Renal Cell Cancer
(1) Functional analysis of renal cell cancer tumour suppressor genes from the short arm of chromosome 3
Clear cell Renal Cell Cancer (ccRCC) is thought to arise by malignant transformation of the epithelial cells of the proximal tubuli of the kidney (PTECs). A characteristic of ccRCC is the loss of one copy of almost the entire short arm of chromosome 3. This loss is seen as one of the two necessary genetic alterations leading to the inactivation of a tumor suppressor gene (TSG). The other allele may be inactivated by a more subtle mutation in VHL, located at 3p25, which was identified as an important ccRCC-specific TSG in 1994. However, as the remaining allele of the VHL gene is mutated in only about 45% of sporadic cases of ccRCC, it was expected that extra, perhaps ccRCC-specific, TSGs would be located on 3p. We, and other groups, have used next-generation sequencing (NGS) techniques and discovered three additional 3p TSGs, e.g. SETD2, PBRM1 and BAP1 (Duns et al., 2016).
Subsequently, we have focused on elucidating how SETD2 and PBRM1 contribute to the first steps in the development of ccRCC by performing lentiviral-based knockdown of their expression in short-term cultures of PTECs. Normally these cells go into senescence after 5-6 passages. However, knockdown of SETD2 prevented this transition and the cells continued to proliferate (Li et al., 2016). Knockdown of PBRM1 did not result in delay of the senescence process, but did lead to marked changes in the cells’ expression profiles, most notably in the group of INF-responsive genes (Jun Li, PhD thesis, 2016). The specific effects from knocking down these genes is now the main focus of our research, including the identification and characterization of long non-coding RNAs that are specifically altered as a result of SETD2 and/or PBRM1 knockdown in PTECs.
Li J, Kluiver J, Osinga J, Westers H, van Werkhoven MB, Seelen MA, Sijmons RH, van den Berg A, Kok K. Functional studies on primary tubular epithelial cells indicate a tumor suppressor role of SETD2 in clear cell renal cell carcinoma. Neoplasia 2016; 18: 339-346.
Li J, Duns G, Westers H, Sijmons R, van den Berg A, Kok K. SETD2: an epigenetic modifier with tumor suppressor functionality. Oncotarget 2016. doi: 10.18632/oncotarget.9368.
Li J. SETD2 and PBRM1 inactivation in the development of clear cell renal cell carcinoma. PhD thesis, University of Groningen. 28 Sept 2016.
Duns G, van den Berg A, van Dijk MC, van Duivenbode I, Giezen C, Kluiver J, van Goor H, Hofstra RM, van den Berg E, Kok K. The entire miR-200 seed family is strongly deregulated in clear cell renal cell cancer compared to the proximal tubular epithelial cells of the kidney. Genes Chromosomes Cancer. 2013;52(2):165-73.
Duns G, Hofstra RM, Sietzema JG, Hollema H, van Duivenbode I, Kuik A, Giezen C, Jan O, Bergsma JJ, Bijnen H, van der Vlies P, van den Berg E, Kok K. Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development. Hum Mutat. 2012;33(7):1059-62.
(2) Inter- and intra-tumor heterogeneity in lung cancer and clear cell renal cell cancer
In collaboration with the Departments of Pathology (Prof. Anke van den Berg) and of Pulmonary Diseases (Prof. Harry Groen and Dr. Jeroen Hiltermann) a research line focuses on the mutational spectrum of lung cancer, particularly non-small cell lung cancer. Our goal is to gain more insight into the mutations and cellular processes that cause resistance to specific therapies. We started by focusing on inter-tumor heterogeneity and comparing the mutational profiles of primary lung cancer cases with metastases in the same patient (Ali Saber Hosseinabadi, 2016). We are also comparing the mutational profiles of tumors before and after development of resistance to therapy (research being carried out by two PhD students, Anthonie van der Wekken and Jiacong Wei).
A project funded by KWF is focusing on the development of a novel technique to identify various types of genomic alterations in a single assay (work of PhD student Jiacong Wei). A major aim is also to make this assay suitable for use as a blood-based assay. This would make it unnecessary to take repeated invasive biopsies from patients. KWF project is a "Alpe D’HuZes" unique chances, high risk (A6U) project.
Another research line, in collaboration with ERIBA (Prof. Peter Lansdorp), is a combined study of inter-and intra-tumor heterogeneity by using single cell sequencing of primary tumors and metastases.
In parallel, there is a large, ongoing study that interrogates inter- and intra-tumor heterogeneity in ccRCC (work of Ferronika Paranita, PhD student).
Genomics of lung cancer: Tumor evolution, heterogeneity and drug resistance. Ali Saber Hosseinabadi, PhD thesis, 2016, University of Groningen. full text
- KWF Alpe D’HuZes grant: Development of a novel technique to identify various types of genomic alterations in a single assay
- RUG2015-8044. Towards a unified assay for the detection of driver and resistance mutations with implications for the treatment of lung cancer. May 2016-2018. Anna Rybczynska has been appointed as a technician to work on this project.
Project leader and staff
Dr. Klaas Kok; Telephone +31 50 3617100
Martijn Terpstra is a technician/bioinformatician responsible for most of the NGS-data analysis for the above projects.
Anna Rybczynska is a technician.
Jan Osinga is working on the ccRCC-project.
And we have a lot of support from the Genome Analysis Facility for the NGS and lab work.
PhD students: Ferronika Paranita, Anthonie van der Wekken, Jiacong Wei
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