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Published on May 21st, 2013 | by Michelle Wedemeyer, M.D., Ph.D.


Hereditary Breast Cancer: What is it and Why is the Treatment So Drastic? Understanding Jolie’s Mastectomy

Approximately 90% of breast cancers are not caused by inherited genes. Of the hereditary breast and ovarian cancers, however, the vast majority are caused by mutations in two genes, the BRCA1 and BRCA2 genes.  In daily life, the DNA of all the cells in our body is subjected to damage which is repaired by an extensive set of proteins coded by tumor suppressor genes.  BRCA1 and BRCA2 are part of this highly efficient DNA repair machinery.

Each of us is born with two copies of BRCA1 and two copies of BRCA2 –one from our mother and one from our father.  As long as one copy of each is functional, the DNA repair machinery is intact and our cells will faithfully repair errors in the DNA sequence.  Loss of both copies of a repiar gene in a cell disrupts the process which repairs errors in the DNA sequence and they begin to accumulate leading to a cancerous cell.  The repair process is not perfect however, so errors accumulate over time.

Based on previous studies into the rate at which errors accumulate in people, we can estimate that the chances of a disabling error occuring in one of these genes is 1/1,000,000 or 1/106 per cell.  According to Knudson’s “Two Hit Hypotheis,” the probability that both copies will be damaged in one cell is 1/106 x 1/106  =  1/1012 or 1/1,000,000,000,000.

If one of the inherited genes is damaged, however, as in the case of BRCA mutations, the chances that an individual cell will develop an error which disables BRCA1 or BRCA2 increases one million-fold from 1/1012 to 1/106.  Multipled over the many cells found in a woman’s breasts and ovaries, this means that the majority of women with the BRCA1 mutation will get breast cancer during their lifetime.  39-46% of BRCA1 carriers and 12-20% of BRCA2 carriers will develop ovarian cancers.  70-75% of women diagnosed with ovarian cancer will die from their disease within 5 years.  This is the reason for the drastic treatment in which both breasts and ovaries are removed to prevent cancer.

Most breast and ovarian cancers are the result of “sporadic” or random accumulation of errors in many genes rather than an inherited error in one of the DNA repair genes.  In a future article, “Hereditary Breast Cancer: Should I Be Screened?”, we explain who should be screened and why this highly costly screening and drastic therapy is not necessary for the great majority of women.

Michelle Wedemeyer, M.D., Ph.D., serves on the scientific advisory board of ScientiFIT. For more information on Michelle, click here.


  1.  MW Nachman and SL Crowell.  Estimate of the Mutation Rate per Nucleotide in Humans. Genetics 156(1):297-304
  2. AG Knudson.  Mutation and Cancer: Statistical Study of Retinoblastoma. Proc Natl Acad Sci U S A. 1971 April; 68(4): 820–823.
  3. B.J.B Ashely.  The two “hit” and and multiple “hit” theories of carcinogenesis.   Br J Cancer. 1969 June; 23(2): 313–328.
  4. Practice Bulletin #103 “Hereditary Breast and Ovarian Cancer Syndrome” The American College of Obstetricians and Gynecologists
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