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Morphological Features and Mismatch Repair in Colorectal Tumors

Halvarsson, Britta LU (2007) In 2007:9
Abstract
Corlorectal cancer affects 5% of individuals in the Western world and heredity is estimated to cause at least 10% of the tumors. Defective mismatch repair (MMR) is a tumorigenic mechanism through which about 15% of colorectal cancer develops and this feature characterizes tumors associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome. The underlying molecular mechanism in HNPCC is a germline mutation in one of the MMR genes MLH1, PMS2, MSH2 or MSH6 and these tumors are characterized by microsatellite instability (MSI) and loss of immunostaining for the affected MMR protein.



The aims of these thesis were to investigate the use of immunostaining for the identification of MMR defective... (More)
Corlorectal cancer affects 5% of individuals in the Western world and heredity is estimated to cause at least 10% of the tumors. Defective mismatch repair (MMR) is a tumorigenic mechanism through which about 15% of colorectal cancer develops and this feature characterizes tumors associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome. The underlying molecular mechanism in HNPCC is a germline mutation in one of the MMR genes MLH1, PMS2, MSH2 or MSH6 and these tumors are characterized by microsatellite instability (MSI) and loss of immunostaining for the affected MMR protein.



The aims of these thesis were to investigate the use of immunostaining for the identification of MMR defective adenocarcinomas (studies I-II) and adenomas (study III), to assess morphologic heterogeneity in tumors caused by the same underlying germline mutation (study IV), and to evaluate whether morphology can be used to identify MMR defective tumors (study V).



In study I immunostaining for MLH1, MSH2 and MSH6 identified MMR defects with a sensitivity of 92% and a specificity of 100%. When PMS2 immunostaining was added in study II the sensitivity raised to >95%. Hence, MMR protein immunostaining reliably pinpoints the mutated gene and thereby facilitates mutation analysis. I study III, HNPCC-associated adenomas were studied and immunostaining identified MMR defects with a sensitivity of 66%, although higher frequencies were found in larger and proximally located adenomas.



Study IV assessed morphological heterogeneity in tumors from two HNPCC-families and demonstrated extensive variability in tumors from the same individual as well as from the same family. This indicates that other mechanisms than the underlying germline mutation influence the tumor phenotype. In study V, 238 tumors were morphologically characterized with specific focus on features associated with MMR defective tumors. Overall, a MMR defective phenotype was identified in 23% of the tumors. A proximal tumor location, an expanding growth pattern, poor differentiation, absence of necrosis, a Crohn's like reaction, peritumoral lymphocytes, and tumor-infiltrating lymphocytes were significantly more often found in the MMR defective tumors and an index combinding these features was constructed for the identification of tumors that develop through defective MMR. (Less)
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author
supervisor
opponent
  • Associate professor Palmqvist, Richard, Department of Pathology, Umeå University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Patologi (allmän), patologisk anatomi, Lynch syndrome, Colorectal tumors, HNPCC, Mismatch repaire, pathological anatomy, General pathology, Genetik, cytogenetik, cytogenetics, Genetics, Medicin (människa och djur), Medicine (human and vertebrates), Immunohistochemistry
in
2007:9
pages
95 pages
publisher
Lund University, Faculty of Medicine Doctoral Dissertation
defense location
Museum of Medical History in Helsingborg, Bergaliden 20
defense date
2007-01-26 13:00
ISSN
1652-8220
ISBN
91-85559-78-4
language
English
LU publication?
yes
id
e8e4d4cc-5bba-4315-80f6-051fd6ad2a16 (old id 547855)
date added to LUP
2007-09-12 07:48:00
date last changed
2016-09-19 08:44:57
@phdthesis{e8e4d4cc-5bba-4315-80f6-051fd6ad2a16,
  abstract     = {Corlorectal cancer affects 5% of individuals in the Western world and heredity is estimated to cause at least 10% of the tumors. Defective mismatch repair (MMR) is a tumorigenic mechanism through which about 15% of colorectal cancer develops and this feature characterizes tumors associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome. The underlying molecular mechanism in HNPCC is a germline mutation in one of the MMR genes MLH1, PMS2, MSH2 or MSH6 and these tumors are characterized by microsatellite instability (MSI) and loss of immunostaining for the affected MMR protein.<br/><br>
<br/><br>
The aims of these thesis were to investigate the use of immunostaining for the identification of MMR defective adenocarcinomas (studies I-II) and adenomas (study III), to assess morphologic heterogeneity in tumors caused by the same underlying germline mutation (study IV), and to evaluate whether morphology can be used to identify MMR defective tumors (study V).<br/><br>
<br/><br>
In study I immunostaining for MLH1, MSH2 and MSH6 identified MMR defects with a sensitivity of 92% and a specificity of 100%. When PMS2 immunostaining was added in study II the sensitivity raised to &gt;95%. Hence, MMR protein immunostaining reliably pinpoints the mutated gene and thereby facilitates mutation analysis. I study III, HNPCC-associated adenomas were studied and immunostaining identified MMR defects with a sensitivity of 66%, although higher frequencies were found in larger and proximally located adenomas.<br/><br>
<br/><br>
Study IV assessed morphological heterogeneity in tumors from two HNPCC-families and demonstrated extensive variability in tumors from the same individual as well as from the same family. This indicates that other mechanisms than the underlying germline mutation influence the tumor phenotype. In study V, 238 tumors were morphologically characterized with specific focus on features associated with MMR defective tumors. Overall, a MMR defective phenotype was identified in 23% of the tumors. A proximal tumor location, an expanding growth pattern, poor differentiation, absence of necrosis, a Crohn's like reaction, peritumoral lymphocytes, and tumor-infiltrating lymphocytes were significantly more often found in the MMR defective tumors and an index combinding these features was constructed for the identification of tumors that develop through defective MMR.},
  author       = {Halvarsson, Britta},
  isbn         = {91-85559-78-4},
  issn         = {1652-8220},
  keyword      = {Patologi (allmän),patologisk anatomi,Lynch syndrome,Colorectal tumors,HNPCC,Mismatch repaire,pathological anatomy,General pathology,Genetik,cytogenetik,cytogenetics,Genetics,Medicin (människa och djur),Medicine (human and vertebrates),Immunohistochemistry},
  language     = {eng},
  pages        = {95},
  publisher    = {Lund University, Faculty of Medicine Doctoral Dissertation},
  school       = {Lund University},
  series       = {2007:9},
  title        = {Morphological Features and Mismatch Repair in Colorectal Tumors},
  year         = {2007},
}