title: Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.
abstract: BACKGROUND
  Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer.
  
  
  RESULTS
  The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery.
  
  
  CONCLUSIONS
  Tumor Nmut was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative mechanisms.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America ; Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Nicolai Juul
authors.initials: NJ
authors.lastname: Birkbak
authors.forename: Bose
authors.initials: B
authors.lastname: Kochupurakkal
authors.forename: Jose M G
authors.initials: JM
authors.lastname: Izarzugaza
authors.forename: Aron C
authors.initials: AC
authors.lastname: Eklund
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Joyce
authors.initials: J
authors.lastname: Liu
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: J Dirk
authors.initials: JD
authors.lastname: Iglehart
authors.forename: Zhigang C
authors.initials: ZC
authors.lastname: Wang
mesh_terms: D000367:Age Factors; D002869:Chromosome Aberrations; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D016896:Treatment Outcome