Multi-omic analysis of uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer patients

AbstractPathogenic mutations in fumarate hydratase (FH) drive hereditary leiomyomatosis and renal cell cancer (HLRCC) and increase the risk of developing uterine leiomyomas (ULMs). An integrated proteogenomic analysis of ULMs from HLRCC (n = 16; FH-mutation confirmed) and non-syndromic (NS) patients (n = 12) identified a significantly higher protein:transcript correlation in HLRCC (R = 0.35) vs. NS ULMs (R = 0.242, MWU p = 0.0015). Co-altered proteins and transcripts (228) included antioxidant response element (ARE) target genes, such as thioredoxin reductase 1 (TXNRD1), and correlated with activation of NRF2-mediated oxidative stress response signaling in HLRCC ULMs. We confirm 185 transcripts previously described as altered between HLRCC and NS ULMs, 51 co-altered at the protein level and several elevated in HLRCC ULMs are involved in regulating cellular metabolism and glycolysis signaling. Furthermore, 367 S-(2-succino)cysteine peptides were identified in HLRCC ULMs, of which sixty were significantly elevated in HLRCC vs. NS ULMs (LogFC = 1.86, MWU p < 0.0001). These results confirm and define novel proteogenomic alterations in uterine leiomyoma tissues collected from HLRCC patients and underscore conserved molecular alterations correlating with inactivation of the FH tumor suppressor gene.

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Novel Fumarate Hydratase Mutation in Siblings With Early Onset Uterine Leiomyomas and Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

International Journal of Gynecological Pathology ◽

10.1097/pgp.0000000000000423 ◽

2018 ◽

Vol 37 (3) ◽

pp. 256-261 ◽

Cited By ~ 6

Author(s):

Vinay Gunnala ◽

Nigel Pereira ◽

Mohamad Irani ◽

Debra Lilienthal ◽

Edyta C. Pirog ◽

...

Keyword(s):

Renal Cell Cancer ◽

Early Onset ◽

Renal Cell ◽

Cell Cancer ◽

Fumarate Hydratase ◽

Uterine Leiomyomas ◽

Cancer Syndrome ◽

Hereditary Leiomyomatosis

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361: Serum Levels of Angiogenin and Vascular Endothelial Growth Factor (VEGF) Predict Metastatic Disease in Renal Cell Cancer Patients

The Journal of Urology ◽

10.1016/s0022-5347(18)34614-7 ◽

2005 ◽

Vol 173 (4S) ◽

pp. 99-99 ◽

Cited By ~ 1

Author(s):

Marcus Horstmann ◽

Axel S. Merseburger ◽

Markus A. Kuczyk ◽

Arnulf Stenzl ◽

Karl-Horst Bichler ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Cancer Patients ◽

Renal Cell Cancer ◽

Metastatic Disease ◽

Renal Cell ◽

Cell Cancer ◽

Serum Levels ◽

Vascular Endothelial ◽

Endothelial Growth Factor

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Toxicities of axitinib, sunitinib and temsirolimus: implications for progression-free and overall survival in metastatic renal cell cancer

Future Oncology ◽

10.2217/fon-2020-0900 ◽

2020 ◽

Author(s):

Annemarie Uhlig ◽

Johannes Uhlig ◽

Lutz Trojan ◽

Michael Woike ◽

Marianne Leitsmann ◽

...

Keyword(s):

Overall Survival ◽

Cancer Patients ◽

Skin Reaction ◽

Renal Cell Cancer ◽

Renal Cell ◽

Cell Cancer ◽

Progression Free Survival ◽

Cox Models ◽

Metastatic Renal Cell Cancer ◽

Hand Foot Skin Reaction

The aim of this study was to evaluate the association between axitinib, sunitinib and temsirolimus toxicities and patient survival in metastatic renal cell cancer patients. Overall survival (OS) and progression-free survival (PFS) of metastatic renal cell cancer patients from the prospective multicenter STAR-TOR study were assessed using multivariable Cox models. A total of 1195 patients were included (n = 149 axitinib; n = 546 sunitinib; n = 500 temsirolimus). The following toxicities significantly predicted outcomes: hand–foot skin reaction (hazard ratio [HR] = 0.29) for PFS with axitinib; stomatitis (HR = 0.62) and pneumonitis (HR = 0.23) for PFS with temsirolimus; stomatitis (HR = 0.52) and thrombocytopenia (HR = 0.6) for OS with temsirolimus; fatigue (HR = 0.71) for PFS with sunitinib; hand–foot skin reaction (HR = 0.56) and fatigue (HR = 0.58) for OS with sunitinib. In conclusion, in metastatic renal cell cancer, axitinib, sunitinib and temsirolimus demonstrate specific toxicities that are protective OS/PFS predictors.

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An Italian, multicenter, real-world, retrospective study of first-line pazopanib in unselected metastatic renal-cell carcinoma patients: the ‘Pamerit’ study

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa193 ◽

2020 ◽

Author(s):

Alessandra Mosca ◽

Ugo De Giorgi ◽

Giuseppe Procopio ◽

Umberto Basso ◽

Giacomo Cartenì ◽

...

Keyword(s):

Cancer Patients ◽

Renal Cell Cancer ◽

Real World ◽

Renal Cell ◽

Cell Cancer ◽

Progression Free Survival ◽

First Line ◽

Free Survival ◽

Metastatic Renal Cell Cancer ◽

Metastatic Rcc

Abstract Objective Despite the current immunotherapy era, VEGFR inhibitors maintain effectiveness in metastatic renal cell cancer. Real-world data concerning pazopanib are limited. The aim of this study is to add information about efficacy and safety of pazopanib as first-line treatment in metastatic renal cell cancer patients not enrolled into clinical trials. Methods Retrospective analysis (the PAMERIT study) of first-line pazopanib in real-world metastatic renal cell cancer patients among 39 Centers in Italy. Outcomes were progression-free survival, overall survival, objective response rate and treatment-related adverse events. Kaplan–Meier curves, log-rank test and multivariable Cox’s models were used and adjusted for age, histology, previous renal surgery, International Metastatic RCC Database Consortium score and pazopanib initial dose. Results Among 474 patients, 87.3% had clear cell metastatic renal cell cancer histology. Most of them (84.6%) had upfront renal surgery. Median progression-free survival and overall survival were 15.8 and 34.4 months, respectively, significantly correlating with International Metastatic RCC Database Consortium’s good prognosis (P < 0.001), ECOG PS 0 (P < 0.001), age (<75 years, P = 0.005), surgery (P < 0.001) and response to pazopanib (P < 0.001). After 3 months of pazopanib, overall disease control rate have been observed in 76.6% patients. Among International Metastatic RCC Database Consortium’s favorable group patients, 57/121 (47%) showed complete/partial response. No unexpected AEs emerged. Conclusions In this real-world study, metastatic renal cell cancer patients treated with first-line pazopanib reached greater progression-free survival and overall survival than in pivotal studies and had high response rates when belonging to International Metastatic RCC Database Consortium’s favorable group, without new toxicities. Pazopanib has been confirmed a valid first-line option for International Metastatic RCC Database Consortium’s good prognosis metastatic renal cell cancer patients who cannot be submitted to immunotherapy.

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