b'Redefining Research & CareSDCBP2ASB1PLCG2The kidney is made up of about 1 million structures that filterPDK1IP1the blood, eliminating waste products. These structures are composed of a filter called the Bowman capsule. The BowmanGLYATcapsule is like a toilet that collects waste products from the blood, which are then processed further through a series ofDiscoveries with Genentech led to a five-gene pipes or tubules and are eventually discarded in the form oflist that distinguishes subtypes of nccRCC.urine. Investigators at UTSW have discovered that cells around the Bowman capsule give rise to kidney cancer. (Gu et al., Cancer Discov, 2017) -1.5 -1 -0.5 0 0.5 1 1.5 2Using the protein tests, the team has(see page 67). In contrast, the cancers thatTo address the question moreSeeking Drugs Targeting AggressiveDrs. Kapur and Brugarolas teamed up expanded its studies in collaboration witharose in the PBRM1-defective kidneysdefinitively, the Brugarolas team inducedBAP1 Mutant Cancers with Dr. Seshagiri and his group at the Mayo Clinic, which has assembled a cohortdeveloped significantly later and were ofmutations in BAP1 and PBRM1 (alongKidney tumors with mutations in BAP1 arebiotechnology company Genentech of more than 1,400 patients with kidneylower grade. These results strongly suggestwith mutations in VHL) in differentmost aggressive. Biochemist Dr. Yonghaoto perform next-generation sequenc-cancer. Samples from these patients werethat BAP1 and PBRM1 are not just markerscell types of the mouse kidney. WhenYu is investigating how BAP1 loss inducesing analyses. Tumors from 167 patients analyzed at UT Southwestern, leading toof high and low aggressive kidney cancer,mutations were targeted to cells of theaggressive kidney cancer.at UT Southwestern were evaluated. validation of previous discoveries. but are the very cause of the differentialproximal convoluted tubule, tumors didThe BAP1 protein belongs to a class ofThey included 67 papillary cancers, 49 These findings have advanced the field,aggressiveness. (Gu et al., Cancer Discov, not develop. Rather, investigators foundproteins that controls the levels of otherchromophobe, 8 unclassified, 6 trans-which now recognizes that ccRCC is made2017) that when the mutations were inducedproteins in the cell. These proteins dolocation RCC, and 2 that were primarily up of these four fundamental subtypes.in a kidney structure called the Bowmanthis by removing a tag that is placed onsarcomatoid. The analysis also included (Pea-Llopis et al., Nat Genet, 2012; KapurWhich Kidney Cells Give capsule, kidney tumors readily formed.proteins to earmark them for shredding.35 oncocytomas.et al., Lancet Oncol, 2013; Kapur et al., JRise to Cancer? These results suggest that kidney The tag, called ubiquitin, is cleaved offThis study, the first integrated genomic Urol, 2014; Joseph et al., Cancer, 2014;Extensive studies have sought to find whichcancer arises from the Bowman capsuleby BAP1 and related proteins. However,study of nccRCC to be published, made Joseph et al., J Urol, 2016) cell type in the kidney, among a couple ofcells. Notably, the Bowman capsuleprecisely which proteins BAP1 controls issignificant discoveries. It implicated dozen, gives rise to kidney cancer. Effortscontains mother cells that maintainpoorly understood. Further, ubiquitin tagsseveral new genes in the development Genes That Control Tumorhave focused on evaluating tumors for theand help repair the kidney when damagenot only control shredding, but may alsoof nccRCC, including NF2, PTEN, TSC1, Aggressiveness presence of features (markers) that distin- occurs. This population of cells may beinfluence proteins in other ways.and MTOR in papillary RCC. In addition, it Whitney Wheeler was diagnosed with nccRCC at To address whether BAP1 and PBRM1guish the different cell types. Frequently, thisresponsible for cancer development.With funding from the SPORE, Dr. Yu isimplicated mutations in LATS1 in papil- age 28. After radiosurgery for brain metastases and are indeed responsible for controllinginvolves comparing ON and OFF instruc- Another conclusion of the study isleveraging mass spectrometry technologylary RCC. four lines of therapy, she passed away 11 months later. Research is ongoing at the Kidney Cancer tumor aggressiveness, the Brugarolas labtions in tumors to the particular instructionsthat tumors with BAP1 and PBRM1to map all the proteins that BAP1 controls.Additionally, the team identified a setProgram to find effective treatments. genetically engineered mice with eitherthat characterize different kidney cellmutations may arise from the sameThese proteins may then become targetsof five genes that distinguished tumors mutant BAP1 or mutant PBRM1 in theirtypes. Using this approach, investigatorscell type.for drug development. that may be hard to distinguish undernccRCC. The research also refined the kidneys (together with a mutation in VHL).have concluded that ccRCC arises fromThat the Bowman capsule isthe microscope, such as chromophobecurrent classification of nccRCC. (Durinck Investigators found that, as for kidneycells lining the proximal convoluted tubule.the source of kidney cancer is alsoA Better Understanding of RCC and benign renal oncocytoma.et al., Nat Genet, 2015) cancer in humans, cancers that arose in theHowever, the analysis assumes that havingsupported by studies of human kidneyRare Kidney Cancers Two subtypes of chromophobe tumors BAP1-mutant kidneys developed early inthe particular marker or signature is reveal- specimens by Dr. Kapur. (Gu et al.,NccRCC (non-clear cell RCC) accounts forwere characterized: an aggressive sub- Modeling nccRCC in the Mousethe life of the mouse and were of high gradeing of the cell of origin. Cancer Discov, 2017) about 30 percent of all RCC. This group oftype with p53 and PTEN mutations,Developmental biologist Thomas Carroll, tumors is made up of different subtypesand a second subtype more akin toPh.D., is evaluating the role of the LATS1 These results strongly suggest that BAP1 and PBRM1 are not just markersand it has received less attention. Further,benign oncocytomas.and the LATS2 genes in kidney cancer of high and low aggressive kidney cancer, but are the very cause of thenccRCC lacks specific treatments. Their findings provide fruitful targetsdevelopment using mice. With fund-differential aggressiveness. To learn more about nccRCC,in the development of novel therapies foring from the SPORE, Dr. Carroll has 42 43'