p53 and p16 expression profiles in vulvar cancer - a translational analysis by the AGO-CaRE- study group
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p53 and p16 expression profiles in vulvar cancer - a translational analysis by the AGO-CaRE- study group. / Woelber, Linn; Prieske, Katharina; Eulenburg, Christine; Oliveira-Ferrer, Leticia; DE Gregorio, Nikolaus; Klapdor, Ruediger; Kalder, Matthias; Braicu, Ioana; Fuerst, Sophie; Klar, Maximilian; Straub, Hans-Georg; Beckmann, Matthias; Meier, Werner; Ignatov, Atanas; Mustea, Alexander; Jueckstock, Julia; Schmidt, Georg; Bauernschlag, Dirk; Hellriegel, Martin; Canzler, Ulrich; Petry, Karl Ulrich; Kommoss, Stefan; Hantschmann, Peer; Heubner, Martin; Mahner, Sven; Burandt, Eike; AGO-CaRE translational investigators.
In: AM J OBSTET GYNECOL, Vol. 224, No. 6, 06.2021, p. 595.e1-595.e11.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - p53 and p16 expression profiles in vulvar cancer - a translational analysis by the AGO-CaRE- study group
AU - Woelber, Linn
AU - Prieske, Katharina
AU - Eulenburg, Christine
AU - Oliveira-Ferrer, Leticia
AU - DE Gregorio, Nikolaus
AU - Klapdor, Ruediger
AU - Kalder, Matthias
AU - Braicu, Ioana
AU - Fuerst, Sophie
AU - Klar, Maximilian
AU - Straub, Hans-Georg
AU - Beckmann, Matthias
AU - Meier, Werner
AU - Ignatov, Atanas
AU - Mustea, Alexander
AU - Jueckstock, Julia
AU - Schmidt, Georg
AU - Bauernschlag, Dirk
AU - Hellriegel, Martin
AU - Canzler, Ulrich
AU - Petry, Karl Ulrich
AU - Kommoss, Stefan
AU - Hantschmann, Peer
AU - Heubner, Martin
AU - Mahner, Sven
AU - Burandt, Eike
AU - AGO-CaRE translational investigators
N1 - Copyright © 2021 Elsevier Inc. All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - BACKGROUND: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed.OBJECTIVE: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance.STUDY DESIGN: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction.RESULTS: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042).CONCLUSION: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.
AB - BACKGROUND: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed.OBJECTIVE: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance.STUDY DESIGN: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction.RESULTS: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042).CONCLUSION: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.
KW - Adult
KW - Aged
KW - Biomarkers, Tumor/metabolism
KW - Carcinoma, Squamous Cell/diagnosis
KW - Cyclin-Dependent Kinase Inhibitor p16/metabolism
KW - Female
KW - Follow-Up Studies
KW - Germany/epidemiology
KW - Humans
KW - Immunohistochemistry
KW - Middle Aged
KW - Mutation
KW - Papillomavirus Infections/complications
KW - Phenotype
KW - Prognosis
KW - Retrospective Studies
KW - Survival Analysis
KW - Tissue Array Analysis
KW - Translational Medical Research
KW - Tumor Suppressor Protein p53/genetics
KW - Up-Regulation
KW - Vulvar Neoplasms/diagnosis
U2 - 10.1016/j.ajog.2020.12.1220
DO - 10.1016/j.ajog.2020.12.1220
M3 - SCORING: Journal article
C2 - 33453182
VL - 224
SP - 595.e1-595.e11
JO - AM J OBSTET GYNECOL
JF - AM J OBSTET GYNECOL
SN - 0002-9378
IS - 6
ER -
