Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors

Abstract

Malignant tumors result from the accumulation of genetic alterations in oncogenes and tumor suppressor genes. Much less is known about the genetic changes in benign tumors. Seborrheic keratoses (SK) are very frequent benign human epidermal tumors without malignant potential. We performed a comprehensive mutational screen of genes in the FGFR3-RAS-MAPK and phosphoinositide 3-kinase (PI3K)-AKT pathways from 175 SK, including multiple lesions from each patient. SK commonly harbored multiple bona fide oncogenic mutations in FGFR3, PIK3CA, KRAS, HRAS, EGFR, and AKT1 oncogenes but not in tumor suppressor genes TSC1 and PTEN. Despite the occurrence of oncogenic mutations and the evidence for downstream ERK/MAPK and PI3K pathway signaling, we did not find induction of senescence or a DNA damage response. Array comparative genomic hybridization (aCGH) analysis revealed that SK are genetically stable. The pattern of oncogenic mutations and X chromosome inactivation departs significantly from randomness and indicates that spatially independent lesions from a given patient share a clonal relationship. Our findings show that multiple oncogenic mutations in the major signaling pathways involved in cancer are not sufficient to drive malignant tumor progression. Furthermore, our data provide clues on the origin and spread of oncogenic mutations in tissues, suggesting that apparently independent (multicentric) adult benign tumors may have a clonal origin.

Are oncogenes sufficient to cause human cancer?

“…Patients with germline mutations in FGFR3 that result in the same codon change as in somatic mutations found in SK do not develop malignant epithelial skin tumors at increased frequency (2). The authors show that the sites of mutations found at the highest frequency in SK are found at much lower frequency in malignant tumors and vice versa (1). Although a subset of the mutations found in SK exhibits lower transforming activity than those found more frequently in malignant tumors, many of these mutations do predispose to tumor development in animal models.…”

“…Nonmalignant or low-grade urothelial tumors that derive from an epithelial structure related to skin may inform the findings of Hafner et al (1). These tumors frequently harbor the same FGFR3 mutations, tend to be genomically stable, and arise in a mulifocal manner (14).…”

“…Oncogeneinduced senescence has been similarly observed with HRAS, KRAS, or AKT expression and can be overcome by loss of specific tumor suppressors (7). Using β-galactosidase activity and a set of senescence markers, Hafner et al (1) fail to observe evidence of senescence in SK. …”

“…Hafner et al (1) perform an extensive analysis of hot spot mutations in genes in the FGFR3-RAS-MAPK and PI3K-AKT pathways in 175 independent SK lesions from 25 SK patients. They showed a high frequency of FGFR3 (71%), PIK3CA (50%), KRAS (20%), EGFR (7%), HRAS (3%), and AKT (2%) mutations in the benign tumors (1). A complete sequence analysis is likely to identify an even higher mutation rate, suggesting that most, if not all, SK lesions have at least one and likely several putative oncogenic mutations.…”

“…A number of benign lesions without malignant potential accumulate genomic aberrations and have the potential to inform on the changes that are tolerated in benign tumors; however, they are insufficient to induce malignant transformation. In PNAS, Hafner et al (1) comprehensively investigate the mutation status, mechanistic barriers to malignancy, and clonal relationship of seborrheic keratoses (SK), a tumor lineage that is without malignant potential.…”