| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Division of Gastrointestinal/Liver Pathology, Department
of Pathology*
and Oncology Center,
The Johns Hopkins University School of Medicine, Baltimore, Maryland;
Department of Medicine,
Hereditary Cancer
Center, Creighton University School of Medicine, Omaha, Nebraska;
Department of Pathology,§
School of Medicine,
University of Auckland, New Zealand; and Memorial University of
Newfoundland,¶
Health Sciences Centre, St.
John's, Newfoundland, Canada
A subset of hereditary and sporadic colorectal carcinomas is defined by microsatellite instability (MSI), but the spectra of gene mutations have not been characterized extensively. Thirty-nine hereditary nonpolyposis colorectal cancer syndrome carcinomas (HNPCCa) and 57 sporadic right-sided colonic carcinomas (SRSCCa) were evaluated. Of HNPCCa, 95% (37/39) were MSI-positive as contrasted with 31% (18/57) of SRSCCa (P < 0.000001), but instability tended to be more widespread in SRSCCa (P = 0.08). Absence of nuclear hMSH2 mismatch repair gene product by immunohistochemistry was associated with germline hMSH2 mutation (P = 0.0007). The prevalence of K-ras proto-oncogene mutations was similar in HNPCCa and SRSCCa (30% (11/37) and 30% (16/54)), but no HNPCCa from patients with germline hMSH2 mutation had codon 13 mutation (P = 0.02), and two other HNPCCa had multiple K-ras mutations attributable to subclones. 18q allelic deletion and p53 gene product overexpression were inversely related to MSI (P = 0.0004 and P = 0.0001, respectively). Frameshift mutation of the transforming growth factor ß type II receptor gene was frequent in all MSI-positive cancers (85%, 46/54), but mutation of the E2F-4 transcription factor gene was more common in HNPCCa of patients with germline hMSH2 mutation than in those with germline hMLH1 mutation (100% (8/8) versus 40% (2/5), P = 0.04), and mutation of the Bax proapoptotic gene was more frequent in HNPCCa than in MSI-positive SRSCCa (55% (17/31) versus 13% (2/15), P = 0.01). The most common combination of mutations occurred in only 23% (8/35) of evaluable MSI-positive cancers. Our findings suggest that the accumulation of specific genetic alterations in MSI-positive colorectal cancers is markedly heterogeneous, because the occurrence of some mutations (eg, ras, E2F-4, and Bax genes), but not others (eg, transforming growth factor ß type II receptor gene), depends on the underlying basis of the mismatch repair deficiency. This genetic heterogeneity may contribute to the heterogeneous clinical and pathological features of MSI-positive cancers.
This article has been cited by other articles:
 |
|
 |
|
  E. Y. Chang, P. B. Dorsey, J. Frankhouse, R. G. Lee, D. Walts, W. Johnson, G. Anadiotis, and N. Johnson Combination of Microsatellite Instability and Lymphocytic Infiltrate as a Prognostic Indicator in Colon Cancer Arch Surg, June 1, 2009; 144(6): 511 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Pino, M. Mino-Kenudson, B. M. Wildemore, A. Ganguly, J. Batten, I. Sperduti, A. J. Iafrate, and D. C. Chung Deficient DNA Mismatch Repair Is Common in Lynch Syndrome-Associated Colorectal Adenomas J. Mol. Diagn., May 1, 2009; 11(3): 238 - 247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.H.S. Gylling, T.T. Nieminen, W.M. Abdel-Rahman, K. Nuorva, M. Juhola, E.I. Joensuu, H.J. Jarvinen, J.-P. Mecklin, M. Aarnio, and P.T. Peltomaki Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors Carcinogenesis, July 1, 2008; 29(7): 1351 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Das, K. Vaiphei, D. Jain, and Jai Dev Wig p53 and mdm2 Expression in Colorectal Carcinoma: A Correlative Analysis With Clinical Staging and Histological Parameters International Journal of Surgical Pathology, October 1, 2007; 15(4): 335 - 345. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Sanchez-de-Abajo, M. de la Hoya, M. van Puijenbroek, A. Tosar, J.A. Lopez-Asenjo, E. Diaz-Rubio, H. Morreau, and T. Caldes Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways Clin. Cancer Res., October 1, 2007; 13(19): 5729 - 5735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Reimer, S. Sadr, A. Wiedemair, S. Stadlmann, N. Concin, G. Hofstetter, E. Muller-Holzner, C. Marth, and A. G. Zeimet Clinical Relevance of E2F Family Members in Ovarian Cancer--An Evaluation in a Training Set of 77 Patients Clin. Cancer Res., January 1, 2007; 13(1): 144 - 151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Oliveira, J. L. Westra, D. Arango, M. Ollikainen, E. Domingo, A. Ferreira, S. Velho, R. Niessen, K. Lagerstedt, P. Alhopuro, et al. Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status Hum. Mol. Genet., October 1, 2004; 13(19): 2303 - 2311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Li, N.-G. Kim, S. H. Kim, C. Park, H. Kim, H. J. Kang, K. H. Koh, S. N. Kim, W. H. Kim, N. K. Kim, et al. Chromosomal Imbalances in the Colorectal Carcinomas with Microsatellite Instability Am. J. Pathol., October 1, 2003; 163(4): 1429 - 1436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Kuismanen, A.-L. Moisio, P. Schweizer, K. Truninger, R. Salovaara, J. Arola, R. Butzow, J. Jiricny, M. Nystrom-Lahti, and P. Peltomaki Endometrial and Colorectal Tumors from Patients with Hereditary Nonpolyposis Colon Cancer Display Different Patterns of Microsatellite Instability Am. J. Pathol., June 1, 2002; 160(6): 1953 - 1958. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Duval and R. Hamelin Mutations at Coding Repeat Sequences in Mismatch Repair-deficient Human Cancers: Toward a New Concept of Target Genes for Instability Cancer Res., May 1, 2002; 62(9): 2447 - 2454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Lindor, L. J. Burgart, O. Leontovich, R. M. Goldberg, J. M. Cunningham, D. J. Sargent, C. Walsh-Vockley, G. M. Petersen, M. D. Walsh, B. A. Leggett, et al. Immunohistochemistry Versus Microsatellite Instability Testing in Phenotyping Colorectal Tumors J. Clin. Oncol., February 15, 2002; 20(4): 1043 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Young, L. A. Simms, K. G. Biden, C. Wynter, V. Whitehall, R. Karamatic, J. George, J. Goldblatt, I. Walpole, S.-A. Robin, et al. Features of Colorectal Cancers with High-Level Microsatellite Instability Occurring in Familial and Sporadic Settings : Parallel Pathways of Tumorigenesis Am. J. Pathol., December 1, 2001; 159(6): 2107 - 2116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Hawkins and R. L. Ward Sporadic Colorectal Cancers With Microsatellite Instability and Their Possible Origin in Hyperplastic Polyps and Serrated Adenomas J Natl Cancer Inst, September 5, 2001; 93(17): 1307 - 1313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhang, P. M. Laborde, K. R. Coombes, D. A. Berry, and S. R. Hamilton Cancer Genomics: Promises and Complexities Clin. Cancer Res., August 1, 2001; 7(8): 2159 - 2167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Ward, A Meagher, I Tomlinson, T O'Connor, M Norrie, R Wu, and N Hawkins Microsatellite instability and the clinicopathological features of sporadic colorectal cancer Gut, June 1, 2001; 48(6): 821 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Wagner, Y Hendriks, E J Meijers-Heijboer, W J F de Leeuw, H Morreau, R Hofstra, C Tops, E Bik, A H J T Bröcker-Vriends, C van der Meer, et al. Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree J. Med. Genet., May 1, 2001; 38(5): 318 - 322. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. Watanabe, T.-T. Wu, P. J. Catalano, T. Ueki, R. Satriano, D. G. Haller, A. B. Benson, and S. R. Hamilton Molecular Predictors of Survival after Adjuvant Chemotherapy for Colon Cancer N. Engl. J. Med., April 19, 2001; 344(16): 1196 - 1206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Samowitz, J. A. Holden, K. Curtin, S. L. Edwards, A. R. Walker, H. A. Lin, M. A. Robertson, M. F. Nichols, K. M. Gruenthal, B. J. Lynch, et al. Inverse Relationship between Microsatellite Instability and K-ras and p53 Gene Alterations in Colon Cancer Am. J. Pathol., April 1, 2001; 158(4): 1517 - 1524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Shitoh, F Konishi, M Miyaki, T Iijima, T Furukawa, T Tsukamoto, and H Nagai Pathogenesis of non-familial colorectal carcinomas with high microsatellite instability J. Clin. Pathol., November 1, 2000; 53(11): 841 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J R JASS;, B CURRAN, K LENEHAN, H MULCAHY, O TIGHE, M A BENNETT, E W KAY, D P O'DONOGHUE, M LEADER, and D T CROKE Replication error phenotype in colorectal cancer Reply Gut, October 1, 2000; 47(4): 597 - 598. [Full Text] [PDF]
|
|
|
|
|
|
A. Low-Baselli, W. W. Huber, M. Kafer, K. Bukowska, R. Schulte-Hermann, and B. Grasl-Kraupp Failure to demonstrate chemoprevention by the monoterpene perillyl alcohol during early rat hepatocarcinogenesis: a cautionary note Carcinogenesis, October 1, 2000; 21(10): 1869 - 1877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J R JASS;, L CAWKWELL, M F DIXON, P QUIRKE;, and I TALBOT hMLH1 and hMSH2 immunostaining in colorectal cancer Reply Reply Gut, August 1, 2000; 47(2): 315 - 316. [Full Text] [PDF]
|
|
|
|
|
|
N. J. Hawkins, P. Gorman, I. P. M. Tomlinson, P. Bullpitt, and R. L. Ward Colorectal Carcinomas Arising in the Hyperplastic Polyposis Syndrome Progress through the Chromosomal Instability Pathway Am. J. Pathol., August 1, 2000; 157(2): 385 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H Iino, L Simms, J Young, J Arnold, I M Winship, S I Webb, K L Furlong, B Leggett, and J R Jass DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer Gut, July 1, 2000; 47(1): 37 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Ahrendt, P. A. Decker, K. Doffek, B. Wang, L. Xu, M. J. Demeure, J. Jen, and D. Sidransky Microsatellite Instability at Selected Tetranucleotide Repeats Is Associated with p53 Mutations in Non-Small Cell Lung Cancer Cancer Res., May 1, 2000; 60(9): 2488 - 2491. [Abstract] [Full Text]
|
|
|
|
|
|
K. D. Berg, C. L. Glaser, R. E. Thompson, S. R. Hamilton, C. A. Griffin, and J. R. Eshleman Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction J. Mol. Diagn., February 1, 2000; 2(1): 20 - 28. [Abstract] [Full Text]
|
|
|
|
|
|
I M FRAYLING Microsatellite instability Gut, July 1, 1999; 45(1): 1 - 4. [Full Text] [PDF]
|
|
|
|
|
|
M. Perucho, C. R. Boland, S. N. Thibodeau, S. R. Hamilton, D. Sidransky, J. R. Eshleman, R. W. Burt, S. J. Meltzer, M. A. Rodriguez-Bigas, R. Fodde, et al. Correspondence re: C. R. Boland et al. A National Cancer Institute Workshop on Microsatellite Instability for Cancer Detection and Familial Predisposition: Development of International Criteria for the Determination of Microsatellite Instability in Colorectal Cancer. Cancer Res., 58: 5248-5257, 1998 Cancer Res., January 1, 1999; 59(1): 249 - 256. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
