Novel mutations discovered in a form of ovarian cancer Hosein Kouros-Mehr

A recent paper* in Nature Genetics discovered mutations in the SMARCA4 gene in a form of ovarian cancer known as small cell carcinoma of the ovary.  This cancer is highly aggressive and mostly affects young women.  The authors sequenced tumors from 12 patients and discovered loss of function mutations in SMARCA4 in 100% of the patients (probability of that happening by chance is less than 0.0000000000000002).  The importance of this finding is that it may lead to targeted therapies that can be tailored for patients with this disease.  

The SMARCA4 gene is an ATP-dependent helicase that is part of the SWI/SNF complex.  This complex regulates chromatin remodeling and is important for transcriptional activation of genes that may be normally silenced in heterochromatin.  SWI/SNF complex is composed of many proteins and its mechanism of action is largely unknown, but it is thought that SWI/SNF can destabilize histone-DNA interaction in an ATP-dependent manner and lead to chromatin remodeling of target genes, thereby altering the accessibility and transcription of the target genes.  SMARCA4 is a ATP-dependent helicase, which means it helps separate/unwind the strands of DNA using energy derived from ATP hydrolysis.  

The authors found that SMARCA4 mutations in these patients were all loss of function mutations that lead to significantly less SMARCA4 protein in the cells. Interestingly, the overexpression of SMARCA4 in SMARCA4-null cancer cell lines led to suppression of cell growth, suggesting that SMARCA4 is a bona fide tumor suppressor.  The depletion of SMACA4 using lentiviral shRNA knockdown led to increase cell growth in cell lines.  

SMARCA4 mutations are also found in bladder cance, stomach cancer, lung cancer, and glioma (5-8% frequency).  Most of these are missense mutations of uncertain consequence, though lung cancers contained frequent inactivating SMARCA4 mutations.  Further work will be necessary to identify candidate targets for drug discovery in SMARCA4 mutant tumors.  For example, the SMARCA2 ATPase may be upregulated in SMARCA4 mutant tumors and could be a candidate target in this patient population.  Further validation will be necessary to evaluate this potential new target.  

Jelinic, P., et. al.  (2014).  Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.  

Nature Genetics

 

(2014) 

23 March 2014

Hosein Kouros-Mehr