title: Molecular Genetic Analysis of Ovarian Brenner Tumors and Associated Mucinous Epithelial Neoplasms: High Variant Concordance and Identification of Mutually Exclusive RAS Driver Mutations and MYC Amplification.
abstract: Benign ovarian Brenner tumors often are associated with mucinous cystic neoplasms, which are hypothesized to share a histogenic origin and progression, however, supporting molecular characterization is limited. Our goal was to identify molecular mechanisms linking these tumors. DNA from six Brenner tumors with paired mucinous tumors, two Brenner tumors not associated with a mucinous neoplasm, and two atypical proliferative (borderline) Brenner tumors was extracted from formalin-fixed, paraffin-embedded tumor samples and sequenced using a 358-gene next-generation sequencing assay. Variant calls were compared within tumor groups to assess somatic mutation profiles. There was high concordance of the variants between paired samples (40% to 75%; P < 0.0001). Four of the six tumor pairs showed KRAS hotspot driver mutations specifically in the mucinous tumor. In the two paired samples that lacked KRAS mutations, MYC amplification was detected in both of the mucinous and the Brenner components; MYC amplification also was detected in a third Brenner tumor. Five of the Brenner tumors had no reportable potential driver alterations. The two atypical proliferative (borderline) Brenner tumors both had RAS mutations. The high degree of coordinate variants between paired Brenner and mucinous tumors supports a shared origin or progression. Differences observed in affected genes and pathways, particularly involving RAS and MYC, may point to molecular drivers of a divergent phenotype and progression of these tumors.
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, New Hampshire; Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Electronic address: laura.j.tafe@hitchcock.org.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Tafe
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, New Hampshire; Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Muller
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
authors.forename: Guruprasad
authors.initials: G
authors.lastname: Ananda
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
authors.forename: Talia
authors.initials: T
authors.lastname: Mitchell
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Spotlow
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Patterson
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, New Hampshire; Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tsongalis
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Mockus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001948:Brenner Tumor / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004273:DNA, Neoplasm; C117307:KRAS protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras)