Alterations of the p53 and PIK3CA/AKT/mTOR pathways in angiosarcomas: a pattern distinct from other sarcomas with complex genomics.
BACKGROUND
The p53 and phosphoinositide-3-kinase, catalytic, alpha polypeptide/v-akt murine thymoma viral oncogene homolog/mechanistic target of rapamycin (PIK3CA/AKT/mTOR) pathways frequently are altered in sarcoma with complex genomics, such as leiomyosarcoma (LMS) or undifferentiated pleomorphic sarcoma (UPS). The scale of genetic abnormalities in these pathways remains unknown in angiosarcoma (AS).


METHODS
The authors investigated the status of critical genes involved in the p53 and PIK3CA/AKT/mTOR pathways in a series of 62 AS.


RESULTS
The mutation and deletion rates of tumor protein 53 (TP53) were 4% and 0%, respectively. Overexpression of p53 was detected by immunohistochemistry in 49% of patients and was associated with inferior disease-free survival. Although p14 inactivation or overexpression of the human murine double minute homolog (HDM2) were frequent in LMS and UPS and could substitute for TP53 mutation or deletion, such alterations were rare in angiosarcomas. Phosphorylated ribosomal protein S6 kinase (p-S6K) and/or phosphorylated eukaryotic translation initiation factor 4E binding protein 1 (p-4eBP1) overexpression was observed in 42% of patients, suggesting frequent activation of the PIK3CA/AKT/mTOR pathway in angiosarcomas. Activation was not related to intragenic deletion of phosphatase and tensin homolog (PTEN), an aberration that is frequent in LMS and UPS but absent in angiosarcomas.


CONCLUSIONS
The current results indicated that angiosarcomas constitute a distinct subgroup among sarcomas with complex genomics. Although TP53 mutation and PTEN deletion are frequent in LMS and UPS, these aberrations are rarely involved in the pathogenesis of angiosarcoma.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. italiano@bergonie.org
Antoine
A
Italiano
Chun-Liang
CL
Chen
Rachael
R
Thomas
Matthew
M
Breen
Françoise
F
Bonnet
Nicolas
N
Sevenet
Michel
M
Longy
Robert G
RG
Maki
Jean-Michel
JM
Coindre
Cristina R
CR
Antonescu
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D016158:Genes, p53; D023281:Genomics; D006394:Hemangiosarcoma / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D058570:TOR Serine-Threonine Kinases; C497206:MDM2 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C482119:BRAF protein, human; C494929:PTEN protein, human