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.

Figure 1

A: Brenner tumor. B: Atypical proliferative Brenner tumor. C: Mucinous cystadenoma. D: Mucinous borderline tumor. Original magnification, ×10.

Figure 2

Brenner 2 with MYC and CCND1 amplification (A) and paired MCA 1 (B) also showing MYC amplification and 4.6 copies of CCND1. Brenner 3 with CDK4 copy number 5.0 and MYC copy number 3.6 (C) and paired MCA 2 with MYC and CDK4 (D) amplification. The blue circles indicate the areas of increased copy number; with this assay, amplification is defined as more than six copies of a gene per cell.

Figure 3

Proposed histogenesis of Brenner, atypical proliferative Brenner, and mucinous cystic neoplasms of the ovary and important associated molecular alterations. HD, homozygous deletion; LOH, loss of heterozygosity.