Cancer due to a single gene mutation

As the ovum prepares to be released at ovulation, the surrounding granulosa cells secrete a follicular fluid that creates a cavity or antrum. This mass of tissue, fluid, and ovum is called the Graafian follicle. Adult granulosa cell tumors (AGCT) are the most common type of non-epithelial tumors of the ovary. GACTs occur more frequently after menopause and have a favorable prognosis. Aggressive, often fatal, recurrences can occur in up to 50% of diagnosed cases. Because these tumors grow slowly, they can recur even 30 years after removal of the primary tumor.

Most of these tumors have a DNA variant of the gene that encodes the FOXL2 protein. In addition, there are FOXL2 variants inherited by the germ line that are responsible for blepharophimosis syndrome, a hereditary disease characterized by malformation of the eyelid and the development of premature ovarian failure in many of the women who suffer from it.

FOXL2 is a protein that binds to DNA regulating the expression of numerous genes in different tissues, such as the developing mesenchymal tissue that will give rise to the eyelids and ovarian follicles, as well as in the ovaries of adult women. Its function is essential for the differentiation and maintenance of the ovaries, as well as for the repression of the testicular differentiation program during embryonic development.

Most solid tumors are characterized by presenting several mutations in different genes (oncogenes or suppressor genes), which are responsible for the development and progression of cancer. Through massive sequencing of the AGCTs genome, it has been determined for more than a decade that one of the numerous mutations present in their genomes is located in the FOXL2 gene in more than 90% of this type of tumors. It should be noted that the mutation described is identical in all AGCTs sequenced and consists of a point mutation in the FOXL2 gene. Specifically, a change of the cytosine base to guanine occurs, which causes the substitution of a single amino acid of the 376 that make up the complete FOXL2 protein, that is, it changes the cysteine ​​(C) amino acid at position 134 by a tryptophan ( W), designated C134W.

At this point, the team led by Alberto M. Pendás, from the Cancer Research Center in Spain, has investigated the mutations found in other genes to determine if they cooperate with the mutated version of FOXL2 in the generation of ovarian tumors. Their proposed objective was to verify the causality of the C134W mutation. If there is causation, the mere presence of FOXL2-C134W is the sole driver of the initiation and progression of ovarian tumors.

Reduction in the number of ovarian follicles (causing premature ovarian failure) in mice with the humanized FOXL2 variant. (Image: Cancer Research Center (CSIC-USAL))

The research team also includes, among others, Reiner Veitia, from the University of Paris in France, and Elena Llano, from the University of Salamanca in Spain.

“Our group -says Elena Llano- has developed for the first time a mouse model that harbors the C134W variant in its FOXL2 gene, present in human tumors, in order to be able to evaluate in vivo the unknown role of FOXL2 in tumor initiation and development . To our surprise, these mice display the eyelid hypoplasia seen in blepharophimosis syndrome. Curiously, females with this mutation have reduced fertility and, what is more relevant, all of them spontaneously develop AGCT. That is, they gradually progress from abnormal ovaries with aberrant granulosa cells to ovaries with stromal hyperplasia and atypia, eventually leading to the appearance of ovarian tumors in all animals before 18 months of age. Therefore, this process appears to be driven solely by the presence of the FOXL2 variant.”

Pendás highlights: “When we compare these data with previous results in human AGCTs, we observed similar deregulated pathways. Finally, a mutational analysis of the transcriptomic data of the mouse AGCTs suggested the absence of additional driver mutations other than FOXL2-C134W. These results provide a clear in vivo example where a single gene mutation triggers the development of a tumor with profound alterations in the expression of numerous genes crucial for normal ovarian homeostasis.”

The study is titled “The oncogenic FOXL2 C134W mutation is a key driver of granulosa cell tumors. And it has been published in the academic journal Cancer Research. (Source: Almudena Timón / CIC/ CSIC / US)