unmasks autosomal recessive disorders, we hypothesized that the frequency of CMMR-D is inflated in the highly consanguineous population of Saudi Arabia. In this study, 371 pediatric and young adult patient samples from Saudi Arabia that cover the tumor spectrum of CMMR-D syndrome were analyzed for biallelic germline mutations in the MLH1, MSH2, MSH6 and PMS2 with the use of direct genomic sequencing. However, none of the 371 patients involved in the study was found to have biallelic pathological mutations of MLH1, MSH2, MSH6 or PMS2. This result indicates that CMMR-D is exceptionally rare among pediatric cancer patients and adult early onset cancer patients, even in the highly consanguineous Saudi population. Our findings suggest that larger cohorts will be needed, particularly in outbred populations, to determine the frequency of CMMR-D and that routine screening for this syndrome among cancer patients is not warranted.


Cite this paper
R. Bu, A. Siraj, P. Bavi, A. Belgaumi, S. Uddin and F. Alkuraya, "Constitutional Mismatch Repair-Deficiency Syndrome Is a Rare Cause of Cancer Even in a Highly Consanguineous Population," Journal of Cancer Therapy, Vol. 4 No. 5, 2013, pp. 996-1004. doi: 10.4236/jct.2013.45114.
References
[1]   B. Liu, N. C. Nicolaides, S. Markowitz, J. K. Willson, R. E. Parsons, J. Jen, N. Papadopolous, P. Peltomaki, A. de la Chapelle, S. R. Hamilton, et al., “Mismatch Repair Gene Defects in Sporadic Colorectal Cancers with Microsatellite Instability,” Nature Genetics, Vol. 9, No. 1, 1995, pp. 48-55. doi:10.1038/ng0195-48

[2]   G. Marra and J. Jiricny, “DNA Mismatch Repair and Colon Cancer,” Advances in Experimental Medicine and Biology, Vol. 570, 2005, pp. 85-123. doi:10.1007/1-4020-3764-3_4

[3]   C. P. Kratz, C. M. Niemeyer, E. Juttner, M. Kartal, A. Weninger, A. Schmitt-Graeff, U. Kontny, M. Lauten, S. Utzolino, J. Radecke, C. Fonatsch and K. Wimmer, “Childhood T-Cell Non-Hodgkin’s Lymphoma, Colorectal Carcinoma and Brain Tumor in Association With CafeAu-Lait Spots Caused by a Novel Homozygous PMS2 Mutation,” Leukemia, Vol. 22, No. 5, 2008, pp. 1078-1080. doi:10.1038/sj.leu.2405008

[4]   F. Alarcon, C. Lasset, J. Carayol, V. Bonadona, H. Perdry, F. Desseigne, Q. Wang and C. Bonaiti-Pellie, “Estimating Cancer Risk in HNPCC by the GRL Method,” European Journal of Human Genetics, Vol. 15, No. 8, 2007, pp. 831-836. doi:10.1038/sj.ejhg.5201843

[5]   M. A. Jenkins, J. G. Dowty, J. L. Hopper and M. C. Southey, “Molecular Screening of All Colorectal Tumors Diagnosed before Age 50 Years Followed by Genetic Testing Efficiently Identifies Lynch Syndrome Cases,” International Journal of Cancer, Vol. 124, No. 5, 2009, pp. x-i. doi:10.1002/ijc.24173

[6]   F. Quehenberger, H. F. Vasen and H. C. van Houwelingen, “Risk of Colorectal and Endometrial Cancer for Carriers of Mutations of the Hmlh1 and Hmsh2 Gene: Correction for Ascertainment,” Journal of Medical Genetics, Vol. 42, No. 6, 2005, pp. 491-496. doi:10.1136/jmg.2004.024299

[7]   E. Stoffel, B. Mukherjee, V. M. Raymond, N. Tayob, F. Kastrinos, J. Sparr, F. Wang, P. Bandipalliam, S. Syngal and S. B. Gruber, “Calculation of Risk of Colorectal and Endometrial Cancer among Patients with Lynch Syndrome,” Gastroenterology, Vol. 137, No. 5, 2009, pp. 1621-1627. doi:10.1136/jmg.2004.024299

[8]   M. Aarnio, J. P. Mecklin, L. A. Aaltonen, M. NystromLahti and H. J. Jarvinen, “Life-Time Risk of Different Cancers in Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Syndrome,” International Journal of Cancer, Vol. 64, No. 6, 1995, pp. 430-433. doi:10.1002/ijc.2910640613

