Discovery of Genetic Mutation May Improve Diagnosis and Treatment of Granulosa-Cell Ovarian Tumors

Roxanne Nelson

June 12, 2009

June 12, 2009 — Granulosa-cell tumors (GCTs) are relatively rare, accounting for less than 5% of all ovarian cancers. Traditional chemotherapeutic approaches have limited efficacy in treating patients with advanced-stage or recurrent disease, indicating the need for more effective treatment regimens. However, in a study published online June 10 in the New England Journal of Medicine, researchers report having identified a single mutation in the genetic code of GCTs.

The whole-transcriptome sequencing of 4 GCTs identified a single recurrent somatic mutation (402C→G) in FOXL2, a gene encoding a transcription factor known to be critical for the development of granulosa cells. The mutation was present in almost all morphologically identified adult-type GCTs, but absent from 49 other ovarian sex-cord stromal tumors (SCSTs) and 329 unrelated ovarian or breast tumors.

"GCTs are sometimes problematic to diagnose," said senior author David G. Huntsman, MD, a genetic pathologist at the British Columbia Cancer Agency and Vancouver General Hospital and associate professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia. "This finding will assist in making an accurate diagnosis."

We think the mutation is the driver of the tumor, and now we have the first clue to developing a treatment.

In this study, Dr. Huntsman told Medscape Oncology, a mutation was identified that appears to be common in all GCT tumors. "There are currently no effective treatments beyond primary surgery," he said. "We think the mutation is the driver of the tumor, and now we have the first clue to developing a treatment."

Methods for rapidly sequencing whole cancer genomes have recently been developed. "A suite of new technologies has emerged that allow sequencing of whole genomes," said Dr. Huntsman. "We can undertake genomic research in ways that we never could have considered doing even just a few years ago."

Mutation Common in GCTs, Rare in Other Tumors

Initial studies suggested that hundreds of samples of any type of malignancy would have to be sequenced to derive clinically useful information or make any clinically useful discoveries, but Dr. Huntsman and colleagues hypothesized that knowledge could be gained from much smaller studies if the cancers were carefully selected and represented clinically homogenous diseases.

Since GCTs are genomically stable, the researchers speculated that common GCT-specific molecular abnormalities in the transcriptomes of GCTs could be identified through the analysis of a limited number of samples. They analyzed 4 ovarian adult-type GCTs (1 primary and 3 recurrent tumors), 10 ovarian carcinomas, and 1 cell line derived from a serous borderline tumor. Frozen tissue samples from 149 epithelial ovarian tumors and 180 breast carcinomas were also analyzed.

In addition, the researchers analyzed a second series of formalin-fixed paraffin-embedded ovarian SCSTs that consisted of 95 tumor samples: 27 adult-type GCTs, 8 juvenile-type GCTs, 23 fibromas, 14 Sertoli–Leydig cell tumors, 13 thecomas, and 10 steroid-cell tumors.

Dr. Huntsman and his team found that all 4 index GCTs had a missense point mutation, 402C→G (C134W), in FOXL2. The FOXL2 mutation was also detected in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%).

However, the mutation was not observed in 49 of the other types of SCSTs or in 329 unrelated ovarian or breast tumors.

"This is the first example of the way new technology will enhance our understanding of cancer and provide the knowledge to really allow the personalization of cancer care," said Dr. Huntsman. "This is a really exciting taste of what's to come. The technology is going to change they way we look at these diseases."

May Improve Diagnostic Accuracy

Although there are limitations to the study, the researchers successfully applied transcriptome sequencing to identify a consistently occurring somatic mutation in GCTs, according to an accompanying editorial.

"This demonstrates that transcriptome sequencing has strong potential as an efficient and cost-effective alternative to whole-genome sequencing," writes Jay Shendure, MD, PhD, from the University of Washington in Seattle, and Colin J. Stewart, MB, ChB, from King Edward Memorial Hospital and Bendat Cancer Centre at St. John of God Hospital in Perth, Australia.

Although immunohistochemical techniques that have been developed during the past decade have proved to be very helpful in diagnosing GCTs, they note, none of the currently available markers are completely reliable. "Thus, as with other tumors that show characteristic genetic alterations, an adjunct molecular test involving FOXL2 analysis offers the possibility of improving diagnostic accuracy in patients with GCTs."

The study was supported by grants from the British Columbia Cancer Foundation, the Vancouver General Hospital Foundation, Genome Canada, the Michael Smith Foundation for Health, the Genome Sciences Centre, Eli Lilly Canada, and the Canadian Institutes of Health Research's Training Program on Clinician-Scientists in Molecular Oncologic Pathology. Dr. Huntsman reports receiving grant support from Sanofi-Aventis and Novartis, and is listed as an inventor on a provisional patent application filed by the British Columbia Cancer Agency on the diagnostic use of the FOXL2 402C→G mutation and its development as a therapeutic target. Coauthor Martin Köbel, MD, from Vancouver General Hospital and the British Columbia Cancer Agency, reports receiving grant support from Eli Lilly. Dr. Shendure reports receiving consulting fees from Complete Genomics, lecture fees from Illumina, and grant support from Agilent, and holding patents related to DNA sequencing.

N Engl J Med. Published online ahead of print June 10, 2009. Abstract

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