T.P. Conrads

Recent advances and opportunities in proteomic analyses of tumour heterogeneity: Tumour tissue proteomics

Solid tumour malignancies comprise a highly variable admixture of tumour and non‐tumour cellular populations, forming a complex cellular ecosystem and tumour microenvironment. This tumour heterogeneity is not incidental, and is known to correlate with poor patient prognosis for many cancer types. Indeed, non‐malignant cell populations, such as vascular endothelial and immune cells, are known to play key roles supporting and, in some cases, driving aggressive tumour biology, and represent targets of emerging therapeutics, such as antiangiogenesis and immune checkpoint inhibitors. The biochemical interplay between these cellular populations and how they contribute to molecular tumour heterogeneity remains enigmatic, particularly from the perspective of the tumour proteome. This review focuses on recent advances in proteomic methods, namely imaging mass spectrometry, single‐cell proteomic techniques, and preanalytical sample processing, that are uniquely positioned to enable detailed analysis of discrete cellular populations within tumours to improve our understanding of tumour proteomic heterogeneity. This review further emphasizes the opportunity afforded by the application of these techniques to the analysis of tumour heterogeneity in formalin‐fixed paraffin‐embedded archival tumour tissues, as these represent an invaluable resource for retrospective analyses that is now routinely accessible, owing to recent technological and methodological advances in tumour tissue proteomics. Copyright

Racial disparities in molecular subtypes of endometrial cancer

OBJECTIVESnRacial differences in the molecular subtypes of endometrial cancer and associations with progression-free survival (PFS) were evaluated.nnnMETHODSnMolecular, clinical and PFS data were acquired from the Cancer Genome Atlas (TCGA) including classification into the integrative, somatic copy number alteration and transcript-based subtypes. The prevalence and prognostic value of the aggressive molecular subtypes (copy number variant [CNV]-high, cluster 4 or mitotic) were evaluated in Black and White patients.nnnRESULTSnThere were 337 patients including 14% self-designated as Black, 27% with advanced stage, and 82% with endometrioid histology. The CNV-high subtype was more common in Black than White patients (61.9% vs. 23.5%, P=0.0005) and suggested worse PFS in Black patients (hazard ratio [HR]=3.4, P=0.189). The cluster 4 subtype was more prevalent in Black patients (56.8% vs. 20.9%, P<0.0001) and associated with worse PFS in Black patients (HR=3.4, P=0.049). The mitotic subtype was more abundant in Black patients (64.1% vs. 33.7%, P=0.002), indicated worse PFS in Black patients (HR=4.1, P=0.044) including the endometrioid histology (HR=6.1, P=0.024) and exhibited race-associated enrichment in cell cycle signaling and pathways in cancer including PLK1 and BIRC7. All of these aggressive molecular subtypes also indicated worse PFS in White patients, with unique enrichments in mitotic signaling different from Black patients.nnnCONCLUSIONSnThe aggressive molecular subtypes from TCGA were more common in Black endometrial cancer patients and indicated worse PFS in both Black and White patients. The mitotic subtypes also indicated worse PFS in Black patients with endometrioid histology. Enrichment patterns in mitotic signaling may represent therapeutic opportunities.

Impact of age at diagnosis on racial disparities in endometrial cancer patients

INTRODUCTIONnAlthough black patients with endometrial cancer (EC) have worse survival compared with white patients, the interaction between age/race has not been examined. The primary objective was to evaluate the impact of age at diagnosis on racial disparities in disease presentation and outcome in EC.nnnMETHODSnWe evaluated women diagnosed with EC between 1991 and 2010 from the Surveillance, Epidemiology, and End Results. Mutation status for TP53 or PTEN, or with the aggressive integrative, transcript-based, or somatic copy number alteration-based molecular subtype were acquired from the Cancer Genome Atlas. Logistic regression model was used to estimate the interaction between age and race on histology. Cox regression model was used to estimate the interaction between age and race on survival.nnnRESULTSn78,184 white and 8518 black patients with EC were analyzed. Median age at diagnosis was 3-years younger for black vs. white patients with serous cancer and carcinosarcoma (P<0.0001). The increased presentation of non-endometrioid histology with age was larger in black vs. white patients (P<0.0001). The racial disparity in survival and cancer-related mortality was more prevalent in black vs. white patients, and in younger vs. older patients (P<0.0001). Mutations in TP53, PTEN and the three aggressive molecular subtypes each varied by race, age and histology.nnnCONCLUSIONSnAggressive histology and molecular features were more common in black patients and older age, with greater impact of age on poor tumor characteristics in black vs. white patients. Racial disparities in outcome were larger in younger patients. Intervention at early ages may mitigate racial disparities in EC.

Nestin: A biomarker of aggressive uterine cancers

OBJECTIVEnEvidence of potential prognostic and predictive value for nestin was investigated in well-annotated uterine cancers (UCs).nnnMETHODSnNestin expression and previously-published biomarkers were evaluated by immunohistochemistry (IHC) in UC tissue microarrays. Biomarkers were categorized as low vs. high, and nestin was cut at 10% positive staining. Relationship between nestin and clinicopathologic factors, biomarkers and outcome were evaluated using exact/log-rank testing or logistic/Cox modeling.nnnRESULTSnThere were 323 eligible cases, 34% had advanced stage disease, 37% had type II disease, and 5% were carcinosarcomas. High nestin, observed in 19% of cases, was more common in advanced vs. early stage disease, type II cancers or uterine carcinosarcoma vs. type I cancers, grade 3 disease, positive lymphovascular space invasion (LVSI) and tumors >6cm (p<0.05). Nestin was inversely correlated with ER, PR and TFF3, and correlated with p53 and IMP3. Women with high vs. low nestin had worse progression-free survival (PFS) and cancer-specific survival overall, and worse PFS in the subset who received no adjuvant therapy or radiation, or had early stage, type I disease or tumors with both low and high ER, PR, TFF3, PTEN, p53 or IMP3. The relationship between nestin and PFS was independent of stage, LVSI and risk categorization but not type of UC.nnnCONCLUSIONSnHigh nestin was more common in UCs with aggressive features and poor outcome. Nestin may represent a predictive biomarker for treatment selection for patients previously considered to be lower risk and a candidate for no or radiation-based adjuvant therapy, and compliment ER/PR testing.