[9]   K. Wimmer and J. Etzler, “Constitutional Mismatch Repair-Deficiency Syndrome: Have We So Far Seen Only the Tip of an Iceberg?” Human Genetics, Vol. 124, No. 2, 2008, pp. 105-122. doi:10.1007/s00439-008-0542-4

[10]   T. Ripperger, C. Beger, N. Rahner, K. W. Sykora, C. L. Bockmeyer, U. Lehmann, H. H. Kreipe and B. Schlegelberger, “Constitutional Mismatch Repair Deficiency and Childhood Leukemia/Lymphoma—Report on a Novel Biallelic MSH6 Mutation,” Haematologica, Vol. 95, No. 5, 2010, pp. 841-844. doi:10.3324/haematol.2009.015503

[11]   K. Wimmer and C. P. Kratz, “Constitutional Mismatch Repair-Deficiency Syndrome,” Haematologica, Vol. 95, No. 5, 2010, pp. 699-701. doi:10.3324/haematol.2009.021626

[12]   K. Jasperson, W. Samowitz and R. Burt, “Constitutional Mismatch Repair-Deficiency Syndrome Presenting as Colonic Adenomatous Polyposis: Clues from the Skin,” Clinical Genetics, Vol. 80, No. 4, 2010, pp. 394-397.

[13]   K. E. Felton, D. M. Gilchrist and S. E. Andrew, “Constitutive Deficiency in DNA Mismatch Repair,” Clinical Genetics, Vol. 71, No. 6, 2007, pp. 483-498. doi:10.1111/j.1399-0004.2007.00803.x

[14]   Q. Wang, C. Lasset, F. Desseigne, D. Frappaz, C. Bergeron, C. Navarro, E. Ruano and A. Puisieux, “Neurofibromatosis and Early Onset of Cancers in hMLH1-Deficient Children,” Cancer Research, Vol. 59, No. 2, 1999, pp. 294-297.

[15]   S. Kruger, M. Kinzel, C. Walldorf, S. Gottschling, A. Bier, S. Tinschert, A. von Stackelberg, W. Henn, H. Gorgens, S. Boue, K. Kolble, R. Buttner and H. K. Schackert, “Homozygous PMS2 Germline Mutations in Two Families with Early-Onset Haematological Malignancy, Brain Tumours, HNPCC-Associated Tumours, and Signs of Neurofibromatosis Type 1,” European Journal of Human Genetics, Vol. 16, No. 1, 2008, pp. 62-72. doi:10.1038/sj.ejhg.5201923

[16]   M. De Vos, B. E. Hayward, R. Charlton, G. R. Taylor, A. W. Glaser, S. Picton, T. R. Cole, E. R. Maher, C. M. McKeown, J. R. Mann, J. R. Yates, D. Baralle, J. Rankin, D. T. Bonthron and E. Sheridan, “PMS2 Mutations in Childhood Cancer,” Journal of the National Cancer Institute, Vol. 98, No. 5, 2006, pp. 358-361. doi:10.1093/jnci/djj073

[17]   C. P. Kratz, S. Holter, J. Etzler, M. Lauten, A. Pollett, C. M. Niemeyer, S. Gallinger and K. Wimmer, “Rhabdomyosarcoma in Patients with Constitutional MismatchRepair-Deficiency Syndrome,” Journal of Medical Genetics, Vol. 46, No. 6, 2009, pp. 418-420. doi:10.1136/jmg.2008.064212

[18]   J. W. Poley, A. Wagner, M. M. Hoogmans , F. H. Menko, C. Tops, J. M. Kros, R. E. Reddingius, H. Meijers-Heijboer, E. J. Kuipers and W. N. Dinjens, “Biallelic Germline Mutations of Mismatch-Repair Genes: A Possible Cause for Multiple Pediatric Malignancies,” Cancer, Vol. 109, No. 11, 2007, pp. 2349-2356. doi:10.1002/cncr.22697

[19]   M. A. El-Hazmi, A. R. Al-Swailem, A. S. Warsy, A. M. Al-Swailem, R. Sulaimani and A. A. Al-Meshari, “Consanguinity among the Saudi Arabian Population,” Journal of Medical Genetics, Vol. 32, No. 8, 1995, pp. 623-626. doi:10.1002/cncr.22697

[20]   M. I. El-Mouzan, A. A. Al-Salloum, A. S. Al-Herbish, M. M. Qurachi and A. A. Al-Omar, “Regional Variations in the Prevalence of Consanguinity in Saudi Arabia,” Saudi Medical Journal, Vol. 28, No. 12, 2007, pp. 1881-1884.

