GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer

Genetic studies have examined body-shape measures adjusted for body mass index (BMI), while allometric indices are additionally adjusted for height. We performed the first genome-wide association study of A Body Shape Index (ABSI), Hip Index (HI) and the new Waist-to-Hip Index and compared these with traditional indices, using data from the UK Biobank Resource for 219,872 women and 186,825 men with white British ancestry and Bayesian linear mixed-models (BOLT-LMM). One to two thirds of the loci identified for allometric body-shape indices were novel. Most prominent was rs72959041 variant in RSPO3 gene, expressed in visceral adipose tissue and regulating adrenal cell renewal. Highly ranked were genes related to morphogenesis and organogenesis, previously additionally linked to cancer development and progression. Genetic associations were fewer in men compared to women. Prominent region-specific associations showed variants in loci VEGFA and HMGA1 for ABSI and KLF14 for HI in women, and C5orf67 and HOXC4/5 for ABSI and RSPO3, VEGFA and SLC30A10 for HI in men. Although more variants were associated with waist and hip circumference adjusted for BMI compared to ABSI and HI, associations with height had previously been reported for many of the additional variants, illustrating the importance of adjusting correctly for height.

Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors

Testicular adrenal rest tumors (TART) are a common complication in male patients with classic 21-hydroxylase deficiency (21OHD). TART are considered to have steroid-producing properties and may contribute to the androgen excess in 21OHD patients. This study aims to define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART. Steroids were measured in left (n=7) and right (n=4) spermatic vein- and simultaneously taken peripheral plasma (n=7) samples from seven men with 21OHD and TART using liquid chromatography-tandem mass spectrometry. In addition, steroids were quantified in TART cell- and adrenal cell-conditioned medium, with and without adrenocorticotropic hormone (ACTH) stimulation. Compared to peripheral blood of 21OHD patients with TART, the spermatic vein samples displayed the highest gradient for 11-hydroxytestosterone (11OHT; 96-fold) of the 11oxC19 steroids, followed by 11-ketotestosterone (47-fold) and 11-hydroxyandrostenedione (11OHA4; 29-fold), suggesting production of these steroids in TART. TART cell-conditioned medium contained higher levels of testosterone, and lower levels of androstenedione and 11OHA4 after ACTH stimulation compared to adrenal cell-conditioned medium, indicating ACTH-induced production of testosterone in TART. TART cells also produced 11OHT after 48 h of ACTH stimulation. Thus, in patients with 21OHD, TART produce 11oxC19 steroids, but in different proportions than the adrenals. The very high ratio of 11OHT in spermatic vein- versus peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in-vitro results indicate that this metabolism is ACTH-sensitive.

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

Tumor to normal single cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Neuroblastoma is an embryonal childhood cancer that arises from aberrant development of the neural crest, mostly within the fetal adrenal medulla. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n=16,591) with fetal adrenal single cell transcriptomes (n=57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients and clinical phenotypes. We substantiated our findings in 652 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that there exists a pan-neuroblastoma cancer cell state which may be an attractive target for novel therapeutic avenues.

Adrenal and Renal-Oncologic Interventions

Oncologic processes commonly involve the kidneys and adrenal glands. Renal cell carcinoma is the primary malignancy that affects the kidney, though other primary and metastatic tumors can also involve the kidneys. In contrast, the adrenal is a site frequently affected by metastatic tumors; indeed, primary adrenal cell carcinomas are extremely rare. A variety of oncologic interventions aim to either diagnose or treat renal and adrenal tumors. This chapter will discuss the role interventional oncology as it pertains to tumors of the kidneys and adrenal glands.