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Molecular Landscape of Non-Muscle Invasive Bladder Cancer

2017; Cell Press; Volume: 32; Issue: 5 Linguagem: Inglês

10.1016/j.ccell.2017.08.015

1878-3686

Joshua J. Meeks, Seth P. Lerner,

Ferroptosis and cancer prognosis

In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Tumors from female patients have a higher frequency of KDM6A mutations. In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Tumors from female patients have a higher frequency of KDM6A mutations. Urothelial carcinoma is the sixth-most common cancer in the US, and the majority of these tumors are non-invasive stage Ta at first diagnosis without evidence of invasion. Due to the high prevalence of Ta cancers (estimated at 700,000 in the US [Howlader et al., 2016Howlader N. Noone A.M. Krapcho M. Miller D. Bishop K. Kosary C.L. Yu M. Ruhl J. Tatalovich Z. Mariotto A. et al.SEER Cancer Statistics Review, 1975–2014. National Cancer Institute, 2016Google Scholar]), these cancers are a significant financial and emotional burden. The risk of progression of a Ta bladder cancer is low, but even patients with the lowest risk features (low grade and size under 3 cm) have a significant risk of recurrence. Non-invasive tumors are treated surgically with endoscopic resection, and patients determined to be at high risk of recurrence receive intravesical chemotherapy or immunotherapy with BCG (Bacillus Calmette–Guérin) to decrease the risk of recurrence (Chang et al., 2016Chang S.S. Boorjian S.A. Chou R. Clark P.E. Daneshmand S. Konety B.R. Pruthi R. Quale D.Z. Ritch C.R. Seigne J.D. et al.J. Urol. 2016; 196: 1021-1029Abstract Full Text Full Text PDF PubMed Scopus (721) Google Scholar). Despite a high initial response rate, the majority will recur. Insight into the molecular drivers of non-invasive cancers has great potential benefit for precision therapeutics but also molecular diagnostics and risk stratification. In this issue of Cancer Cell, Hurst et al. address this critical need by combining cytogenetics, gene-expression sequencing, and limited whole-exome sequencing of 140 non-invasive tumors (Hurst et al., 2017Hurst C.D. Alder O. Platt F.M. Droop A. Stead L.F. Burns J.E. Burghe G.J. Jain S. Klimczak L.J. Lindsay H. et al.Cancer Cell. 2017; 32 (this issue): 701-715Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). The cohort is largely comprised of WHO 1973 grade 1 and 2 tumors, and after application of the current WHO/ISUP 2004 criteria many grade 2 tumors were reclassified as high grade, accounting for 39% of all tumors. The authors performed low-pass sequencing and CGH array analysis on 141 tumors, microarray analysis on 79 tumors, and whole-exome sequencing on 24 samples. Unsupervised clustering of tumors first by cytogenetic analysis identified a remarkably simple clustering in which 78 tumors had no cytogenetic changes (genomic subtype 1; GS1), and 58 of 63 had a well-described loss of 9q (GS2) (Hirao et al., 2005Hirao S. Hirao T. Marsit C.J. Hirao Y. Schned A. Devi-Ashok T. Nelson H.H. Andrew A. Karagas M.R. Kelsey K.T. Cancer. 2005; 104: 1918-1923Crossref PubMed Scopus (28) Google Scholar). A genomic stratification of only two subtypes provides molecular evidence to support the binary WHO/ISUP 2004 risk stratification, because the majority of GS2 tumors were high grade. Although there are many candidate genes lost on 9q, the genetic driver (or cluster of drivers) that may be involved in the initiation of cancer located on 9q is not known. Candidate genes include the negative regulator of AKT/PI3K/mTOR pathway, TSC1 (Iyer et al., 2012Iyer G. Hanrahan A.J. Milowsky M.I. Al-Ahmadie H. Scott S.N. Janakiraman M. Pirun M. Sander C. Socci N.D. Ostrovnaya I. et al.Science. 2012; 338: 221Crossref PubMed Scopus (572) Google Scholar), and the membrane-expressed developmental regulator, NOTCH1. Mutations affecting both the mTOR and Notch pathways have been implicated as drivers of bladder cancer initiation and/or progression. Integrating gene-expression analysis of a subset of GS2 tumors identified increased expression and activity of mTORC1 pathway. Unregulated activity of the mTOR pathway may identify a potential weakness of non-invasive tumors. Intravesical delivery of agents targeting the mTOR pathway (such as evorlimus) is a rational therapeutic option in GS2 tumors with TSC1 mutations or 9q deletion. Of note, there are currently 16 trials targeting the mTOR pathway for patients with bladder cancer in the US, including two targeting non-muscle invasive cancer (NCT02753309 and NCT02009332). Treatment of non-muscle invasive bladder cancer with immunotherapy dates back to 1975 as urologists have applied intravesical BCG to decrease recurrence of high-grade bladder cancers. Yet this therapy has not proved to be as effective for lower-grade tumors. Mutation analysis by Hurst et al. identified a low overall median mutation rate of 1.64 mutation/MB (Hurst et al., 2017Hurst C.D. Alder O. Platt F.M. Droop A. Stead L.F. Burns J.E. Burghe G.J. Jain S. Klimczak L.J. Lindsay H. et al.Cancer Cell. 2017; 32 (this issue): 701-715Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar), significantly less than 5.5 mutations/MB identified in MIBC (Cancer Genome Atlas Research Network, 2014Cancer Genome Atlas Research NetworkNature. 