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Simple Summary: A subset of patients with an intermediate risk for renal cell carcinoma have an indolent disease course. For these patients, the initiation of treatment for metastatic disease can be safely delayed by entering a watchful waiting period. At present, we are not able to identify those patients with indolent disease and the minor group of patients with rapidly progressive disease requiring earlier initiation of systemic treatment. In this study, we investigate whether cell-free DNA (cfDNA) can be used as a blood-based biomarker to identify those patients with rapid progression. Methylated cfDNA profiles were used as a proxy for tumor load in blood. cfDNA methylation patterns were associated with the time to radiological progression, but not with the watchful waiting time. The results of this study do not provide definite proof that cfDNA methylation patterns are associated with WW time. According to the current guidelines, watchful waiting (WW) is a feasible option for patients with good or intermediate prognosis renal-cell carcinoma (RCC). However, some patients rapidly progress during WW, requiring the initiation of treatment. Here, we explore whether we can identify those patients using circulating cell-free DNA (cfDNA) methylation. We first defined a panel of RCC-specific circulating methylation markers by intersecting differentially methylated regions from a publicly available dataset with known RCC methylation markers from the literature. The resulting RCC-specific methylation marker panel of 22 markers was subsequently evaluated for an association with rapid progression by methylated DNA sequencing (MeD-seq) in serum from 10 HBDs and 34 RCC patients with a good or intermediate prognosis starting WW in the IMPACT-RCC study. Patients with an elevated RCC-specific methylation score compared to HBDs had a shorter progression-free survival (PFS, p = 0.018), but not a shorter WW-time (p = 0.15). Cox proportional hazards regression showed that only the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria were significantly associated with WW time (HR 2.01, p = 0.01), whereas only our RCC-specific methylation score (HR 4.45, p = 0.02) was significantly associated with PFS. The results of this study suggest that cfDNA methylation is predictive of PFS but not WW. [ABSTRACT FROM AUTHOR]

PURPOSE: Apolipoprotein B mRNA-Editing Catalytic Polypeptide-like (APOBEC) enzymes are mutagenic factors contributing to tumor progression and therapy resistance. However, the effects of APOBEC-induced protein changes have not been systematically assessed. Here, we describe the effects of APOBEC on the coding sequence in primary and metastatic estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2–) breast cancer (BC). METHODS: We determined the enrichment of amino acid (AA) changes resulting from APOBEC mutagenesis in 323 primary BC tumors and 424 metastatic breast cancer (mBC) lesions via comparison with a simulated mutational genomic landscape not under selection pressure. We subsequently explored genes with recurrent APOBEC-associated AA changes and investigated the clonality of individual APOBEC-associated mutations. Using public sequencing data from an independent primary BC and mBC cohort, we further confirm our findings by reporting genes having these enriched AA changes in an APOBEC context. RESULTS: Our analysis demonstrated that several APOBEC-derived AA changes are significantly enriched compared with a simulated AA change distribution drawn at random. Among the enriched AA changes, Glutamate(E)>Lysine(K) and Glutamate(E)>Glutamine(Q) were mostly found at hotspots in oncogenes, whereas termination codons (Glutamine[Q]>STOP[X] and Serine[S]>STOP[X]) occurred in tumor suppressor genes and, mostly, not at hotspot locations. These mutations are found in genes contributing to BC initiation, eg, introduction of termination codons in TP53 , MAP3K1 , and CDH1 (in lobular BC) and two oncogenic hotspots in PIK3CA (p.E542K and p.E545K). In endocrine-resistant BC, we observed APOBEC-induced termination codons at ER-modulating genes, KMT2C , ARID1A , NF1 , and ZFHX3. Finally, in mBC, compared with single PIK3CA mutations, dual PIK3CA mutations occurred more frequently in an APOBEC context (Fisher's exact P <.001). CONCLUSION: Our results show that APOBEC mutagenesis recurrently targets various known drivers of BC initiation, progression, and endocrine resistance. APOBEC drives early, metastatic and endocrine resistant disease in ER+/HER2- breast cancer [ABSTRACT FROM AUTHOR]