Novel genetic variants in miR-191 gene and familial ovarian cancer.
BACKGROUND
Half of the familial aggregation of ovarian cancer can't be explained by any known risk genes, suggesting the existence of other genetic risk factors. Some of these unknown factors may not be traditional protein encoding genes. MicroRNA (miRNA) plays a critical role in tumorigenesis, but it is still unknown if variants in miRNA genes lead to predisposition to cancer. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk.


RESULTS
To test this hypothesis in familial ovarian cancer, we screened for genetic variants in thirty selected miRNA genes, which are predicted to regulate key ovarian cancer genes and are reported to be misexpressed in ovarian tumor tissues, in eighty-three patients with familial ovarian cancer. All of the patients are non-carriers of any known BRCA1/2 or mismatch repair (MMR) gene mutations. Seven novel genetic variants were observed in four primary or precursor miRNA genes. Among them, three rare variants were found in the precursor or primary precursor of the miR-191 gene. In functional assays, the one variant located in the precursor of miR-191 resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR-191. In further analysis, we found that this particular variant exists in five family members who had ovarian cancer.


CONCLUSIONS
Our findings suggest that there are novel genetic variants in miRNA genes, and those certain genetic variants in miRNA genes can affect the expression of mature miRNAs and, consequently, might alter the regulation of TSGs or oncogenes. Additionally, the variant might be potentially associated with the development of familial ovarian cancer.
Shen
Jie
J
Department of Cancer Prevention and Controls, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
DiCioccio
Richard
R
Odunsi
Kunle
K
Lele
Shashikant B
SB
Zhao
Hua
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D005260:Female; D016147:Genes, Tumor Suppressor; D014644:Genetic Variation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D010051:Ovarian Neoplasms / Q000235:genetics*; D012307:Risk Factors
C546177:MIRN191 microRNA, human; D035683:MicroRNAs