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Printable Handouts
Navigable Slide Index
- Introduction
- Renal carcinoma
- Stage I kidney cancer
- Stage IV kidney cancer
- Human renal epithelial neoplasms
- Loss of alleles in renal cell carcinoma
- Mapping the minimal 3p loss region
- Studying cancer families to identify genes
- Identification of kidney cancer genes
- Inherited forms of renal carcinoma
- von Hippel Lindau (VHL) CCRC
- VHL clinical features
- VHL: renal cell carcinoma
- VHL: multiple clear cell renal carcinomas
- VHL-associated RCC high persistence rate
- VHL: advanced RCC
- NCI VHL kindreds
- VHL: surgical management
- NIH clinical center (1)
- Genetic analysis of VHL families
- VHL gene is on chromosome 3
- VHL gene localization map
- Human VHL gene
- Germline VHL mutations
- NCI VHL germline mutations
- VHL gene: sporadic RCC
- Sporadic clear cell RCC VHL gene mutations
- Clear cell renal carcinoma
- Papillary renal carcinoma
- VHL is a two hit loss of function tumor suppressor
- VHL -/- athymic nude mice
- Mouse with RCC + VHL gene
- How does the VHL gene function?
- Degradation of HIF alpha
- Downstream effects of VHL mutation
- Targeting VHL/HIF in clear cell RCC
- TCGA clear cell kidney cancer
- Intratumor Heterogeneity
- Intratumor heterogeneity: implications for therapy
- Warburg effect in clear cell kidney cancer
- Non-clear cell RCC
- Locally advanced kidney cancer
- Papillary kidney cancer: patient 1 (pathology)
- Papillary kidney cancer: patient 2
- Papillary kidney cancer: patient 2 (pathology)
- Papillary kidney cancer: patient 3A
- Papillary kidney cancer: patient 3B
- Papillary kidney cancer: patient 3C
- Papillary kidney cancer patient 3 (pathology)
- Hereditary papillary renal carcinoma (HPRC)
- Inherited renal carcinoma
- HPRC: renal tumors
- Hereditary papillary renal carcinoma type 1
- Penetrance of MET mutation H1210R
- HPRC: high prevalence
- HPRC: surgical management
- NIH clinical center (2)
- MET gene is on chromosome 7
- Location of the HPRC gene
- MET is the HPRC gene
- HPRC: mutations in the tyrosine kinase domain
- Location of MET mutations in HPRC patients
- NCI HPRC kindreds
- Early onset HPRC
- Targeting MET RCC gene pathway
- Potential small molecule target
- Foretinib: dual VEGFR and MET inhibitor
- MiT kidney cancer TFE3, TFEB, MITF
- Back to locally advanced kidney cancer patient
- Samples from patient
- UOK124: papillary kidney cancer cell line
- TFE3 kidney cancer
- TFE3 kidney cancer epidemiology
- Microphthalmia transcription factor (MITF)
- TFEB kidney cancer patient 1
- TFEB kidney cancer patient 2
- TFE3 translocation kidney cancer patient
- TFE3 translocation patient (lymph node spread)
- Inherited renal carcinoma Birt-Hogg-Dube (BHD)
- BHD cutaneous manifestations (obvious)
- BHD cutaneous manifestations (subtle)
- Kidney tumors in BHD
- Kidney tumors in BHD (solitary)
- Kidney tumors in BHD (bi-lateral)
- Kidney tumors in BHD (spread)
- Different cancer types in BHD
- BHD renal tumor pathology
- BHD: surgical management
- BHD lung cysts (patient 1)
- BHD lung cysts (patient 2)
- BHD lung cysts (patient 3)
- Identification of the BHD gene
- NIH Clinical Center (3)
- Cutaneous fibrofolliculomas as a marker
- BHD gene is on chromosome 17
- BHD gene locus
- BHD protein sequence
- FLCN mutation spectrum
- FLCN Mutation analysis
- What kind of gene is FLCN?
- BHD gene analysis in BHD-associated RCC
- Somatic mutations in BHD renal tumors
- Mutations in tumors from a single BHD patient
- BHD -/- RCC cell line is tumorigenic
- BHD restored RCC cell line is not tumorigenic
- How does the FLCN gene function?
- Folliculin-FNIP1/2-AMPK interactions
- mTORC1/mTORC2 activation
- BHD deletion specifically in the kidney
- BHDf/d/KSPCre mouse kidney histology
- BHD deletion specifically in the kidney - survival
- Rapamycin treatment
- mTORC1/mTORC2 activation - treatment
- Young patient had HLRCC kidney cancer
- HLRCC kidney cancer in patient's family
- Inherited renal carcinoma (HLRCC)
- features of HLRCC
- HLRCC kindred
- HLRCC: cutaneous manifestations
- HLRCC: uterine leiomyomas
- HLRCC kidney cancer (patient 1)
- HLRCC kidney cancer (patient 2)
- HLRCC renal mass (patient 2)
- HLRCC kidney cancer: papillary type 2
- HLRCC: orangophilic nucleoli + perinucleolar halos
- HLRCC: occurrence in young patients
- HLRCC: occurrence in elderly patients
- 7mm HLRCC renal tumor (1)
- 7mm HLRCC renal tumor (2)
- 7mm HLRCC renal tumor (3)
- HLRCC patient - no tumors in 2003
- HLRCC patient - no tumors in 2006
- HLRCC patient - large tumor in 2010 (1)
- HLRCC patient - large tumor in 2010 (2)
- HLRCC patient - tumor removal and metastasis
- HLRCC: surgical management
- Fumarate hydratase gene is on chromosome 1
- Fumarate hydratase (FH): HLRCC gene
- HLRCC: mutation analysis
- FH is a two hit loss of function tumor suppressor
- UOK-262 EV (empty vector) treated mouse
- UOK-262 FHWT (WT replaced) treated mouse
- Loss of a Krebs cycle enzyme and kidney cancer
- Impaired citric acid cycle and “Warburg effect”
- HLRCC-renal cancer: glucose-dependent
- HLRCC tumors in vivo detection (patient 1)
- HLRCC tumors in vivo detection (patient 2)
- HLRCC retroperitoneal tumor: PET scan
- HLRCC chest tumor: PET scan
- HLRCC patient with cutaneous leioymyoma
- Cutaneous leioymyomas in vivo detection
- Uterine leiomyomas
- Krebs cycle modifications
- HLRCC novel treatment approaches
- HLRCC: effects of increased fumarate
- Summary of kidney cancer pathology
- Kidney cancer is a metabolic disease
- Acknowledgements
- Urologic Oncology Branch NCI
Topics Covered
- Renal Carcinoma
- Stage I , Stage IV kidney cancer
- Human Renal Epithelial Neoplasms
- Loss of alleles in renal cell carcinoma
- Mapping the Minimal 3p Loss Region in Clear Cell Renal Carcinoma
- Studying Cancer Families to Identify Renal Carcinoma Genes
- Identification of Kidney Cancer Genes
- Inherited Forms of Renal Carcinoma
- Clear Cell Renal Carcinoma: von Hippel Lindau (VHL)
- VHL Gene
- VHL Gene Localization Map
- Germline VHL Mutations
- Papillary Renal Carcinoma
- Mouse Studies of VHL gene
- VHL Gene Function
- HIFα
- Downstream effects of VHL mutation
- Targeting VHL/HIF in Clear Cell RCC
- TCGA Clear Cell Kidney Cancer
- Intratumor Heterogeneity
- Warburg effect in clear cell kidney cancer
- Non-Clear Cell RCC
- Locally Advanced Kidney Cancer
- Hereditary Papillary Renal Carcinoma (HPRC)
- Inherited Renal Carcinoma
- Type 1 Papillary Renal Carcinoma
- Penetrance of MET Mutation H1210R
- MET Gene: Type 1 Papillary RCC
- Location of the HPRC Gene
- HPRC: Activating Mutations in the Tyrosine Kinase Domain of MET
- Location of MET Mutations in the HPRC Patients
- Targeting MET RCC Gene Pathway
- Potential Small Molecule Target: MET Tyrosine Kinase Inhibition
- Foretinib: Dual VEGFR and MET Inhibitor
- MiT Kidney Cancer TFE3, TFEB, MITF
- UOK124, Papillary Kidney Cancer
- UOK124, UOK120, UOK 146 & TFE3 Kidney Cancer
- Inherited Renal Carcinoma Birt-Hogg-Dubé (BHD)
- Birt Hogg Dubé Cutaneous Manifestations
- Kidney Tumors in BHD
- BHD Renal Tumor Pathology
- BHD Lung Cysts
- Identification of the BHD Gene
- Cutaneous Fibrofolliculomas
- BHD Gene: Chromophobe RCC
- BHD Gene Locus: Chromosome 17
- BHD Protein Sequence
- FLCN Mutation Spectrum
- Therapeutic Approach: What Kind of Gene is FLCN?
