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Predominance of CIN versus MSI in the development of rectal cancer at young age.

Fernebro E, Halvarsson B, Baldetorp B, Nilbert M - BMC Cancer (2002)

Bottom Line: Development of proximal and distal colorectal cancers involve partly different mechanisms associated with the microsatellite instability (MSI) and the chromosomal instability (CIN) pathways.However, MSI and CIN may play different roles in the development of colon cancer and rectal cancer, and we have specifically investigated their contribution to the development of rectal cancer at young age.MSI occurs only in a small fraction of the tumors from young patients with rectal cancer, but when present it strongly indicates an underlying HNPCC-causing mutation, and other mechanisms than HNPCC thus cause rectal cancer in the majority of young patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, University Hospital, Lund, Sweden. Eva.Fernebro@onk.lu.se

ABSTRACT

Background: Development of proximal and distal colorectal cancers involve partly different mechanisms associated with the microsatellite instability (MSI) and the chromosomal instability (CIN) pathways. Colorectal cancers in patients under 50 years of age represent about 5% of the total number of tumors and have been associated with an increased frequency of MSI tumors. However, MSI and CIN may play different roles in the development of colon cancer and rectal cancer, and we have specifically investigated their contribution to the development of rectal cancer at young age.

Methods: Thirty rectal cancers diagnosed before the age of 50 were characterized for DNA-ploidy, MSI, mutations of KRAS and CTNNB1 and immunohistochemical expression of p53, beta-catenin and of the mismatch repair (MMR) proteins MLH1 and MSH2.

Results: DNA aneuploidy was detected in 21/30 tumors, KRAS mutations in 6 tumors, no mutations of CTNNB1 were detected but immunohistochemical staining for beta-catenin showed nuclear staining in 6 tumors, and immunohistochemical expression of p53 was detected in 18 tumors. MSI was detected in 3/30 tumors, all of which showed and immunohistochemical loss of staining for the MMR protein MSH2, which strongly indicates a phenotype associated with hereditary nonpolyposis colorectal cancer (HNPCC).

Conclusions: MSI occurs only in a small fraction of the tumors from young patients with rectal cancer, but when present it strongly indicates an underlying HNPCC-causing mutation, and other mechanisms than HNPCC thus cause rectal cancer in the majority of young patients.

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Immunohistochemical staining of tumor 10 a) normal nuclear staining for MLH1 in the tumor as well as in stromal tissue, b) loss of nuclear expression of MSH2 in tumor tissue but retained staining in stromal cells, c) nuclear staining for p53, and d) membraneous and intense cytoplasmic staining for β-catenin.
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Figure 1: Immunohistochemical staining of tumor 10 a) normal nuclear staining for MLH1 in the tumor as well as in stromal tissue, b) loss of nuclear expression of MSH2 in tumor tissue but retained staining in stromal cells, c) nuclear staining for p53, and d) membraneous and intense cytoplasmic staining for β-catenin.

Mentions: Fresh 5-μM sections from paraffin embedded tumor blocks were transferred to glass slides (DAKO ChemMate capillary gap microscope slides, 75 μM, DAKO A/S, Denmark). Following deparaffinisation in xylene and rehydration through graded ethanol, the sections were microwave treated at 750 W in citrate or EDTA buffer (Table 2) for 15 min to achieve antigen retrieval. Staining was performed in an automated immunostainer (TechMate™ 500 Plus, DAKO A/S, Denmark) using the biotin-streptavidin-peroxidase procedure with diaminobenzidine as the chromogen. Endogenous peroxidase activity was blocked by incubation in H2O2. All antibodies used were commercially available mouse monoclonal IgG's (Table 2). After counterstaining with hematoxylin the slides were dehydrated in ascending concentrations of alcohol and mounted. The immunohistochemical staining (Fig. 1) was independently evaluated by two of the investigators (E.F. and M.N.). The staining for MLH1 and MSH2 was nuclear and was classified as present or absent in the tumor tissue, and retained expression was in all tumors identified in surrounding normal crypts and in the tumor stroma. Nuclear p53 staining was evaluated in 5 high power fields (HPFs) (x40) and was classified as positive if >5% of the tumor cell nuclei were stained. Immunohistochemical staining for β-catenin normally results in a membraneous and/or a weak cytoplasmic staining, whereas a mutation leading to β-catenin stabilization is reflected as an increased cytoplasmic or nuclear staining. We classified the predominant β-catenin staining pattern in 5 HPFs according to cellular localization as membraneous, cytoplasmic or nuclear.


