"Resistance to therapy caused by intragenic deletion in BRCA2"
"Secondary mutations as a mechanism ofs cisplatin resistance in BRCA2-mutated cancers"

The BRCA2 protein directly binds to and regulates RAD51 and repair damaged DNA. Germline mutations in BRCA2 predispose carriers to the development of breast, ovarian, and a variety of other cancers. The tumors in BRCA2 carriers are more sensitive to DNA-damaging chemotherapy.One of the most difficult problems in the treatment of BRCA2 tumors is acquired resistance to chemotherapy. Interestingly, the researchers have recently found that, when exposed to cisplatin, some ovarian cancer cells develop secondary mutations on their BRCA2 gene that restore the gene's ability to repair DNA and gained new insights into how changes in BRCA2 can affect a cancer's resistance to therapy.The team, led by Toshiyasu Taniguchi, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, found that the HCC1428 cisplatin-resistant BRCA2-mutated breast-cancer cell line had a secondary genetic change that restored BRCA2 function. This restoration of gene function makes the cancer cells resistant to chemotherapy. The researchers suspect they may be able to generalize their findings regarding secondary mutations in BRCA2 may help explain drug resistance to a variety of cancers, including those of the breast, prostate and pancreas.Another study showed the similar mechanism involved in resistance to PARP (Poly　ADP-Ribose polymerase) inhibitors which are known to be more effective in BRCA1/2 mutation cases. Intragenic deletion of the protein-truncating c.6174delT frameshift mutation and restoration of the open reading frame allowed expression of new BRCA2 isoforms with resistance to PARP inhibitors.These observations raise the possibility that blocking BRCA2 function in such patients might allow doctors to overcome drug resistance and continue with cisplatin treatment. (Commentary : Dr.Naoko Abe, M.D.)

"Resistance to therapy caused by intragenic deletion in BRCA2"
Stacey L. Edwards, et al.
Nature vol 451, 1111-1115, 28 February 2008

"Secondary mutations as a mechanism ofs cisplatin resistance in BRCA2-mutated cancers"
Wataru Sakai, et al.
Nature vol 451, 1116-1120, 28 February 2008

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