b'Redefining Research & CareUT Southwestern investigators discovered that ccRCC can be Paving the Way withsubclassified based on BAP1 and PBRM1 status Genomic Discoveries into four types: wild-type (wt) tumors with normal BAP1 and PBRM1 (associated with best outcomes), tumors with Genes are key to new treatments.mutant PBRM1 (1.5 times higher odds of mortality), Pioneering discoveries at the Kidney Cancertumors with mutant Program provide insight into the biologyBAP1 (3 times higher odds), and a subset of and lay the foundation for the next wave ofinfrequent tumors with targeted drugs. mutations in both genes their contents and dividing. This occursthe answer. Dr. Brugarolas discovered that(5 times higher odds).Clear cell renal cell carcinoma (ccRCC) istrillions of times over a human lifetime.in humans there were other genes that, like characterized by mutations in the VHL geneWhen cells copy their contents, errors mayVHL, also protected kidney cells from can- A kidney of a (von Hippel-Lindau). VHL is one of somebe introduced. They are perpetuated fromcer development, and that these genes weremouse with 22,000 genes in the human genome. Eachmother to daughter cell, and as such, thenext to each other in the genome, one mighta mutation in PBRM1 showing gene represents an instruction. Instructionsnumber of errors accumulates over time.say, on the same page. In contrast, thesemultiple tumors.are stored in the form of DNA. All genes areIn addition, some chemicals can damageinstructions (BAP1, PBRM1, and SETD2 found in every cell, but in every cell not allthe genes/instructions, increasing the rategenes) were located on different pages in instructions are turned on. For an instructionof mutation. Cancer-causing chemicalsthe mouse genome. What this meant was to be turned on, it must be translated into a(carcinogens), such as those from tobacco,that a single mutation (like ripping out a protein. When a gene instruction becomes aare picked up by the blood in the lungspage from the instruction book) disrupted protein in the cell, the instruction is ON. and filtered by the kidneys, where they canall four genes in humans, but three pages Genes carrying instructions can because mutations and increase the risk ofneeded to be ripped out in the mouse corrupted and become faulty. This processkidney cancer.for the same result. Given that ripping is referred to as mutation. Most often, thisThe VHL gene normally protects kidneyout pages of the genome, so-called large means that the particular instruction will nocells from cancer development, but whendeletions, is not frequent, having genesWhy Are Some Renal (see page 67). To explore this notion further,be classified into four subtypes: tumors longer function. Less frequently, the instruc- the gene is altered (mutated), the cancerseparated protected the mice from kidneyTumors So Aggressive?the team compared groups of patientswhere both genes were normal, where one tion can be changed to mean somethingprocess begins. VHL can be mutated incancer development.Kidney tumors behave differently. at UT Southwestern whose cancers hador the other was mutated, or where both else or to become super-active. the germ cells, where it gives rise to VHLIn studies funded by the NationalUT Southwestern investigators have foundone mutation or the other. They foundwere mutated.Mutations can occur in the germ cellssyndrome. VHL patients develop multipleInstitutes of Health and Cancer Preventionthat the answer is in the genes. Theirthat the life expectancy for patients withBecause the mutations typically result (the sperm or the egg). When they occurcancers over the life span (see page 59)and Research Institute of Texas, thediscoveries are revolutionizing how kidneyBAP1-mutant tumors was about half thatin the loss of the protein inside the cells, there, they are found in every cell of theincluding multiple kidney cancers. MostBrugarolas team tested this hypothesis:tumors are classified, launching a modernof patients with PBRM1-mutated tumors.protein tests (immunohistochemistry tests) body. They are also transmitted to the off- often, the VHL gene is mutated in kidneyThey generated mice in which two genescatalogue. By classifying kidney tumors byThese results were confirmed using a sec- can assess the status of BAP1 and PBRM1 spring (see page 59). cells in adult individuals. In fact, VHL iswere inactivated simultaneously. Theytheir genes rather than their appearance,ond nationwide cohort. in patient samples. Dr. Kapur has developed Mutations can also occur during devel- thought to be the first gene to be mutated instarted with VHL and BAP1. As they hadinvestigators hope to identify groups ofAccording to the status of these twoa protein test obviating the need for more opment or after birth. In those instances,the process of kidney cancer development,hypothesized, these mice developed kid- tumors that share the same biology andgenes, BAP1 and PBRM1, ccRCC couldcomplex gene testing. they are only passed on to the particularand, as such, plays an important role.ney cancer.respond to treatment similarly. cells offspring. Cells multiply by copyingThe findings, which were published inDr. Brugarolas and colleagues pre-Discovering Kidney Cancers Source the journal Proceedings of the Nationalviously discovered a gene, BAP1, thatUNDERSTANDING THE LANGUAGEWhen the VHL gene was discovered, sci- Academy of Sciences, have profound impli- is inactivated in about 15 percent of entists sought to model von Hippel-Lindaucations. They not only report the first mouseccRCCs. Interestingly, ccRCCs with theBEHIND KIDNEY CANCER MUTATIONSDID YOU KNOW? syndrome in mice. Mice were engineered tomodel to recapitulate ccRCC, but alsoBAP1 mutation typically lacked a muta-have a faulty VHL gene. As in humans, thesuggest that cancer predisposition, whichtion in another gene, PBRM1, which isThe Brugarolas lab previouslyPBRM1-mutant tumors that also UT Southwestern investigatorsdefective copy was passed from parents tovaries across species, is a function (at leastmutated in almost half of ccRCCs. Theshowed that mutations in BAP1 andacquire mutations in SETD2 tend to implicated several new genesoffspring. Unlike humans, mice with a VHLin part) of the arrangement of genes in thefinding that either one or the other genePBRM1 tend to be mutually exclu- be more aggressive. With funding leading to a biological classifica- mutation did not develop kidney cancer. Thegenome. In other words, how instructionswas mutated began to reveal the logic ofsive in ccRCC, and that mutationsfrom the Kidney Cancer Program tion of kidney tumors, enablingsame approach had worked with countlessare arranged in the pages of one playbookccRCC development.in PBRM1 and SETD2 tend toSPORE, molecular biologist Laura personalized approaches. (Pea- other cancer genes, but this was not thecan have a profound impact on whether aDr. Kapur noticed that tumors withoccur together. In collaboration withBanaszynski, Ph.D., is studying how Llopis et al., Nat Genet, 2012;case for the VHL gene. This puzzled investi- species is predisposed to a particular typeBAP1 mutations looked more aggressiveDr. Kapur and Dr. Thai Ho, from themutations in SETD2 contribute to Durinck et al., Nat Genet, 2015) gators for more than a decade.of cancer. (Wang et al., Proc Natl Acadunder the microscope than those withMayo Clinic group, they showed thatkidney cancer development.UT Southwestern investigators foundSciences USA, 2014) PBRM1 mutationsthey had higher grade 40 41'