Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS-MAPK in ovarian serous low malignant potential tumors

Abstract

Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for example, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in >70% of cases compared with approximately 12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2 mutations (6%), but not EGFR, are prevalent among serous LMP tumors. Based on the expression profile signature observed throughout our serous LMP cohort, we propose that RAS-MAPK pathway activation is a requirement of serous LMP tumor development and that other activators of this pathway are yet to be defined. Importantly, as few nonsurgical options exist for treatment of recurrent LMP tumors, therapeutic targeting of this pathway may prove beneficial, especially in younger patients where maintaining fertility is important.

FIGURE 1.

Invasive serous ovarian carcinomas and serous LMP tumors readily segregate by gene expression patterns. A. Experimental samples from 90 tumors were sorted by unsupervised hierarchical clustering of expression measurements made on 2,947 probes and depicted as a dendrogram with all experiment ID numbers. Samples are color coded for their corresponding pathologic diagnosis: LMP, blue; Invasive (INV), orange. B. A gene expression matrix, heat map. Coregulated gene clusters enriched for particular gene ontologies (as defined by ontology classification tools DAVID and Panther) are highlighted and labeled along the vertical axis.

FIGURE 2.

Principal component analysis (PCA) of the expression dataset. A. Three-dimensional visualization of principal components suggests a distinct separation between LMP and invasive (INV) serous ovarian tumors. Two LLI tumors are visible within the cluster of LMPs. B. Principal component analysis (PCA) plot focusing on LMP (30 larger spheres) and LLI (8 smaller spheres) tumors, color coded by mutation status. A great deal of overlap between mutants and wild-type tumors is observed; no clear segregation is identifiable. NK, unknown/untested; WT, wild-type for all tested genes. Specific gene expression patterns contributing to the variation are further discussed in the text.

FIGURE 3.

Tissue sections from a representative LLI tumor and an invasive ovarian serous carcinoma were immunostained for p53. A. Low power magnification of LLI tumor 32054 with regions characteristic of both LMP and more invasive histology. Staining seems to be negative overall, with no suggestion of focal positivity or high-intensity staining across the whole section. B. High-power magnification of the green box-marked region from A, representing LMP-like histology in this sample. C. High-power magnification of the red box-marked region from A, representing invasive histology in this sample. D and E. Low-power and high-power magnification of an invasive serous ovarian carcinoma (70054 positive control) tumor section illustrating high-level positive immunostaining for p53. Scale bars, 1 mm in low power or 100 μm in high power.