Significance of Alterations of the RB1 Pathway in High Grade Serous Carcinoma
Anca Milea, Sophia HL George, Hal Berman, Mona Gauthier, Patricia A Shaw. University Health Network, Toronto, Canada
Background: High grade serous carcinoma (HGSC) of the ovary/tube is characterized by a low prevalence of recurrent mutations, numerous DNA copy number changes and promotor methylation events. An understanding of the aberrant genes and pathways should lead to more effective targeted therapies. The mechanisms of one commonly deregulated pathway, the RB pathway, are not well understood and we hypothesize that different mechanisms may identify clinically distinct subgroups of HGSC.
Design: All cases included for study were HGSC, controlled for grade, stage, and treatment, with followup data avalable. Snap frozen tissue samples from 75 cases were obtained for molecular profiling, including RB1 loss of heterozygosity (LOH), gene expression analysis, and SNP and copy number analysis. Immunohistochemistry for RB1, CDKN2A, CCNE1, CCND1, CCND2 was completed using 102 cancer cases and 15 tubal epithelial precursor lesions. Correlations between RB pathway alterations were determined and prognostic significance assessed.
Results: RB1 LOH was frequent, seen in 76% of 42 cases, with RB1 hemizygous deletions present in 33% of 75 cases. CDKN2A hemizygous deletions were seen in 8%, and amplification in 16% of cases. Immunohistochemistry for p16 showed a diffusely strong homogenous pattern of positivity in 51%, low or negative staining in 20%, and a heterogeneous pattern in 29%. RB1 staining was positive in 60%. RB1 LOH did not correlate with RB1 protein expression, but there was a strong correlation with p16 staining. Clinical outcome was predicted by three patterns of RB1/ p16 staining. The RB1+/p16 homogeneous pattern subgroup identified 38% of tumors with the shortest recurrence free survival at 14 months, while the RB1+/p16 heterogeneous subgroup (30%) and the RB1-/p16 homogenous subgroup (32%) had an improved recurrence free survival of 22.5 months. Patterns of RB1/p16 staining seen in HGSC were identical in synchronous Tubal Intraepithelial Carcinomas.
Conclusions: Deregulation of the RB pathway is frequent in HGSC, and occurs through various non-redundant mechanisms. A strong homogeneous pattern of CDKN2A protein expression identifies a significant percentage but not all of HGSC, and correlates with RB1 LOH. RB1 protein expression stratifies CDKN2A staining into 3 clinically distinct groups, reflecting differences in tumor biology which may have treatment implications. The presence of similar staining patterns in the immediate precursor lesion of HGSC suggests RB pathway abrogation is an early genetic alteration.
Category: Gynecologic & Obstetrics
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 194, Tuesday Morning