Pre-invasive ovarian mucinous tumors are characterized by CDKN2A and RAS pathway aberrations.
BACKGROUND
Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histologic subtype remains undetermined. Although these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors.


METHODS
To explore the spectrum of genomic alterations common to mucinous tumors we carried out high-resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n = 20) and borderline tumors (n = 22).


RESULTS
Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors.


CONCLUSIONS
This study is the largest and highest resolution analysis of mucinous benign and borderline tumors carried out to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways.
Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Sally M
SM
Hunter
Kylie L
KL
Gorringe
Michael
M
Christie
Simone M
SM
Rowley
David D
DD
Bowtell
Ian G
IG
Campbell
D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D018291:Cystadenoma, Mucinous / Q000235:genetics / Q000473:pathology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D018631:ras Proteins