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Are sufficient to cause human ?

Scott E. Woodman and Gordon B. Mills1 Medical , Systems Biology, Kleberg Center for Molecular Markers, University of Texas, MD Anderson Cancer Center, Houston, TX 77030

fundamental aim of cancer re- contrast, the frequency of comutations in sequences is warranted to identify the search is to identify the molecu- FGFR3 and KRAS or PIK3CA and KRAS spectrum of mutations in this benign tu- A lar changes that cause normal was lower than predicted by chance, sug- mor and explore the mechanisms pre- cells to evolve into malignant gesting either a lack of selective pressure for venting malignant conversion. tumors. has both mutations to occur or a negative in- To examine the functional conse- been proposed to occur as a consequence teraction between the consequences of quences of the mutations in of the accumulation of genomic aberra- each mutation. SK, Hafner et al. (1) examine phosphory- tions that successively overcome the cel- Multiple lines of evidence, including lation of ERK and AKT. Compared lular barriers to . Although their presence in SK, indicate that muta- with normal skin, SK showed significantly a concerted effort has been made to tions in oncogenes are insufficient to in- elevated levels of phosphorylated AKT. discover the complement of molecular duce malignancy. Patients with germline These findings are consistent with many aberrations required for malignant trans- mutations in FGFR3 that result in the tyrosine kinase receptors, which prefer- formation, the spectrum of events that same codon change as in somatic muta- entially signal through the PI3K–AKT must occur in a single , including which tions found in SK do not develop malig- pathway, as opposed to RAS–RAF mu- oncogene activation and tumor suppressor nant epithelial skin tumors at increased tants, which signal primarily through gene inactivation events can cooperate frequency (2). The authors show that the the MEK–ERK pathway (6). It will be of to induce malignant transformation, has sites of mutations found at the highest interest to learn if SK harboring KRAS or remained elusive. A number of benign le- frequency in SK are found at much lower HRAS mutations also exhibits a preferen- sions without malignant potential accu- frequency in malignant tumors and vice tial signaling profile linked to ERK. The mulate genomic aberrations and have the versa (1). Although a subset of the muta- interaction of oncogene activation and potential to inform on the changes that tions found in SK exhibits lower trans- tumor suppressor loss in malignant cells are tolerated in benign tumors; however, forming activity than those found more typically drives cellular proliferation and fi they are insuf cient to induce malignant frequently in malignant tumors, many of survival programs. The oncogene muta- transformation. In PNAS, Hafner et al. (1) these mutations do predispose to tumor tions in SK were not sufficient to alter the comprehensively investigate the mutation development in animal models. The sites proliferation index, as measured by ele- status, mechanistic barriers to malignancy, of FGFR3 and PIK3CA mutations in SK vated Ki67 levels, or induction of apopto- and clonal relationship of seborrheic are similar to those observed in pre- sis, as measured by activated caspase 3 keratoses (SK), a tumor lineage that is cancerous and less aggressive forms of levels. Thus, SK has the capacity to abro- without malignant potential. bladder and prostate , compatible gate the expected functional outcomes with a low malignant potential (3, 4). of activation of RAS/ERK and PI3K/ Discussion However, it is important to note that the AKT pathways. Fibroblast growth factor receptor 3 (FGFR3) frequency and spectrum of mutations in Senescence has been proposed to play PIK3CA and phosphatidylinositol 3-kinase catalytic vary markedly across tumor line- a major role in preventing malignant PIK3CA subunit (PIK3CA) mutations have been ages, and the mutations in ob- transformation of melanocytic nevi (7). previously identified in SK (2, 3). Hafner served in SK are located at hot spots that Indeed, nevi often harbor the same BRAF et al. (1) perform an extensive analysis of are seen recurrently in malignant tumors. (V600E) mutation present in ∼60% of hot spot mutations in genes in the FGFR3– Nevertheless, the mutations in cases where malignant melanoma; however, melano- RAS–MAPK and PI3K–AKT pathways in members of both the PI3K and RAS cytic nevi rarely become malignant (8). 175 independent SK from 25 SK pathways are mutated were not sufficient BRAF (V600E) expression in mouse patients. They showed a high frequency of to develop malignant tumors. models results in induction of senescence FGFR3 (71%), PIK3CA (50%), KRAS Hafner et al. (1) observe that, unlike in , and senescent markers are (20%), EGFR (7%), HRAS (3%), and AKT many malignant tumors (5), SK is rela- highly expressed in human melanocytic (2%) mutations in the benign tumors (1). A tively genomically stable, and inactivating nevi (9). In contrast, BRAF (V600E) ex- complete sequence analysis is likely to mutations in the tumor suppressors phos- pression in the setting of PTEN loss identify an even higher mutation rate, sug- phatase and tensin homolog (PTEN), tu- in murine models is sufficient to induce gesting that most, if not all, SK lesions have berous sclerosis 1 (TSC1), or p53 are rare metastatic (10). Oncogene- at least one and likely several putative or absent. Thus, the malignant potential of induced senescence has been similarly oncogenic mutations. Strikingly, despite oncogene mutations is likely lineage-de- observed with HRAS, KRAS, or AKT their lack of malignant potential, 89% of pendent, interacting with intrinsic gene expression and can be overcome by loss SK had at least one mutation, and 45% expression patterns, and it must occur in of specific tumor suppressors (7). Using had more than one mutation in a well- the context of other genomic aberrations, β-galactosidase activity and a set of se- characterized oncogene. Mutations ob- likely including loss of tumor suppressor nescence markers, Hafner et al. (1) fail to served in SK are present in malignant function, to facilitate malignant trans- observe evidence of senescence in SK. tumors and when expressed in transgenic formation. Although