- BHD Gene Analysis in BHD-Associated RCC
- Somatic mutations in renal tumors from BHD patients
- UOK 257, BHD -/- RCC cell line Study
- How Does the FLCN Gene Function?
- Folliculin-FNIP1/2-AMPK Interactions
- mTORC1/mTORC2 Activation: FLCN-Deficient Kidney Cancer
- BHD Deletion Specifically in the Kidney
- BHDf/d/KSPCre Mouse Kidney Study
- Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC)
- HLRCC: Cutaneous Manifestations, Uterine Leiomyomas
- HLRCC: Papillary Kidney Cancer Type 2
- Orangophilic Nucleoli + Perinucleolar Halos
- Fumarate Hydratase Gene: HLRCC
- UOK-262 Study
- Loss of a Krebs Cycle Enzyme Can Lead to Kidney Cancer
- Impaired citric acid cycle and “Warburg effect”
- HLRCC-Renal Cancer: Glucose-Dependent
- PET Scan
- HLRCC novel treatment approaches
- Kidney Cancer: a Metabolic Disease
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Linehan, W.M. (2014, September 3). The genetic basis of kidney cancer [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 12, 2024, from https://doi.org/10.69645/ZHUI8368.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. W. Marston Linehan has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Other Talks in the Series: The Kidney in Health and Disease
Transcript
Please wait while the transcript is being prepared...
0:00
I'm Marston Linehan,
I'm the chief of the Urologic
Oncology branch at the
National Cancer Institute,
at the National
Institutes of Health.
And we're going to talk about the
genetic basis of kidney cancer.
0:16
Kidney cancer affects nearly 300,000
patients worldwide each year,
and is responsible for nearly
120,000 deaths worldwide, annually.
It's predicted that there
are 200,000 patients alive
with kidney cancer
in the United States.
0:35
I'm a urologic surgeon, and if a
patient came to someone like me
with localized kidney cancer,
we remove their tumor.
We could cure to 95%
of those patients.
0:52
However, if a patient comes to
someone like me, or to a physician,
with advanced disease, they
have only a 19% or 20%,
two-year survival.
So it's been nearly 30 years ago now
that we started working on kidney
cancer, and our goal was to identify
the gene-- we thought it was
a gene at the time, we didn't
realize it was genes-- to identify
the gene that causes kidney cancer.
And our hope was that we could then
study that gene pathway to develop
an approach for therapy for patients
with advanced forms of kidney
cancer.
1:33
So I'm going to talk with you about
our process over the past 30 years
or so, and our
experience and what we've
learned about kidney
cancer in that time.
So when we started, kidney cancer
was thought to be a single disease.
We treated all patients
the same surgically,
did the same operation for each.
We gave patients with
metastatic or advanced disease
the same drugs, none
of which worked.
We now know that kidney cancer
is not a single disease.
It's a number of
different types of cancer
that happen to occur in the kidney.
They have different histologies,
as you can see on this slide.
The patients undergo
different clinical courses.
They respond differently to therapy.
And as I'll show you, they're
caused by different genes.