SMAD4 as a prognostic marker in colorectal cancer

Hafid Alazzouzi, Pia Alhopuro, Reijo Salovaara, Heli Sammalkorpi, Heikki J Järvinen, Jukka-Pekka Mecklin, Akseli Hemminki, Simo Schwartz, Lauri A Aaltonen, Diego Arango

    Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

    Sammanfattning

    "More than 50% of patients with Dukes C colorectal cancer have disease recurrence and die within 5 years after surgical removal of their primary tumor. It is currently not possible to distinguish patients with good and bad prognosis. SMAD4 is an important tumor suppressor gene that mediates transforming growth factor-P superfamily signaling and is located in chromosome 18q21, a region with frequent genetic losses in these tumors. Allelic imbalance in 18q has been linked to poor prognosis in a subset of colorectal cancer patients. Therefore, we generated a tissue microarray containing triplicate tumor samples from 86 Dukes C patients and used immunohistochemistry to assess the relative expression level of SMAD4 and its value as a prognostic marker. In addition, SMAD4 was screened for mutations and two polymorphic microsatellite markers were used to assess the presence of allelic imbalance in these tumors. Patients with tumors expressing high SMAD4 levels had significantly better overall (P < 0.025) and disease-free (P < 0.013) survival than patients with low levels. This identifies SMAD4 as a prognostic marker for Dukes C colorectal cancer. Although all tumors with absent SMAD4 staining showed allelic imbalance in 18q21, tumors with 18q21 allelic imbalance as a group showed no difference in SMAD4 levels compared with tumors without allelic imbalance, suggesting that additional mechanisms of SMAD4 down-regulation exist. In addition, although SMAD4 mutations were found in five tumors, they were not associated with shorter survival. In conclusion, the level of expression of SMAD4 was found to be a more sensitive marker than 18q21 allelic imbalance and SMAD4 mutations, which were of no prognostic significance for these patients."
    Originalspråkengelska
    TidskriftClinical Cancer Research
    Volym11
    Utgåva7
    Sidor (från-till)2606-2611
    Antal sidor6
    ISSN1078-0432
    DOI
    StatusPublicerad - 2005
    MoE-publikationstypA1 Tidskriftsartikel-refererad

    Vetenskapsgrenar

    • 311 Basmedicin

    Citera det här

    Alazzouzi, H., Alhopuro, P., Salovaara, R., Sammalkorpi, H., Järvinen, H. J., Mecklin, J-P., ... Arango, D. (2005). SMAD4 as a prognostic marker in colorectal cancer. Clinical Cancer Research, 11(7), 2606-2611. https://doi.org/10.1158/1078-0432.CCR-04-1458
    Alazzouzi, Hafid ; Alhopuro, Pia ; Salovaara, Reijo ; Sammalkorpi, Heli ; Järvinen, Heikki J ; Mecklin, Jukka-Pekka ; Hemminki, Akseli ; Schwartz, Simo ; Aaltonen, Lauri A ; Arango, Diego. / SMAD4 as a prognostic marker in colorectal cancer. I: Clinical Cancer Research. 2005 ; Vol. 11, Nr. 7. s. 2606-2611.
    @article{7ad07cf5223049f09705dad78a49946c,
    title = "SMAD4 as a prognostic marker in colorectal cancer",
    abstract = "{"}More than 50{\%} of patients with Dukes C colorectal cancer have disease recurrence and die within 5 years after surgical removal of their primary tumor. It is currently not possible to distinguish patients with good and bad prognosis. SMAD4 is an important tumor suppressor gene that mediates transforming growth factor-P superfamily signaling and is located in chromosome 18q21, a region with frequent genetic losses in these tumors. Allelic imbalance in 18q has been linked to poor prognosis in a subset of colorectal cancer patients. Therefore, we generated a tissue microarray containing triplicate tumor samples from 86 Dukes C patients and used immunohistochemistry to assess the relative expression level of SMAD4 and its value as a prognostic marker. In addition, SMAD4 was screened for mutations and two polymorphic microsatellite markers were used to assess the presence of allelic imbalance in these tumors. Patients with tumors expressing high SMAD4 levels had significantly better overall (P < 0.025) and disease-free (P < 0.013) survival than patients with low levels. This identifies SMAD4 as a prognostic marker for Dukes C colorectal cancer. Although all tumors with absent SMAD4 staining showed allelic imbalance in 18q21, tumors with 18q21 allelic imbalance as a group showed no difference in SMAD4 levels compared with tumors without allelic imbalance, suggesting that additional mechanisms of SMAD4 down-regulation exist. In addition, although SMAD4 mutations were found in five tumors, they were not associated with shorter survival. In conclusion, the level of expression of SMAD4 was found to be a more sensitive marker than 18q21 allelic imbalance and SMAD4 mutations, which were of no prognostic significance for these patients.{"}",
    keywords = "311 Basic medicine",
    author = "Hafid Alazzouzi and Pia Alhopuro and Reijo Salovaara and Heli Sammalkorpi and J{\"a}rvinen, {Heikki J} and Jukka-Pekka Mecklin and Akseli Hemminki and Simo Schwartz and Aaltonen, {Lauri A} and Diego Arango",
    year = "2005",
    doi = "10.1158/1078-0432.CCR-04-1458",
    language = "English",
    volume = "11",
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    journal = "Clinical Cancer Research",
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    Alazzouzi, H, Alhopuro, P, Salovaara, R, Sammalkorpi, H, Järvinen, HJ, Mecklin, J-P, Hemminki, A, Schwartz, S, Aaltonen, LA & Arango, D 2005, 'SMAD4 as a prognostic marker in colorectal cancer', Clinical Cancer Research, vol. 11, nr. 7, s. 2606-2611. https://doi.org/10.1158/1078-0432.CCR-04-1458

