The authors analyzed genetic expression from 537 patients from 2 separate cohorts: The Cancer Genome Atlas (TCGA, 446 individuals) and the International Cancer Genome Consortium (ICGC, 91 individuals). Close to 50% of all the patients included in the study were classified as stage I.
DYSF was the only gene analyzed that was associated with patient survival. At baseline, DYSF gene expression was higher in patients with ccRCC compared with normal kidney tissue. In all patients regardless of stage, higher levels of DYSF was associated with improved survival rates compared with those with low DYSF expression in patients in both the TCGA (hazard ratio [HR], 0.457; P <.0001) and ICGC (HR, 0.281; P =.0011) cohorts. When broken down into stages, the survival rates were higher in patients within the TCGA cohort when they had higher DYSF expression in stages I and II (HR, 0.535, P =.05) as well as stages III and IV (HR, 0.603; P =.05). This exact pattern was not seen in the ICGC cohort, with a statistically significant difference only seen in stage III and stage IV patients (HR, 0.208, P =.035) and not stage I and stage II (HR, 0.420, P =.11).
Within the both the TCGA (HR, 0.618, 95% CI, 0.416-0.918, P =.017) and ICGC (HR, 0.300; 95% CI, 0.127-0.707, P =.006) cohorts using a multivariate analysis, DYSF expression was found to be an independent prognostic predictor. Using an area under the curve (AUC) analysis and receiver operating characteristic (ROC) curves, the authors also deemed DYSF a prognostic biomarker for ccRCC.
The authors concluded that there were higher levels of DYSF found in ccRCC cells compared with normal kidney cells and that within patients with ccRCC, increased levels of DYSF was a predictor of improved prognosis.
This type of relationship — where gene expression is higher in cancer cells and associated with better prognosis — has been seen in other malignancies such as breast cancer. Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene which is different than a tumor suppressor gene. Typically patients with breast cancer have higher levels of BRMS1 compared with those without breast cancer, and those patients with cancer with higher BRMS1 levels have a better prognosis.4 The authors, therefore, proposed that although the entire role of dysferlin in ccRCC is not yet fully understood, it is possible DYSF acts as a metastasis suppressor gene.4,8 These types of suppressor genes are different than “typical” tumor suppressor genes, as they act by inhibiting metastases to secondary sites but have no impact on primary tumor growth when they are overexpressed.8 These suppressor genes can work through multiple receptors: MAPK, cytoskeletal, G-protein coupled receptors, and cell adhesion molecules,8 — therefore, future research is needed to compare how these pathways vary between different malignancies with respect to metastatic suppressor gene expression.
The DYSF data in ccRCC is still accumulating but it will be interesting to see if future studies can replicate the type of results found in this study. In addition to obtaining more data in ccRCC, future studies could also aim to determine if DYSF plays a role in other subtypes of RCC as well as other malignancies that frequently develop paraneoplastic syndromes associated with hypercalcemia such as lung, pancreatic, ovarian, thyroid, breast, and prostate cancers.
- Choueiri TK and Motzer J. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376:354-366.
- Crumley SM et al. Renal cell carcinoma: evolving and emerging subtypes. World J Clin Cases. 2013;1(9):262-275.
- Amin MB, Tamboli P, Javidan J, et al. Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol. 2002;26(3):281-291.
- Ha M, Jeong H, Roh JS, et al. DYSF expression in clear cell renal cell carcinoma: A retrospective study of 2 independent cohorts. Urol Oncol. 2019;37(10):735-741.
- Mao Q, Chen Z, Zhuang Q, Shen J, Xu R, Lu H, He X. Prognostic role of corrected calcium levels in renal cell carcinoma: a systematic review and meta-analysis. Int J Clin Exp Med. 2018;11(3):2847-2855.
- DeFour A, Van der Meulen JH, Bhat R, et al. Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion. Cell Death Dis. 2014;5:e1306.
- Izzedine H, Brocheriou I, Eymard B, et al. Loss of podocyte dysferlin expression is associated with minimal change nephropathy. Am J Kidney Dis. 2006;48(1):143-50.
- Khan I, Steeg PS. Metastasis suppressors: functional pathways. Lab Invest. 2018;98(2):198-210.