the paucity of muta- mice, are sufficient to induce tumors. Thus, tions in tumor suppressors and the relative a potent mechanism must constrain malig- genomic stability in SK likely provide Author contributions: S.E.W. and G.B.M. wrote the paper. nant conversion in SK. The frequency of a partial explanation for the lack of ma- The authors declare no conflict of interest. comutations in FGFR3 and PIK3CA was lignant transformation, further compre- See companion article on page 20780. approximately that predicted by chance, hensive analysis of SK both in terms of 1To whom correspondence should be addressed. E-mail: suggesting that they are not coselected. In genomic events and functional con- [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1015563107 PNAS Early Edition | 1of2 Downloaded by guest on September 30, 2021 Further markers of accumulated DNA pendent SK lesions. Intriguingly, in most function; this suggests that this alteration damage were also absent in SK. Thus, an cases, each SK showed only a single may be an essential hit lacking in SK, ex- as yet unexplained mechanism must con- FGFR3 mutation, suggesting that each SK plaining the failure to acquire a malig- strain malignant transformation in SK. lesion likely represents the outgrowth of nant phenotype. Many possible mechanisms may account a dominant subclone from the original SK , the most common for the nonmalignant potential of cells clone. An analysis of mutations at the benign tumors of the , support the apart from senescence, including in- single cell level will be required to ensure notion that tumor suppressor loss is an hibitory feedback signals, lack of a critical that the multiple mutations detected in an important precondition for metastatic pattern of genetic aberrations, and epige- individual SK lesion occur in a single or competence. Angiomyolipomas can arise netic phenomena that cannot be de- different subclone. sporadically but are common features of termined by the techniques used in this Nonmalignant or low-grade urothelial lymphangiomyomatosis (LAM), which study. Feedback mechanisms for the tumors that derive from an epithelial – – arises in patients with . MEK ERK and PI3K AKT pathways structure related to skin may inform the The proliferating cells have been described (11, 12). In addition, findings of Hafner et al. (1). These tumors fi FGFR3 within LAM associated with tuberous FGFR3 is suf cient to induce forkhead frequently harbor the same muta- sclerosis are clones of the smooth muscle box protein N1 (FOXN1) expression and tions, tend to be genomically stable, and cells in renal angiomyolipomas (16). An- subsequent differentiation (13). FOXN1 arise in a mulifocal manner (14). Two giomyolipomas harbor mutations in either expression caused squamous cell carci- theories have been proposed to explain TSC1 or TSC2, whose protein products noma cells to transition to a benign SK- multifocality of urothelial cancers. The like phenotype. An investigation into the monoclonal theory holds that a single hamartin and tuberin inhibit the Ras ho- epigenetic alterations within SK and other transformed cell proliferates and spreads molog Rheb; this activates the mTOR benign tumors, as well as the surrounding throughout the urothelium by intraluminal within the target of rapamycin complex 1 normal skin, may yield further clues as implantation or intraepithelial migration. (TORC1 complex). Loss of TSC1 or TSC2 to the mechanisms that prevent malignant The oligoclonal theory holds that a function stimulates signaling through the transformation. causes independent trans- TORC1 complex (17). Angiomyolipomas Using X-chromosome inactivation, the formation of cells in different locations represent a curious example of a benign study by Hafner et al. (1) analyzes in- within the same , resulting in genet- tumor that can distantly metastasize. The dependent SK lesions in eight heterozy- ically unrelated tumors. These two theo- study by Hafner et al. (1) shows SK to lack gous females and shows that 28 of 30 ries are not mutually exclusive, and it is TSC1 loss and loss of other tumor sup- lesions with a single mutant oncogene and possible that both phenomena can occur in pressors, which may contribute to the 18 of 19 with at least two mutations had the same patient (14). The study by Haf- limited potential of SK to give rise selective X-chromosome inactivation sup- ner et al. (1) seems to support the mono- to malignancy. portive of clonality. However, although clonal model of synchronous multifocal lesions with FGFR3 and/or PIK3CA mu- tumor origin, although the few cases in Conclusion tations tended to be in physical proximity, which clonality was not identified could the mutations were frequently located at represent distinct clones. The observation This report by Hafner et al. (1) repre- different sites in FGFR3 and PIK3CA. that the same FGFR3 and/or PI3K sents a comprehensive approach to un- Indeed, some patients had seven in- mutations tend to be observed in SK in derstanding the nature of benign tumors dependent FGFR3 nucleotide aberrations physical proximity also supports a mono- and may enhance our understanding of in different SK lesions. This, combined clonal explanation, and deviations may global genetic alterations that may be fi with the paucity of mutations in PTEN, represent clones that have undergone necessary, but are not suf cient, to result TSC1, and p53, indicates a selective subsequent genetic alterations. These in malignancy. It also supports a model mechanism leading to accumulation of findings raise the intriguing possibility of SK tumor generation from single clones mutations, activation of FGFR3, and that clonal SK cells may undergo intra- that have dispersed within an intra- likely, activation of the other oncogenes epithelial migration within a field before epithelial region. This study provides targeted in SK. Thus, in cases where the emerging as visual tumors. Also of note, a basis for further investigation into the original lesion was clonal, multiple sub- malignant urothelial tumors often show mechanisms by which tumors progress clones with independent FGFR3 muta- loss of the tumor suppressor p53 (15), but may be blocked from becoming tions must have developed into inde- whereas SK failed to show loss of p53 malignant.

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