title: Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas.
abstract: Extrauterine high-grade serous carcinomas can exhibit various histologic patterns including (1) classic architecture that is papillary, micropapillary and infiltrative and (2) solid, endometrioid, and transitional (ie, SET) patterns. Although the SET pattern has been associated with germline BRCA mutations, potential molecular underpinnings have not been fully investigated. DNA was isolated from 174 carcinomas of the fallopian tube, ovary, or peritoneum. Targeted next-generation sequencing was performed and single-nucleotide and copy number variants were correlated with morphologic subtype. Overall, 79% of tumors were classified as high-grade serous carcinoma (n=138), and the most common mutations in high-grade serous carcinomas were TP53 (94%), BRCA1 (25%), BRCA2 (11%), and ATM (7%). Among chemotherapy-naive high-grade serous carcinomas, 40 cases exhibited classic morphology and 40 cases had non-classic morphology (SET or ambiguous features). Mutations in homologous recombination pathways were seen across all tumor histotypes. High-grade serous carcinomas with homologous recombination mutations were six times more likely to be associated with non-classic histology (P=0.002) and were significantly more likely to be platinum sensitive and have improved progression-free survival (PFS) (P=0.007 and P=0.004, respectively). In a multivariate analysis adjusted for age, homologous recombination mutation status and increased copy number variants were independently associated with improved PFS (P=0.008 and P=0.005, respectively). These findings underscore the potential significance of variant morphologic patterns and comprehensive genomic analysis in high-grade serous carcinomas with potential implications for pathogenesis, as well as response to targeted therapies.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Ritterhouse
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Nowak
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Strickland
authors.affiliation: Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Garcia
authors.affiliation: Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.|Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Neal I
authors.initials: NI
authors.lastname: Lindeman
authors.affiliation: Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Macconaill
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Ross S
authors.initials: RS
authors.lastname: Berkowitz
authors.affiliation: Women's and Perinatal Pathology Division, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Marisa R
authors.initials: MR
authors.lastname: Nucci
authors.affiliation: Women's and Perinatal Pathology Division, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.|Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.|Women's and Perinatal Pathology Division, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis / Q000379:methods; D018572:Disease-Free Survival; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009095:Mullerian Ducts / Q000473:pathology*; D015999:Multivariate Analysis; D009154:Mutation; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor