Multi-gene panel testing for hereditary cancer predisposition in unsolved high-risk breast and ovarian cancer patients

• DOI: 10.1007/s10549-017-4181-0
• Publication Date: 2017-03-09T06:59:59Z
• Authors: Beth Crawford; Sophie B. Adams; Taylor Sittler; Jeroen van den Akker; Salina Chan; Ofri Leitner; Lauren Ryan; Elad Gil; Laura van ’t Veer
• Keywords: Cancer Research; DNA Mutational Analysis; Clinical sciences; Panel testing; Breast cancer; 0302 clinical medicine; Risk Factors; 80 and over; 2.1 Biological and endogenous factors; Aetiology; Cancer; Aged, 80 and over; Ovarian Neoplasms; BRCA1 Protein; Brief Report; Middle Aged; Ovarian Cancer; 3. Good health; Oncology; Female; Adult; Ubiquitin-Protein Ligases; Oncology and Carcinogenesis; Clinical Sciences; Mutation, Missense; 610; Breast Neoplasms; 618; Young Adult; 03 medical and health sciences; Rare Diseases; Clinical Research; Ovarian cancer; Breast Cancer; Genetics; Humans; Genetic Predisposition to Disease; Oncology & Carcinogenesis; Genetic Testing; Aged; BRCA2 Protein; Biomedical and Clinical Sciences; Prevention; Tumor Suppressor Proteins; Oncology and carcinogenesis; BRCA1; BRCA2; Hereditary cancer; Checkpoint Kinase 2; Mutation; Missense

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.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.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.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.