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Highlights d We characterize effects of PARP and WEE1 inhibitors on functional proteomics d Concurrent PARP and WEE1 blockade effectively inhibits tumors but is poorly tolerated d Sequential PARP and WEE1 inhibition minimizes toxicity while maintaining efficacy d Basal replication stress influences the therapeutic index of sequential therapy

Purpose Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity. Experimental Design We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of non-sarcomatoid RCC (RCC). We evaluated whole exome sequencing, single nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n=65) and RCC (n=598) across different parent RCC subtypes, including clear cell RCC, papillary RCC, and chromophobe RCC subtypes. Results SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFβ signaling across all subtypes. The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer related genes, despite a higher mutational burden in S-. Notably, sarcomatoid clear cell RCC (SccRCC) showed significantly fewer deletions at 3p21–25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared to clear cell RCC (ccRCC). A two-hit loss involving VHL predicted for ccRCC and a better prognosis whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis. Conclusions Sarcomatoid RCC segregates by parent subtype and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21–25 deletion and showing distinctive mutational and transcriptional profiles. These features prompt a more precise molecular classification of RCC with diagnostic, prognostic, and therapeutic implications.

RESULTSNo relationship was found between prostate volume and digit ratio [correlation coefficient ( r ) = − 0.038, P = 0.466]. But, significant negative correlations were found between digit ratio and PSA ( r = − 0.140, P = 0.007). When the patients were divided into two groups (Group A: digit ratio < 0.95, n = 184; Group B: digit ratio ≥ 0.95, n = 182), Group A had a higher mean PSA level than Group B (3.26 ± 5.54 ng/mL vs 1.89 ± 2.24 ng/mL, P = 0.002) and had significantly higher risks of prostate biopsy [odds ratio (OR) = 1.75, 95% CI = 1.07-2.84] and prostate cancer (OR = 3.22, 95% CI = 1.33-7.78). CONCLUSIONSPatients with a lower digit ratio have higher risks of prostate biopsy and prostate cancer. KEYWORDSDigit ratio, prostate volume, prostatespecific antigen, prostate cancer What's known on the subject? and What does the study add? The Homeobox genes, Hox a and d , control urinogenital system differentiation and digit development. The patterns of digit formation may be related to gonad function and may be reflected in 2nd to 4th digit ratio (digit ratio). Digit ratio is negatively correlated with prenatal testosterone levels and androgen receptor activity which is related to the increased prostate cancer risk.Patients with a lower digit ratio have a higher risk of prostate biopsy due to high PSA level, and of prostate cancer. Digit ratio could be a predictor of high PSA level and the presence of prostate cancer.Study Type -Diagnostic (exploratory cohort) Level of Evidence 2b OBJECTIVETo investigate the relationships between the 2nd to 4th digit ratio (digit ratio) and prostate volume, prostate-specific antigen (PSA) level, and the presence of prostate cancer. PATIENTS AND METHODSOf the men that presented with lower urinary tract symptoms (LUTS) at a single tertiary academic center, 366 men aged 40 or older with a PSA level ≤ 40 ng/mL were prospectively enrolled. Right-hand 2nd and 4th digit lengths were measured prior to the PSA determinations and transrectal ultrasonography (TRUS). Prostate volumes were measured by TRUS without information about digit length. Patients with a PSA level ≥ 3 ng/mL underwent prostate biopsy.

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