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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-04-1128.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 681-689
NEOPLASIA
Hodgkin and Reed-Sternberg cells harbor alterations in the major
tumor suppressor pathways and cell-cycle checkpoints: analyses using
tissue microarrays
Juan F. García,
Francisca
I. Camacho,
Manuel Morente,
Máximo Fraga,
Carlos Montalbán,
Tomás
Álvaro, Carmen Bellas,
Ángel Castaño,
Ana Díez,
Teresa Flores,
Carmen Martín,
Miguel A. Martínez,
Francisco Mazorra,
Javier Menárguez,
Maria J. Mestre,
Manuela Mollejo,
Ana I. Sáez,
Lydia Sánchez, and
Miguel A. Piris for the Spanish Hodgkin Lymphoma Study
Group
From the Lymphoma Group, Molecular Pathology Program,
and Immunohistochemistry and Histology Unit, Centro Nacional
de Investigaciones Oncológicas (CNIO), Madrid;
Departamento Anatomía Patológica, Hospital
Clínico Universitario, Santiago de Compostela; Departamento
Medicina Interna and Anatomía Patológica, Hospital
Ramón y Cajal, Madrid; Departamentos Anatomía
Patológica, Hospital Verge de la Cinta, Tortosa; Hospital Severo
Ochoa, Leganés; Hospital Clínico Salamanca; Hospital
Universitario Clínico San Carlos, Madrid; Hospital
Universitario 12 de Octubre, Madrid; Hospital Marqués de
Valdecilla, Santander; Hospital Gregorio Marañón, Madrid;
Hospital Móstoles, Madrid; and Hospital Virgen de la
Salud, Toledo, Spain.
Tumoral cells in Hodgkin lymphoma (HL) display an increased growth
fraction and diminished apoptosis, implying a profound disturbance of
the cell cycle and apoptosis regulation. However, limitations of
molecular techniques have prevented the analysis of the tumor
suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA)
is a powerful tool for analyzing a large number of molecular variables
in a large series of tumors, although the feasibility of this technique
has not yet been demonstrated in heterogeneous tumors. The expression
of 29 genes regulating the cell cycle and apoptosis were analyzed by
immunohistochemistry and in situ hybridization in 288 HL biopsies using
TMA. The sensitivity of the technique was validated by comparing the
results with those obtained in standard tissue sections. The results
revealed multiple alterations in different pathways and checkpoints,
including G1/S and G2/M transition and apoptosis. Striking findings
were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2,
Bcl-XL, survivin, and NF- B proteins. A multiparametric
analysis identified proteins associated with increased growth fraction
(Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2,
Bcl-XL, survivin, STAT1, and STAT3), and proteins
associated with apoptosis (NF-B, STAT1, and RB). The analysis also
demonstrated that Epstein-Barr virus (EBV)-positive cases
displayed a characteristic profile, confirming the pathogenic role of
EBV in HL. Survival probability depends on multiple biologic factors,
including overexpression of Bcl2, p53, Bax, Bcl-XL, MIB1,
and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells
harbor concurrent and overlapping alterations in the major tumor
suppressor pathways and cell-cycle checkpoints. This appears to
determine the viability of the tumoral cells and the clinical outcome.
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