RESUMEN
Skin cancer risk is increased by exposure to ultraviolet radiation (UVR). Because UVR exposure accumulates over time and lighter skin is more susceptible to UVR, age and skin tone are risk factors for skin cancer. However, measurements of somatic mutations in healthy-appearing skin have not been used to calculate skin cancer risk. In this study, we developed a noninvasive test that quantifies somatic mutations in healthy-appearing sun-exposed skin and applied it to a 1038-subject cohort. Somatic mutations were combined with other known skin cancer risk factors to train a model to calculate risk. The final model (DNA-Skin Cancer Assessment of Risk) was trained to predict personal history of skin cancer from age, family history, skin tone, and mutation count. The addition of mutation count significantly improved model performance (OR = 1.3, 95% confidence interval = 1.14-1.48; P = 5.3 × 10-6) and made a more significant contribution than skin tone. Calculations of skin cancer risk matched the known United States population prevalence, indicating that DNA-Skin Cancer Assessment of Risk was well-calibrated. In conclusion, somatic mutations in healthy-appearing sun-exposed skin increase skin cancer risk, and mutations capture risk information that is not accounted for by other risk factors. Clinical utility is supported by the noninvasive nature of skin sample collection through adhesive patches.
RESUMEN
Docetaxel chemotherapy is a standard treatment option for metastatic castrate resistant prostate cancer (mCRPC) patients. To date, the genomic perturbations underlying the emergence of resistance in mCRPC patients during chemotherapy treatment have not been fully characterized. Previous studies have established that AR, TP53, RB1 and PTEN gene alterations are frequent at this stage of progression and that TP53, RB1 and PTEN, but not AR alterations are associated with poor outcome. However, the clonal dynamics of these key driver cancer genes during chemotherapy in mCRPC patients have not been described. Toward this goal, we performed a retrospective analysis of serially profiled cell-free DNA (cfDNA) alterations in blood samples collected from mCRPC patients before and after starting chemotherapy who were followed for response and clinical outcomes. While AR alterations and measures of mutational load were significantly reduced in patients with stable or decreased PSA levels after 3 cycles of chemotherapy, reductions in RB1, TP53 and PTEN alterations were relatively modest, which may represent the persistence of a clonal signature associated with the emergence of treatment-induced lineage plasticity (TILP) underlying resistance. The ability to monitor these driver gene clonal dynamics during chemotherapy may have utility in the clinical setting.