title: Multi-gene panel testing for hereditary cancer predisposition in unsolved high-risk breast and ovarian cancer patients.
abstract: OBJECTIVE
  Many women with an elevated risk of hereditary breast and ovarian cancer have previously tested negative for pathogenic mutations in BRCA1 and BRCA2. Among them, a subset has hereditary susceptibility to cancer and requires further testing. We sought to identify specific groups who remain at high risk and evaluate whether they should be offered multi-gene panel testing.
  
  
  METHODS
  We tested 300 women on a multi-gene panel who were previously enrolled in a long-term study at UCSF. As part of their long-term care, all previously tested negative for mutations in BRCA1 and BRCA2 either by limited or comprehensive sequencing. Additionally, they met one of the following criteria: (i) personal history of bilateral breast cancer, (ii) personal history of breast cancer and a first or second degree relative with ovarian cancer, and (iii) personal history of ovarian, fallopian tube, or peritoneal carcinoma.
  
  
  RESULTS
  Across the three groups, 26 women (9%) had a total of 28 pathogenic mutations associated with hereditary cancer susceptibility, and 23 women (8%) had mutations in genes other than BRCA1 and BRCA2. Ashkenazi Jewish and Hispanic women had elevated pathogenic mutation rates. In addition, two women harbored pathogenic mutations in more than one hereditary predisposition gene.
  
  
  CONCLUSIONS
  Among women at high risk of breast and ovarian cancer who have previously tested negative for pathogenic BRCA1 and BRCA2 mutations, we identified three groups of women who should be considered for subsequent multi-gene panel testing. The identification of women with multiple pathogenic mutations has important implications for family testing.
authors.affiliation: University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, San Francisco, CA, 94115, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Crawford
authors.affiliation: University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, San Francisco, CA, 94115, USA.|Stanford Children's Health Center, Lucile Packard Children's Hospital Stanford, 401 Quarry Rd, Stanford, CA, 94305, USA.
authors.forename: Sophie B
authors.initials: SB
authors.lastname: Adams
authors.affiliation: University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, San Francisco, CA, 94115, USA.|Color Genomics, 128 Murchison Drive, Burlingame, CA, 94010, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Sittler
authors.affiliation: Color Genomics, 128 Murchison Drive, Burlingame, CA, 94010, USA.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van den Akker
authors.affiliation: University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, San Francisco, CA, 94115, USA.
authors.forename: Salina
authors.initials: S
authors.lastname: Chan
authors.affiliation: Skypax LLC, 112 Timberlyne Court, Chapel Hill, NC, USA.
authors.forename: Ofri
authors.initials: O
authors.lastname: Leitner
authors.affiliation: University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, San Francisco, CA, 94115, USA.|Color Genomics, 128 Murchison Drive, Burlingame, CA, 94010, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Ryan
authors.affiliation: Color Genomics, 128 Murchison Drive, Burlingame, CA, 94010, USA.
authors.forename: Elad
authors.initials: E
authors.lastname: Gil
authors.affiliation: University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, San Francisco, CA, 94115, USA. laura.vantveer@ucsf.edu.
authors.forename: Laura
authors.initials: L
authors.lastname: van 't Veer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics*; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human
keywords: BRCA1; BRCA2; Breast cancer; Hereditary cancer; Ovarian cancer; Panel testing