[21]   R. H. Scott, T. Homfray, N. L. Huxter, S. G. Mitton, R. Nash, M. N. Potter, D. Lancaster and N. Rahman, “Familial T-Cell Non-Hodgkin Lymphoma Caused by Biallelic MSH2 Mutations,” Journal of Medical Genetics, Vol. 44, No. 7, 2007, p. e83. doi:10.1136/jmg.2007.048942

[22]   J. Jiricny, “The Multifaceted Mismatch-Repair System,” Nature Reviews Molecular Cell Biology, Vol. 7, No. 5, 2006, pp. 335-346. doi:10.1038/nrm1907

[23]   A. Peters, H. Born, R. Ettinger, P. Levonian and K. B. Jedele, “Compound Heterozygosity for MSH6 Mutations in a Pediatric Lymphoma Patient,” Journal of Pediatric Hematology/Oncology, Vol. 31, No. 2, 2009, pp. 113-115. doi:10.1038/nrm1907

[24]   R. H. Scott, S. Mansour, K. Pritchard-Jones, D. Kumar, F. MacSweeney and N. Rahman, “Medulloblastoma, Acute Myelocytic Leukemia and Colonic Carcinomas in a Child with Biallelic MSH6 Mutations,” Nature Clinical Practice Oncology, Vol. 4, No. 2, 2007, pp. 130-134. doi:10.1038/nrm1907

[25]   H. Toledano, Y. Goldberg, I. Kedar-Barnes, H. Baris, R. M. Porat, C. Shochat, D. Bercovich, E. Pikarsky, I. Lerer, I. Yaniv, D. Abeliovich and T. Peretz, “Homozygosity of MSH2 c.1906G→C Germline Mutation Is Associated with Childhood Colon Cancer, Astrocytoma and Signs of Neurofibromatosis Type I,” Familial Cancer, Vol. 8, No. 3, 2009, pp. 187-194. doi:10.1007/s10689-008-9227-3

[26]   L. Giunti, V. Cetica, U. Ricci, S. Giglio, I. Sardi, M. Paglierani, E. Andreucci, M. Sanzo, M. Forni, A. M. Buccoliero, L. Genitori and M. Genuardi, “Type A Microsatellite Instability in Pediatric Gliomas as an Indicator of Turcot Syndrome,” European Journal of Human Genetics, Vol. 17, No. 7, 2009, pp. 919-927. doi:10.1038/ejhg.2008.271

[27]   J. Mueller, I. Gazzoli, P. Bandipalliam, J. E. Garber, S. Syngal and R. D. Kolodner, “Comprehensive Molecular Analysis of Mismatch Repair Gene Defects in Suspected Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Cases,” Cancer Research, Vol. 69, No. 17, 2009, pp. 7053-7061. doi:10.1038/ejhg.2008.271

[28]   G. Bougeard, F. Charbonnier, A. Moerman, C. Martin, M. M. Ruchoux, N. Drouot and T. Frebourg, “Early Onset Brain Tumor and Lymphoma in MSH2-Deficient Children,” The American Journal of Human Genetics, Vol. 72, No. 1, 2003, pp. 213-216. doi:10.1086/345297

[29]   W. H. Isbister, M. Murad and Z. Habib, “Rectal Cancer in the Kingdom of Saudi Arabia: The King Faisal Specialist Hospital experience,” Australian & New Zealand Journal of Surgery, Vol. 70, No. 4, 2000, pp. 269-274. doi:10.1086/345297

[30]   “Eight Year Cancer Incidence among Nations of the GCC States. 1998-2005 Cancer Incidence Report of Gulf Cooperation Council States,” Excutive Board of the Health Ministers’ Council, Riyadh, King Fahd National Library Cataloging-in-Publication Data, 2009.

[31]   H. S. Al-Eid, “Cancer Incidence Report Saudi Arabia 1999-2000,” King Faisal Specialist Hospital and Research Centre, Riyadh, 2004.

 
 
Top