Predominance of CIN versus MSI in the development of rectal cancer at young age.

Fernebro E, Halvarsson B, Baldetorp B, Nilbert M - BMC Cancer (2002)

Immunohistochemical staining of tumor 10 a) normal nuclear staining for MLH1 in the tumor as well as in stromal tissue, b) loss of nuclear expression of MSH2 in tumor tissue but retained staining in stromal cells, c) nuclear staining for p53, and d) membraneous and intense cytoplasmic staining for β-catenin.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC130963&req=5

Figure 1: Immunohistochemical staining of tumor 10 a) normal nuclear staining for MLH1 in the tumor as well as in stromal tissue, b) loss of nuclear expression of MSH2 in tumor tissue but retained staining in stromal cells, c) nuclear staining for p53, and d) membraneous and intense cytoplasmic staining for β-catenin.
Mentions: Fresh 5-μM sections from paraffin embedded tumor blocks were transferred to glass slides (DAKO ChemMate capillary gap microscope slides, 75 μM, DAKO A/S, Denmark). Following deparaffinisation in xylene and rehydration through graded ethanol, the sections were microwave treated at 750 W in citrate or EDTA buffer (Table 2) for 15 min to achieve antigen retrieval. Staining was performed in an automated immunostainer (TechMate™ 500 Plus, DAKO A/S, Denmark) using the biotin-streptavidin-peroxidase procedure with diaminobenzidine as the chromogen. Endogenous peroxidase activity was blocked by incubation in H2O2. All antibodies used were commercially available mouse monoclonal IgG's (Table 2). After counterstaining with hematoxylin the slides were dehydrated in ascending concentrations of alcohol and mounted. The immunohistochemical staining (Fig. 1) was independently evaluated by two of the investigators (E.F. and M.N.). The staining for MLH1 and MSH2 was nuclear and was classified as present or absent in the tumor tissue, and retained expression was in all tumors identified in surrounding normal crypts and in the tumor stroma. Nuclear p53 staining was evaluated in 5 high power fields (HPFs) (x40) and was classified as positive if >5% of the tumor cell nuclei were stained. Immunohistochemical staining for β-catenin normally results in a membraneous and/or a weak cytoplasmic staining, whereas a mutation leading to β-catenin stabilization is reflected as an increased cytoplasmic or nuclear staining. We classified the predominant β-catenin staining pattern in 5 HPFs according to cellular localization as membraneous, cytoplasmic or nuclear.

Bottom Line: Development of proximal and distal colorectal cancers involve partly different mechanisms associated with the microsatellite instability (MSI) and the chromosomal instability (CIN) pathways.However, MSI and CIN may play different roles in the development of colon cancer and rectal cancer, and we have specifically investigated their contribution to the development of rectal cancer at young age.MSI occurs only in a small fraction of the tumors from young patients with rectal cancer, but when present it strongly indicates an underlying HNPCC-causing mutation, and other mechanisms than HNPCC thus cause rectal cancer in the majority of young patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, University Hospital, Lund, Sweden. Eva.Fernebro@onk.lu.se

ABSTRACT

Background: Development of proximal and distal colorectal cancers involve partly different mechanisms associated with the microsatellite instability (MSI) and the chromosomal instability (CIN) pathways. Colorectal cancers in patients under 50 years of age represent about 5% of the total number of tumors and have been associated with an increased frequency of MSI tumors. However, MSI and CIN may play different roles in the development of colon cancer and rectal cancer, and we have specifically investigated their contribution to the development of rectal cancer at young age.

Methods: Thirty rectal cancers diagnosed before the age of 50 were characterized for DNA-ploidy, MSI, mutations of KRAS and CTNNB1 and immunohistochemical expression of p53, beta-catenin and of the mismatch repair (MMR) proteins MLH1 and MSH2.

Results: DNA aneuploidy was detected in 21/30 tumors, KRAS mutations in 6 tumors, no mutations of CTNNB1 were detected but immunohistochemical staining for beta-catenin showed nuclear staining in 6 tumors, and immunohistochemical expression of p53 was detected in 18 tumors. MSI was detected in 3/30 tumors, all of which showed and immunohistochemical loss of staining for the MMR protein MSH2, which strongly indicates a phenotype associated with hereditary nonpolyposis colorectal cancer (HNPCC).

Conclusions: MSI occurs only in a small fraction of the tumors from young patients with rectal cancer, but when present it strongly indicates an underlying HNPCC-causing mutation, and other mechanisms than HNPCC thus cause rectal cancer in the majority of young patients.

Show MeSH
Related in: MedlinePlus