Chromophobe Renal Cell Carcinoma TCGA KICH AWG Chairs: Chad - - PowerPoint PPT Presentation

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Chromophobe Renal Cell Carcinoma TCGA KICH AWG Chairs: Chad - - PowerPoint PPT Presentation

Nov 16, 2023 714 likes •1.03k views

Chromophobe Renal Cell Carcinoma TCGA KICH AWG Chairs: Chad Creighton, W. Kim Rathmell Introduction Chromophobe renal cell carcinoma (ChRCC) represents ~5% of cancers arising from the kidney nephron Due in part to its relative rarity,

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Chromophobe Renal Cell Carcinoma

TCGA KICH AWG Chairs: Chad Creighton, W. Kim Rathmell

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Introduction

  • Chromophobe renal cell carcinoma (ChRCC)

represents ~5% of cancers arising from the kidney nephron

  • Due in part to its relative rarity, this disease

has been understudied at the molecular level

  • Comprehensively profiled by TCGA, as the first
  • f its Rare Tumor Projects
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Data summary

Data Type Platforms Cases Data access Whole exome DNA sequence Illumina 66 Controlled Whole genome DNA sequence Illumina 50 Controlled Mitochondria DNA sequence Illumina (LR-PCR) 61 Controlled DNA copy number/genotype Affymetrix SNP 6 66 Controlled mRNA expression Illumina 66 Controlled - BAM files Open - expression files miRNA expression Illumina 66 Controlled - BAM files Open - expression files CpG DNA methylation Illumina 450K 66 Open

66 tumor cases for comprehensive profiling 50 cases with whole genome sequencing 61 cases with mitochondria genome sequencing

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Data summary

Data Type Platforms Cases Data access Whole exome DNA sequence Illumina 66 Controlled Whole genome DNA sequence Illumina 50 Controlled Mitochondria DNA sequence Illumina (LR-PCR) 61 Controlled DNA copy number/genotype Affymetrix SNP 6 66 Controlled mRNA expression Illumina 66 Controlled - BAM files Open - expression files miRNA expression Illumina 66 Controlled - BAM files Open - expression files CpG DNA methylation Illumina 450K 66 Open

66 tumor cases for comprehensive profiling 50 cases with whole genome sequencing 61 cases with mitochondria genome sequencing

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Data summary

Data Type Platforms Cases Data access Whole exome DNA sequence Illumina 66 Controlled Whole genome DNA sequence Illumina 50 Controlled Mitochondria DNA sequence Illumina (LR-PCR) 61 Controlled DNA copy number/genotype Affymetrix SNP 6 66 Controlled mRNA expression Illumina 66 Controlled - BAM files Open - expression files miRNA expression Illumina 66 Controlled - BAM files Open - expression files CpG DNA methylation Illumina 450K 66 Open

66 tumor cases for comprehensive profiling 50 cases with whole genome sequencing 61 cases with mitochondria genome sequencing

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Somatic alterations (copy and whole exome)

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DNA copy alterations

CCRCC ChRCC classic eosinophilic

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Somatically mutated genes

Frequency of mutation (%)

N=66 ChRCC

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DNA methylation and RNA expression

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64,000 differential loci in total

ChRCC CCRCC normal

DNA methylation high low

Widespread differences between ChRCC and CCRCC

Shen H Laird P

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Anatomy of the kidney nephron

http://en.wikipedia.org/wiki/File:Kidney_nephron_molar_transport_diagram.svg

proximal distal

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Anatomy of the kidney nephron

CCRCC? ChRCC?

proximal distal

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Gene expression atlas of the kidney nephron

proximal distal

Cheval et al. PLOS One 2012

Published mRNA profiling dataset

  • f micro-dissected

regions (mouse and human)

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Kidney nephron atlas

ChRCC CCRCC

TCGA Kidney cancer

proximal proximal distal distal

ChRCC versus CCRCC expression differences reflect distal versus proximal nephron

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Mitochondrial DNA alterations

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Events with >50% heteroplasmy shown Red, affects protein coding

