title: Exome profiling of primary, metastatic and recurrent ovarian carcinomas in a BRCA1-positive patient.
abstract: BACKGROUND
  Ovarian carcinoma is a common, and often deadly, gynecological cancer. Mutations in BRCA1 and BRCA2 genes are present in at least a fifth of patients. Uncovering other genes that become mutated subsequent to BRCA1/BRCA2 inactivation during cancer development will be helpful for more effective treatments.
  
  
  METHODS
  We performed exome sequencing on the blood, primary tumor, omental metastasis and recurrence following therapy with carboplatin and paclitaxel, from a patient carrying a BRCA1 S1841R mutation.
  
  
  RESULTS
  We observed loss of heterozygosity in the BRCA1 mutation in the primary and subsequent tumors, and somatic mutations in the TP53 and NF1 genes were identified, suggesting their role along with BRCA1 driving the tumor development. Notably, we show that exome sequencing is effective in detecting large chromosomal rearrangements such as deletions and amplifications in cancer. We found that a large deletion was present in the three tumors in the regions containing BRCA1, TP53, and NF1 mutations, and an amplification in the regions containing MYC. We did not observe the emergence of any new mutations among tumors from diagnosis to relapse after chemotherapy, suggesting that mutations already present in the primary tumor contributed to metastases and chemotherapy resistance.
  
  
  CONCLUSIONS
  Our findings suggest that exome sequencing of matched samples from one patient is a powerful method of detecting somatic mutations and prioritizing their potential role in the development of the disease.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Shi
authors.forename: Emilie
authors.initials: E
authors.lastname: Lalonde
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Luca
authors.initials: L
authors.lastname: Cavallone
authors.forename: Alex
authors.initials: A
authors.lastname: Ferenczy
authors.forename: Walter H
authors.initials: WH
authors.lastname: Gotlieb
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D019398:Genes, BRCA1; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D008875:Middle Aged; D059645:Mutation Rate; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence