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Challenges in the identification of inherited risk of ovarian cancer: where should we go from here?

Published:December 08, 2018DOI:https://doi.org/10.1016/j.ygyno.2018.12.003
      The idea that a mutation in a single gene could lead to a high risk of breast or ovarian cancer used to be a radical idea. It was not until 1990 that Dr. Mary Claire King and her team localized a gene for hereditary breast cancer to chromosome 17q21 [
      • Hall J.M.
      • Lee M.K.
      • Newman B.
      • Morrow J.E.
      • Anderson L.A.
      • Huey B.
      • King M.C.
      Linkage of early-onset familial breast cancer to chromosome 17q21.
      ], which she named BRCA1. This discovery set off a race involving multiple research labs around the globe to clone and sequence the gene, ultimately ending in 1994 when a team led by Mark Skolnick became the first to do so [
      • King M.C.
      “The race” to clone BRCA1.
      ,
      • Goldgar D.E.
      • Fields P.
      • Lewis C.M.
      • Tran T.D.
      • Cannon-Albright L.A.
      • Ward J.H.
      • Swensen J.
      • Skolnick M.H.
      A large kindred with 17q-linked breast and ovarian cancer: genetic, phenotypic, and genealogical analysis.
      ]. Skolnick went on to found Myriad genetics, which then acquired a patent for the sequence of BRCA1, followed shortly the next year with a patent for BRCA2. Due to the patents, from 1996 to 2013, one company provided all commercial sequencing in the United States for BRCA1 and BRCA2, using PCR amplification and Sanger sequencing. Sanger sequencing will detect small insertions, deletions, and single base pair changes, but not larger genomic rearrangements, which represent around 10% of BRCA1 and BRCA2 mutations [
      • Walsh T.
      • Casadei S.
      • Coats K.H.
      • Swisher E.
      • Stray S.M.
      • Higgins J.
      • Roach K.C.
      • Mandell J.
      • Lee M.K.
      • Ciernikova S.
      • Foretova L.
      • Soucek P.
      • King M.C.
      Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer.
      ]. Genomic rearrangement testing in the United States became available commercially in 2006 as a separate test, and was made part of the BRCA1 and BRCA2 sequencing test in 2013. Next generation sequencing technology was developed in the late 2000's, allowing for massively parallel sequencing of multiple genes at once with substantially lower costs [
      • Walsh T.
      • Lee M.K.
      • Casadei S.
      • Thornton A.M.
      • Stray S.M.
      • Pennil C.
      • Nord A.S.
      • Mandell J.B.
      • Swisher E.M.
      • King M.C.
      Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing.
      ], but due to gene patents, panels that included BRCA1 or BRCA2 could not be offered, which limited the clinical use of such testing.
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