2014; 507: 315-322Crossref PubMed Scopus (2125) Google Scholar). Higher total mutational burden (median of 4.42 mutations/MB) in high-grade (GS2) cancers likely results in increased neoantigens. Although response to BCG was not investigated in their study, an increase in the total mutations may explain the improved response to BCG previously reported with high-grade tumors. Alternatively, for low-mutation tumors (such as GS1 with a median of 1.38 mutations/MB), treatment with intravesical chemotherapy may be more effective. Similar to invasive cancers, the APOBEC mutation signature predominated in 75% of non-invasive tumors. Although the role of APOBEC-mediated mutagenesis is unknown, specifically as a driver or secondary response to another genetic insult, the appearance of this signature is predominant in urothelial carcinomas, regardless of stage or grade. Hurst et al. performed expression profiling and confirmed the expression of a luminal gene expression signature with elevated expression of markers PPARG, FOXA1, and GATA3. Comparison of genomic subtyping demonstrated clustering of both GS1 and GS2 subtypes with Urobasal A/luminal tumors. Although GS1 and GS2 are both luminal, the gene expression of non-invasive tumors correlates well with the profile derived from the UROMOL classification as described by Hedegaard et al. (Hedegaard et al., 2016Hedegaard J. Lamy P. Nordentoft I. Algaba F. Høyer S. Ulhøi B.P. Vang S. Reinert T. Hermann G.G. Mogensen K. et al.Cancer Cell. 2016; 30: 27-42Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar), in which class 1 aligns with GS1 and class 2 aligns with GS2. Importantly, basal subtype tumors (class 3) and infiltrated tumors were rare and only identified in eight samples. Because only 79 tumors were profiled with microarray technology, an expanded set of tumors profiled by next-generation sequencing may be necessary to better identify immune-infiltrated cancers. Despite significant differences in expression of 363 genes between GS1 and GS2 subtypes, very few mutations were unique to either genomic subtype. This may be secondary to such a small number of tumors sequenced, but the similarity of the majority of genes with mutations among GS1, GS2, and even MIBC is striking. Two genetic mutations that distinguish non-invasive tumors from MIBC cancers are FGFR3 mutations, found in 79% of non-invasive tumors (only 12% in MIBC), and an absence of TP53 mutations that occur in over 50% of MIBCs. Thus, the loss of the P53/RB1 and CDKN2A checkpoint could be a critical factor responsible for the switch to an invasive phenotype. While the mutation profiles of GS1 and GS2 are similar, differences in gene expression may still occur by epigenetic mechanisms. Bladder carcinomas have a disproportionately high rate of mutations in histone-modifying enzymes, second only to hematologic malignancies in frequency (Cancer Genome Atlas Research Network, 2014Cancer Genome Atlas Research NetworkNature. 2014; 507: 315-322Crossref PubMed Scopus (2125) Google Scholar). These mutations occur most commonly in members of the COMPASS complex, primarily the histone demethylase KDM6A (49%) and/or the histone methyltransferase KMT2C (54%) or KMT2D (28%). Although the function and histone targets of KDM6A or KMT2C/D are different, the frequency of mutations in these genes emphasizes the large and expanding role of the COMPASS complex in bladder cancer. In the Cancer Genome Atlas, KDM6A and KMT2D mutations were nearly mutually exclusive, suggesting that both genes play a significant role and share a common pathway (Cancer Genome Atlas Research Network, 2014Cancer Genome Atlas Research NetworkNature. 2014; 507: 315-322Crossref PubMed Scopus (2125) Google Scholar). Mutations of KDM6A or KMT2C/D may destabilize the large multi-protein COMPASS complex, allowing unbalanced PRC2 (Polycomb complex) activity. Although KDM6A mutations have been previously associated with luminal tumors and low-grade cancers, Hurst et al. are the first to describe an increased frequency of KDM6A mutations found in tumors from female patients. Because KDM6A is located on the X chromosome, females have two copies of KDM6A that may be mutated and increase the total mutations found in KDM6A. The mechanism by which mutations in KDM6A affect tumor aggressiveness is unknown, but recent work targeting an imbalance of H3K27 methylation has demonstrated that loss-of-function mutations in KDM6A can sensitize tumors to EZH2 inhibitors and may be another rational intravesical target for low-grade bladder cancer (Ler et al., 2017Ler L.D. Ghosh S. Chai X. Thike A.A. Heng H.L. Siew E.Y. Dey S. Koh L.K. Lim J.Q. Lim W.K. et al.Sci. Transl. Med. 2017; 9: eaai8312Crossref PubMed Scopus (126) Google Scholar). With the accumulation of integrated data on all stages and grades of urothelial carcinoma, the next decade of science and medicine offer an opportunity to improve survival and quality of life for bladder cancer patients. Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation FrequencyHurst et al.Cancer CellNovember 13, 2017In BriefBy analyzing 140 primary patient samples, Hurst et al. identify two genomic subtypes of stage Ta non-invasive bladder cancer. The more genomically unstable subtype is distinguished by loss of chromosome 9q sequences, upregulated mTORC1 signaling, and altered metabolic profile. They also find that females have a higher frequency of KDM6A mutations than males. Full-Text PDF Open Archive