TY - JOUR
T1 - Role of p16/INK4a in gastrointestinal stromal tumor progression
AU - Ricci, Riccardo
AU - Arena, Vincenzo
AU - Castri, Federica
AU - Martini, Maurizio
AU - Maggiano, Nicola Giuseppe
AU - Murazio, Marino
AU - Pacelli, Fabio
AU - Potenza, Angelo
AU - Vecchio, Fabio Maria
AU - Larocca, Luigi Maria
PY - 2004
Y1 - 2004
N2 - Because the p16 locus is involved consistently in chromosomal losses found in malignant gastrointestinal stromal tumors (GISTs), we studied p16 in a series of 21 GISTs with complete follow-up using immunohistochemical analysis, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and methylation-specific PCR (MSP). A fraction of cells of more than 20% with low or absent p16 immunostaining was detected in 12 GISTs, including all showing malignancy. RT-PCR revealed decreased p16 transcription in all except 2 p16 protein-deficient GISTs. By MSP, 7 cases showed p16 promoter methylation (all hypoexpressing p16; 6 malignant). A fraction of p16-deficient cells of more than 20% was associated with clinical malignancy (P = .003; log-rank test). The percentage of cells underexpressing p16, size, cellularity, mitotic count, and coagulative necrosis were associated with malignancy by Cox proportional hazards univariate analysis; only the former factor was selected by multivariate analysis (P = .039). Thus, p16 down-regulation, partly due to p16 promoter methylation, is implied in GIST progression. Furthermore, p16 immunohistochemical assessment seems a promising method for GIST prognostication.
AB - Because the p16 locus is involved consistently in chromosomal losses found in malignant gastrointestinal stromal tumors (GISTs), we studied p16 in a series of 21 GISTs with complete follow-up using immunohistochemical analysis, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and methylation-specific PCR (MSP). A fraction of cells of more than 20% with low or absent p16 immunostaining was detected in 12 GISTs, including all showing malignancy. RT-PCR revealed decreased p16 transcription in all except 2 p16 protein-deficient GISTs. By MSP, 7 cases showed p16 promoter methylation (all hypoexpressing p16; 6 malignant). A fraction of p16-deficient cells of more than 20% was associated with clinical malignancy (P = .003; log-rank test). The percentage of cells underexpressing p16, size, cellularity, mitotic count, and coagulative necrosis were associated with malignancy by Cox proportional hazards univariate analysis; only the former factor was selected by multivariate analysis (P = .039). Thus, p16 down-regulation, partly due to p16 promoter methylation, is implied in GIST progression. Furthermore, p16 immunohistochemical assessment seems a promising method for GIST prognostication.
KW - Aged
KW - Aged, 80 and over
KW - Cyclin-Dependent Kinase Inhibitor p16
KW - DNA Methylation
KW - Disease Progression
KW - Female
KW - Gastrointestinal Neoplasms
KW - Humans
KW - Immunohistochemistry
KW - Male
KW - Middle Aged
KW - Prognosis
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Stromal Cells
KW - Tumor Markers, Biological
KW - Aged
KW - Aged, 80 and over
KW - Cyclin-Dependent Kinase Inhibitor p16
KW - DNA Methylation
KW - Disease Progression
KW - Female
KW - Gastrointestinal Neoplasms
KW - Humans
KW - Immunohistochemistry
KW - Male
KW - Middle Aged
KW - Prognosis
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Stromal Cells
KW - Tumor Markers, Biological
UR - http://hdl.handle.net/10807/27181
U2 - 10.1309/MJ4X-N2M5-7HNC-8X5H
DO - 10.1309/MJ4X-N2M5-7HNC-8X5H
M3 - Article
SN - 0002-9173
VL - 122
SP - 35
EP - 43
JO - American Journal of Clinical Pathology
JF - American Journal of Clinical Pathology
ER -