Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10−7). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family.

ObjectiveTo evaluate the prognostic value of programmed death ligand‐1 (PD‐L1) and programmed death‐1 (PD‐1) expression in patients with upper tract urothelial carcinoma (UTUC).Patients and methodsA retrospective multicentre study was conducted in 283 patients with UTUC treated with radical nephroureterectomy (RNU) between 2000 and 2015 at 10 French hospitals. Immunohistochemistry analyses were performed using 2 mm‐core tissue microarrays with NAT105® and 28.8® antibodies at a 5% cut‐off for positivity on tumour cells and tumour‐infiltrating lymphocytes to evaluate PD‐L1 and PD‐1 expression, respectively. Multivariable Cox regression models were used to determine the independent predictors of recurrence‐free (RFS), cancer‐specific (CSS) and overall survival (OS).ResultsOverall, 63 (22.3%) and 220 (77.7%) patients with UTUC had PD‐L1‐positive and ‐negative disease, respectively, while 91 (32.2%) and 192 (67.8%) had PD‐1‐positive and ‐negative disease, respectively. Patients who expressed PD‐L1 or PD‐1 were more likely to have pathological tumour stage ≥pT2 (68.3% vs 49.5%, P = 0.009; and 69.2% vs 46.4%, P < 0.001, respectively) and high‐grade (90.5% vs 70.0%, P = 0.001; and 91.2% vs 66.7%, P < 0.001, respectively) disease with lymphovascular invasion (52.4% vs 17.3%, P < 0.001; and 39.6% vs 18.2%, P < 0.001, respectively) as compared to those who did not. In multivariable Cox regression analysis adjusting for each other, PD‐L1 and PD‐1 expression were significantly associated with decreased RFS (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.09–3.08, P = 0.023; and HR 1.59, 95% CI 1.01–2.54, P = 0.049; respectively), CSS (HR 2.73, 95% CI 1.48–5.04, P = 0.001; and HR 1.96, 95% CI 1.12–3.45, P = 0.019; respectively) and OS (HR 2.08, 95% CI 1.23–3.53, P = 0.006; and HR 1.71, 95% CI 1.05–2.78, P = 0.031; respectively). In addition, multivariable Cox regression analyses evaluating the four‐tier combination of PD‐L1 and PD‐1 expression showed that only PD‐L1/PD‐1‐positive patients (n = 38 [13.4%]) had significantly decreased RFS (HR 3.07, 95% CI 1.70–5.52; P < 0.001), CSS (HR 5.23, 95% CI 2.62–10.43; P < 0.001) and OS (HR 3.82, 95% CI 2.13–6.85; P < 0.001) as compared to those with PD‐L1/PD‐1‐negative disease (n = 167 [59.0%]).ConclusionsWe observed that PD‐L1 and PD‐1 expression were both associated with adverse pathological features that translated into an independent and cumulative adverse prognostic value in UTUC patients treated with RNU.

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Background: Although therapeutic lateral neck dissection (LND) may be indicated in thyroid carcinoma, the cervical lymph node groups IIA and IIB, according to Robbins classification, are often not removed. The aim of our study was to determine the relevance of complete comprehensive LND in thyroid carcinoma. Methods:We conducted a retrospective study between January 2011 and August 2018 in a university teaching hospital. Histopathological analysis of LND performed during total thyroidectomy in thyroid carcinoma was reviewed according to lymph node level. To demonstrate that neck dissection of upper groups, IIA/IIB, is necessary when therapeutic LND is indicated in thyroid carcinoma, we compared histopathological involvement in complete comprehensive LND of the upper groups IIA/IIB to the lower groups III/IV/V.Results: A total of 30 LND (24 patients) were suitable for analysis. Analysis by neck side revealed that comprehensive LND dissection samples were negative in 3 cases, and positive in 27. In those 27 positive LND, 15 demonstrated involvement of the groups IIA/IIB, and 12 were positive for involvement of the III/ IV/V groups only. The combined presence of positive IIA/IIB and positive III/IV/V was observed in 15 of the 27 neck sides. There was no positive IIA/IIB without positive involvement of III/IV/V groups. Conclusions:The high rate of positive cervical lymph nodes in the upper groups IIA/IIB supports complete comprehensive LND rather than selective III/IV/V LND in thyroid carcinoma surgery. However, impact on survival and whether postoperative radioactive iodine treatment may be modulated remain to be studied.

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