Muzny D, Buhay C Wang M

mtDNA somatic mutations in ChRCC

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Red, high in ChRCC Blue, low in ChRCC Yellow, mtDNA mutation

mtDNA mutations involve the electron transport chain

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Red, high in ChRCC Blue, low in ChRCC Yellow, mtDNA mutation

ChRCC relies upon oxidative phosphorylation

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Red, high in ChRCC Blue, low in ChRCC Yellow, mtDNA mutation

ChRCC relies upon oxidative phosphorylation

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Whole Genome Analysis

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Kataegis observed in ChRCC

Davis C, Wheeler D

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mRNA correlates

  • f kataegis

Creighton C, Davis C

Cases with kataegis (n=3)

Includes TERT

n=50 ChRCC mRNA expression high low

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Structural breakpoints within TERT promoter region

n=50 ChRCC TERT PM

Davis C

Copy gain Copy loss Breakpoint X

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Structural variants associated with TERT promoter region by WGS analysis

breakpoint A breakpoint B case chr:pos

  • ri gene

chr:pos

  • ri gene

event type KL-8341 5:1116986

  • 1

5:1296148 1 TERT PM tandem dup. KN-8435 5:272199 1 PDCD6 5:1296716 1 TERT PM inversion KM-8438 5:1348783

  • 1

5:1295372 1 TERT PM deletion KL-8346 5:1125430

  • 1

5:1295604 1 TERT PM tandem dup. KL-8323 5:49560803 1 5:1299528

  • 1 TERT PM tandem dup.

KL-8323 5:49563017

  • 1

5:1297603 1 TERT PM del-insertion KM-8443 13:52688659 1 NEK5 5:1305300 1 TERT PM Inter-chr transl.

Davis C, Wang L, Park P Meerkat algorithm

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TERT promoter-associated SVs correlate with high TERT expression

TERT expression 10 100 1000

SV mut WT norm 6 3 57 25

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TERT promoter-associated SVs correlate with high TERT expression

TERT expression 10 100 1000

SV mut WT norm 6 3 57 25

P < 1E-20 P = 0.01

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Validation of TERT PM-associated SVs

Wang M, Muzny D

KN-8435 (inversion) normal tumor

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Validation of TERT PM-associated SVs

Wang M, Muzny D PI-P2 P3-P4 PI-P3 PI-P2 P3-P4 PI-P3

KN-8435 (inversion) normal tumor normal tumor

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Conclusions

  • Comprehensive molecular analysis of a rare

cancer type as a platform for discovery

  • Global molecular patterns may provide clues

as to a cancer’s cell of origin

  • mtDNA sequencing incorporated into multi-

platform molecular characterization of cancer

  • Discovery of recurrent genomic

rearrangements involving TERT promoter region

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Chad Creighton (co-chair) Baylor Lisa Henske Harvard Kimryn Rathmell (co-chair) UNC Donna Muzny Baylor Hui Shen USC Pheroze Tamboli MDACC David Kwiatkowski Harvard Ari Hakimi MSKCC Toni Chouieri Harvard James Hsieh MSKCC Caleb Davis Baylor Victor Reuter MSKCC Richard Gibbs Baylor Christopher Ricketts NIH/NCI David Wheeler Baylor

  • W. Marston Linehan

NIH/NCI Maggi Morgan Baylor Laura Schmidt NIH/NCI Larry Donehower Baylor Maria Merino NIH/NCI Preethi Gunaratne Baylor Brian Shuch NIH/NCI Gordon Robertson BCGSC Satish Tickoo MSKCC Andy Chu BCGSC Billy Kim UNC Andrew Mungall BCGSC Eric Wallen UNC Payal Sipahimalani BCGSC Angie Smith UNC Andrew Cherniack Broad Sahil Seth MDACC Matthew Meyerson Broad Catherine Fahey UNC Raju Kucherlapati Harvard Kate Hacker UNC Sabina Signoretti Harvard Gyan Bhanot Rutgers Lixing Wang Harvard Peter Laird USC Peter Park Harvard STAFF: Jean Claude Zenklusen, Ina Felau, Lindsay Lund, + NCI Senior Leadership; NHGRI Senior Leadership

KICH Analysis Working Group