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Loss-of-function SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily a member 4 (SMARCA4; BRG1) mutations associated with small-cell carcinoma of the ovary, hypercalcemia type (SCCOHT)

Genetic studies suggest loss-of-function mutations in SMARCA4 could help diagnose SCCOHT. Mutations in the chromatin remodeling gene SMARCA4 were identified in patients from three families using whole-genome sequencing, and the association was validated in an additional affected family, preserved tumor samples and a SCCOHT cell line. Loss of SMARCA4 was also detected in 38 of 43 SCCOHT tumor samples but only 1 of 139 samples of other ovarian tumors. In an independent analysis of 12 SCCOHT samples, exome sequencing identified SMARCA4 mutations in all tumors, and immunohistochemistry studies on 9 of the samples showed decreased expression of the protein compared with that in samples from healthy controls. In non-small cell lung cancer (NSCLC) cells lacking SMARCA4, ectopic expression of the gene decreased tumor growth. In a separate study, 9 of 12 SCCOHT tumor and patient germline tissue samples had SMARCA4 mutations, and 14 of 17 SCCOHT tumors showed loss of SMARCA4 protein expression. Next steps include identifying strategies to treat patients with the mutations.

SciBX 7(16); doi:10.1038/scibx.2014.475
Published online April 24, 2014

For first study, findings unpatented; licensing status not applicable

Patent application filed for findings in second study; available for licensing

Patent and licensing status unavailable for findings in third study

Witkowski, L. et al. Nat. Genet.; published online March 23, 2013;
doi:10.1038/ng.2931
Contact: William D. Foulkes, McGill University, Montreal, Quebec, Canada
e-mail:

william.foulkes@mcgill.ca

Jelinic, P. et al. Nat. Genet.; published online March 23, 2014;
doi:10.1038/ng.2922
Contact: Douglas A. Levine, Memorial Sloan Kettering Cancer Center, New York, N.Y.
e-mail:

levine2@mskcc.org

Ramos, P. et al. Nat. Genet.; published online March 23, 2014;
doi:10.1038/ng.2928
Contact: Jeffrey M. Trent, The Translational Genomics Research Institute, Phoenix, Ariz.
e-mail:

jtrent@tgen.org
Contact: David G. Huntsman, The University of British Columbia, Vancouver, British Columbia, Canada
e-mail:

dhuntsma@bccancer.bc.ca