    SMAD4 as a prognostic marker in colorectal cancer. / Alazzouzi, Hafid; Alhopuro, Pia; Salovaara, Reijo; Sammalkorpi, Heli; Järvinen, Heikki J; Mecklin, Jukka-Pekka; Hemminki, Akseli; Schwartz, Simo; Aaltonen, Lauri A; Arango, Diego.

    I: Clinical Cancer Research, Vol. 11, Nr. 7, 2005, s. 2606-2611.

    Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

    TY - JOUR

    T1 - SMAD4 as a prognostic marker in colorectal cancer

    AU - Alazzouzi, Hafid

    AU - Alhopuro, Pia

    AU - Salovaara, Reijo

    AU - Sammalkorpi, Heli

    AU - Järvinen, Heikki J

    AU - Mecklin, Jukka-Pekka

    AU - Hemminki, Akseli

    AU - Schwartz, Simo

    AU - Aaltonen, Lauri A

    AU - Arango, Diego

    PY - 2005

    Y1 - 2005

    N2 - "More than 50% of patients with Dukes C colorectal cancer have disease recurrence and die within 5 years after surgical removal of their primary tumor. It is currently not possible to distinguish patients with good and bad prognosis. SMAD4 is an important tumor suppressor gene that mediates transforming growth factor-P superfamily signaling and is located in chromosome 18q21, a region with frequent genetic losses in these tumors. Allelic imbalance in 18q has been linked to poor prognosis in a subset of colorectal cancer patients. Therefore, we generated a tissue microarray containing triplicate tumor samples from 86 Dukes C patients and used immunohistochemistry to assess the relative expression level of SMAD4 and its value as a prognostic marker. In addition, SMAD4 was screened for mutations and two polymorphic microsatellite markers were used to assess the presence of allelic imbalance in these tumors. Patients with tumors expressing high SMAD4 levels had significantly better overall (P < 0.025) and disease-free (P < 0.013) survival than patients with low levels. This identifies SMAD4 as a prognostic marker for Dukes C colorectal cancer. Although all tumors with absent SMAD4 staining showed allelic imbalance in 18q21, tumors with 18q21 allelic imbalance as a group showed no difference in SMAD4 levels compared with tumors without allelic imbalance, suggesting that additional mechanisms of SMAD4 down-regulation exist. In addition, although SMAD4 mutations were found in five tumors, they were not associated with shorter survival. In conclusion, the level of expression of SMAD4 was found to be a more sensitive marker than 18q21 allelic imbalance and SMAD4 mutations, which were of no prognostic significance for these patients."

    AB - "More than 50% of patients with Dukes C colorectal cancer have disease recurrence and die within 5 years after surgical removal of their primary tumor. It is currently not possible to distinguish patients with good and bad prognosis. SMAD4 is an important tumor suppressor gene that mediates transforming growth factor-P superfamily signaling and is located in chromosome 18q21, a region with frequent genetic losses in these tumors. Allelic imbalance in 18q has been linked to poor prognosis in a subset of colorectal cancer patients. Therefore, we generated a tissue microarray containing triplicate tumor samples from 86 Dukes C patients and used immunohistochemistry to assess the relative expression level of SMAD4 and its value as a prognostic marker. In addition, SMAD4 was screened for mutations and two polymorphic microsatellite markers were used to assess the presence of allelic imbalance in these tumors. Patients with tumors expressing high SMAD4 levels had significantly better overall (P < 0.025) and disease-free (P < 0.013) survival than patients with low levels. This identifies SMAD4 as a prognostic marker for Dukes C colorectal cancer. Although all tumors with absent SMAD4 staining showed allelic imbalance in 18q21, tumors with 18q21 allelic imbalance as a group showed no difference in SMAD4 levels compared with tumors without allelic imbalance, suggesting that additional mechanisms of SMAD4 down-regulation exist. In addition, although SMAD4 mutations were found in five tumors, they were not associated with shorter survival. In conclusion, the level of expression of SMAD4 was found to be a more sensitive marker than 18q21 allelic imbalance and SMAD4 mutations, which were of no prognostic significance for these patients."

    KW - 311 Basic medicine

    U2 - 10.1158/1078-0432.CCR-04-1458

    DO - 10.1158/1078-0432.CCR-04-1458

    M3 - Article

    VL - 11

    SP - 2606

    EP - 2611

    JO - Clinical Cancer Research

    JF - Clinical Cancer Research

    SN - 1078-0432

    IS - 7

    ER -