BRCA1 gene is key for blood forming stem cells

Researchers have found that the BRCA1 gene is required for the survival of blood forming stem cells, which could explain why patients with BRCA1 mutations do not have an elevated risk for leukemia. The stem cells die before they have an opportunity to transform into a blood cancer.

"One of the great mysteries in cancer research is why inherited mutations, such as those in BRCA1, cause cancer only in specific tissues such as the breast and ovaries, rather than in all tissues. Our data suggest a 'die or transform' hypothesis, which could explain this tissue specificity," said senior of the study published in Cell Reports.

Additional data from this study suggest these patients may have a tougher time with the side effects of chemotherapy.

"Patients with certain BRCA1 mutations may be at a higher than expected risk for serious complications during chemotherapy treatment," said the senior author. "If we confirm these clinical findings in upcoming studies, giving patients preventative antibiotics or growth factors may be necessary to lower this increased risk of treatment side effects."

According to the National Cancer Institute, more than 246,660 women will be diagnosed with breast cancer and 22,280 women will be diagnosed with ovarian cancer this year. Of these, about 10-15 percent are estimated to be affected by BRCA1 and BRCA2 genetic mutations, senior author said.

"Our data also illustrate why rare variations in the BRCA1 gene are not always mutations that put women and men at high risk for specific cancers. We and others have learned that most rare 'spellings' of the BRCA1 gene, spellings we call variations of undetermined significance, are not harmful," said the senior author.

Authors generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in the embryonic hematopoietic system (Vav1-iCre; Brca1F22–24/F22–24) developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs). Although mice homozygous for a huBRCA1 knockin allele (Brca1BRCA1/BRCA1) were normal, mice with a mutant huBRCA1/5382insC allele and a null allele (Mx1-Cre;Brca1F22–24/5382insC) had severe hematopoietic defects marked by a complete loss of hematopoietic stem and progenitor cells.

These data show that Brca1 is necessary for HSC maintenance and normal hematopoiesis and that distinct mutations lead to different degrees of hematopoietic dysfunction.

http://www.utsouthwestern.edu/newsroom/news-releases/year-2017/jan/brca-1-mutations-ross.html