| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
1 Division of Human Cancer Genetics, Comprehensive Cancer Center, and 2 Department of Surgical Pathology, The Ohio State University, Columbus, Ohio; and 3 Departments of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
The MutL
heterodimer formed by mismatch repair (MMR) proteins MLH1 and PMS2 is a major component of the MMR complex, yet mutations in the PMS2 gene are rare in the etiology of hereditary nonpolyposis colorectal cancer. Evidence from five published cases suggested that contrary to the Knudson principle, PMS2 mutations cause hereditary nonpolyposis colorectal cancer or Turcot syndrome only when they are biallelic in the germline or abnormally expressed. As candidates for PMS2 mutations, we selected seven patients whose colon tumors stained negative for PMS2 and positive for MLH1 by immunohistochemistry. After conversion to haploidy, truncating germline mutations of PMS2 were found in two patients (2192delTAACT and deletion of exon 8). These mutations abrogated PMS2 protein in germline cells by Western analysis. In two additional patients, PMS2 protein from one allele also was abrogated. Novel or previously described missense variants of PMS2 were detected, but their pathogenicity is undetermined. We detected and characterized a new transcript, PMS2CL, showing 98% sequence identity with exons 9 and 11–15 of PMS2 and emanating from a locus close to PMS2 in chromosome 7p. Its predicted protein product was not detected. Thus, in addition to several previously described PMS2-related genes resembling the 5' end of PMS2, at least one related gene resembles the 3' end of PMS2. In conclusion, both detectable and presently undefined germline mutations are deleterious and produce susceptibility to cancer by the two-hit mechanism. Paralogous genes interfere with mutation detection, resulting in underdiagnosis of PMS2 mutations. Mutation detection in PMS2 requires haploid DNA.
This article has been cited by other articles:
|
|
 |
|
  M Clendenning, L Senter, H Hampel, K L. Robinson, S Sun, D Buchanan, M D Walsh, M Nilbert, J Green, J Potter, et al. A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome J. Med. Genet., June 1, 2008; 45(6): 340 - 345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. South, H. Hampel, I. Comeras, J. A. Westman, W. L. Frankel, and A. de la Chapelle The Frequency of Muir-Torre Syndrome Among Lynch Syndrome Families J Natl Cancer Inst, February 20, 2008; 100(4): 277 - 281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Gururangan, W. Frankel, R. Broaddus, M. Clendenning, L. Senter, M. McDonald, J. Eastwood, D. Reardon, J. Vredenburgh, J. Quinn, et al. Multifocal anaplastic astrocytoma in a patient with hereditary colorectal cancer, transcobalamin II deficiency, agenesis of the corpus callosum, mental retardation, and inherited PMS2 mutation Neuro-oncol, February 1, 2008; 10(1): 93 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Valle, J. Perea, P. Carbonell, V. Fernandez, A. M. Dotor, J. Benitez, and M. Urioste Clinicopathologic and Pedigree Differences in Amsterdam I-Positive Hereditary Nonpolyposis Colorectal Cancer Families According to Tumor Microsatellite Instability Status J. Clin. Oncol., March 1, 2007; 25(7): 781 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R C Niessen, M J W Berends, Y Wu, R H Sijmons, H Hollema, M J L Ligtenberg, H E K de Walle, E G E de Vries, A Karrenbeld, C H C M Buys, et al. Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer Gut, December 1, 2006; 55(12): 1781 - 1788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Lindor, G. M. Petersen, D. W. Hadley, A. Y. Kinney, S. Miesfeldt, K. H. Lu, P. Lynch, W. Burke, and N. Press Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA, September 27, 2006; 296(12): 1507 - 1517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hampel, W. Frankel, J. Panescu, J. Lockman, K. Sotamaa, D. Fix, I. Comeras, J. La Jeunesse, H. Nakagawa, J. A. Westman, et al. Screening for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) among Endometrial Cancer Patients. Cancer Res., August 1, 2006; 66(15): 7810 - 7817. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. M.C. Hendriks, A. E. de Jong, H. Morreau, C. M.J. Tops, H. F. Vasen, J. Th. Wijnen, M. H. Breuning, and A. H.J.T. Brocker-Vriends Diagnostic Approach and Management of Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma): A Guide for Clinicians CA Cancer J Clin, July 1, 2006; 56(4): 213 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. De Vos, B. E. Hayward, R. Charlton, G. R. Taylor, A. W. Glaser, S. Picton, T. R. Cole, E. R. Maher, C. M. E. McKeown, J. R. Mann, et al. PMS2 mutations in childhood cancer. J Natl Cancer Inst, March 1, 2006; 98(5): 358 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W M Grady Molecular basis for subdividing hereditary colon cancer? Gut, December 1, 2005; 54(12): 1676 - 1678. [Full Text] [PDF]
|
|
|
|
|
|
D T Bonthron, B E Hayward, M De Vos, and E Sheridan PMS2 mutations in childhood cancer Gut, December 1, 2005; 54(12): 1821 - 1821. [Full Text] [PDF]
|
|
|
|
|
|
P.-C. Chen, S. Dudley, W. Hagen, D. Dizon, L. Paxton, D. Reichow, S.-R. Yoon, K. Yang, N. Arnheim, R. M. Liskay, et al. Contributions by MutL Homologues Mlh3 and Pms2 to DNA Mismatch Repair and Tumor Suppression in the Mouse Cancer Res., October 1, 2005; 65(19): 8662 - 8670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O. Woods, A. J. Hyde, F. K. Curtis, S. Stuckless, J. S. Green, A. F. Pollett, J. D. Robb, R. C. Green, M. E. Croitoru, A. Careen, et al. High Frequency of Hereditary Colorectal Cancer in Newfoundland Likely Involves Novel Susceptibility Genes Clin. Cancer Res., October 1, 2005; 11(19): 6853 - 6861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gill, N. M. Lindor, L. J. Burgart, R. Smalley, O. Leontovich, A. J. French, R. M. Goldberg, D. J. Sargent, J. R. Jass, J. L. Hopper, et al. Isolated Loss of PMS2 Expression in Colorectal Cancers: Frequency, Patient Age, and Familial Aggregation Clin. Cancer Res., September 15, 2005; 11(18): 6466 - 6471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hampel, W. L. Frankel, E. Martin, M. Arnold, K. Khanduja, P. Kuebler, H. Nakagawa, K. Sotamaa, T. W. Prior, J. Westman, et al. Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) N. Engl. J. Med., May 5, 2005; 352(18): 1851 - 1860. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
