Genetic Cause Found for Rare Aggressive Ovarian Cancer

The genetic cause of a rare type of ovarian cancer known as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), that most often strikes girls and young women has been revealed.

This type of cancer, SCCHOT, usually is not diagnosed until it is in its advanced stages and it does not respond to standard chemotherapy, and 65% of patients die within two years. It can affect girls as young as 14 months, and women as old as 58 years, with a mean age of only 24 years old.


An international team led by the Translational Genomics Research Institute (TGen; Phoenix, AZ, USA) analyzed the genetic etiology of SCCOHT by performing next-generation sequencing on a series of tumors and germline samples from 12 SCCOHT cases. This included nine tumors with four matched germline samples and three additional germline samples, and on the SCCOHT cell line BIN-67. DNA from tumor and blood specimens was analyzed using whole-genome sequencing and whole-exome sequencing.

Genomic DNA from each sample was fragmented to a target size of 300 to 350 base pairs (bp). After ligation, samples were run on a gel to separate products and the products were quantified using the High-Sensitivity DNA chip on an Agilent 2100 Bioanalyzer (Santa Clara, CA, USA). A tissue microarray (TMA) representing nine SCCOHT cases was fabricated at TGen for the study. Protein blot analysis was performed on whole cell extracts.

The scientists identified frequent germline and somatic gene SWItch/Sucrose NonFermentable (SWI/SNF) Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 4 (SMARCA4) mutations and SMARCA4 protein loss in SCCOHT. The loss of SMARCA4 protein expression is extremely specific to SCCOHT and can facilitate the differential diagnosis of SCCOHT.

Jeffrey Trent, PhD, President and Research Director of TGen, and the study's senior author, said, “This is a thoroughly remarkable study. Many genetic anomalies can be like a one-lane road to cancer; difficult to negotiate. But these findings indicate a genetic superhighway that leads right to this highly aggressive disease. The correlation between mutations in SMARCA4 and the development of SCCOHT is simply unmistakable.” The study was published on March 23, 2014, in the journal Nature Genetics.

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