Abstract AP12: CYSTEINE METABOLISM IN CLEAR CELL OVARIAN CANCER
Authors: Cochrane Dawn R. , Hughes Christopher S. , Nazeran Tayyebeh , Karnezis Anthony N. , McConechy Melissa K. , Morin Gregg B. , Huntsman David G. 
Published: June 2017

Our past research has used genomic screens to identify unique features of ovarian cancer subtypes. This has resulted in the description of frequent mutations in ARID1A in both clear cell (CCOC) and endometrioid (ENOC) ovarian cancers and patterns of genomic rearrangements indicative of each subtype. While genomic and RNA expression profiling have been extremely informative, they do not provide a view of the protein expression landscape of cancers. We therefore set out to perform proteomic profiling to better define the key features of the different subtypes and to understand the biology that underpin these diseases.

We have developed a novel mass spectrometry proteomic profiling technique based on para–magnetic bead technology called SP3–Clinical Tumor Proteomics (SP3–CTP). This technique is able to perform sensitive proteomic profiling off of a single formalin–fixed paraffin–embedded (FFPE) section. Using this platform, we performed proteomic profiling of three subtypes of ovarian cancer: high grade serous (HGS), ENOC and CCOC. Many proteins known to be enriched in a particular subtype were validated by our screen. WT1 levels were higher in HGS and HNF1B levels were higher in CCOC, as expected. Perhaps more importantly, this screen also revealed that several proteins were enriched in one subtype, which had not previously been described. One such protein was cystathionine gamma lyase (CTH), which was enriched in CCOC compared to the other two subtypes. We validated these results on an ovarian tumor tissue microarray, which confirmed that the majority of CCOC (75%) express high levels of CTH. Conversely, only 10% ENOCa and less than 2% of HGS express high levels of CTH.

CTH is a transulfuration enzyme which, along with cystathione beta lyase, form the biosynthetic pathway in which methionine is converted to cysteine. High levels of CTH activity can lead to the generation of hydrogen sulfide (H2S), which has been increasingly implicated as a gaseous intracellular signaling molecule. Overexpression of CTH in CCOC could explain the unique metabolism and other clinical features of this disease.

We have found that CTH exhibits a unique staining pattern in the normal endometrium, staining some cells very dark while the rest exhibit little or no CTH staining. It is well documented that endometriosis is the presumed precursor lesion of both CCOC and ENOC. It is not known, however, how such phenotypically different cancers arise from the same precursor. It may be that the metabolic state of cells in the endometrium determines whether it becomes a CCOC or and ENOCa upon receiving a genetic hit.

Our initial findings from our proteomic screen have highlighted CTH overexpression as being a feature common in CCOC and comparatively rare in ENOC and HGS. We believe that high CTH expression could provide a unique perspective into the initiation and pathology of CCOC.

Citation Format: Dawn R. Cochrane, Christopher S. Hughes, Tayyebeh Nazeran, Anthony N. Karnezis, Melissa K. McConechy, Gregg B. Morin and David G. Huntsman. CYSTEINE METABOLISM IN CLEAR CELL OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP12.