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Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma
A Ari Hakimi1, Ying-Bei Chen, James Wren
1Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Background:
Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown.
Objective:
To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC.
Design, Setting, And Participants:
Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded.
Outcome Measurements And Statistical Analysis:
The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]).
Results And Limitations:
PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events.
Conclusions:
Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.
Insights
Mutations in PBRM1, BAP1, SETD2, and KDM5C are common in clear cell renal cell carcinoma (ccRCC). These genetic alterations are linked to advanced disease stage, higher grade, and potentially worse cancer-specific survival (CSS).
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Clear cell renal cell carcinoma (ccRCC) is characterized by frequent mutations in specific genes.
- Historically, VHL gene mutations were prominent, but recent studies reveal frequent mutations in chromatin-modifying genes like PBRM1, SETD2, BAP1, and KDM5C.
- The clinical and pathological significance of these novel mutations in ccRCC remains largely unexplored.
Purpose of the Study:
- To investigate the frequency of mutations in PBRM1, SETD2, BAP1, and KDM5C in ccRCC.
- To determine the association between these mutations and clinical and pathological outcomes in ccRCC patients.
Main Methods:
- Targeted sequencing was performed on 185 ccRCC samples and matched normal tissues.
- Pathological features, patient characteristics, and follow-up data were collected.
- Statistical analyses, including Fisher exact test and permutation log-rank test, were used to correlate mutations with outcomes.
Main Results:
- PBRM1, BAP1, SETD2, and KDM5C mutations were found in 29%, 6%, 8%, and 8% of ccRCCs, respectively.
- Mutations in PBRM1 or the combined group of BAP1, SETD2, or KDM5C were associated with advanced stage (Stage III or higher).
- BAP1 mutations correlated with higher Fuhrman grade and worse cancer-specific survival (CSS).
Conclusions:
- Mutations in chromatin-modulating genes PBRM1, BAP1, SETD2, and KDM5C are frequent in ccRCC and often represent loss-of-function alterations.
- These mutations are associated with advanced disease stage, higher tumor grade, and potentially poorer CSS.
- Further research is needed to validate the clinical impact of these mutations and develop targeted therapies.
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