The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes including BAP1. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations anticorrelate in tumors (P=3×10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q=0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q=0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

Most anticancer drugs entering clinical trials fail to achieve approval from the US FDA. Drug development is hampered by the lack of preclinical models with therapeutic predictive value. Herein, we report the development and validation of a tumorgraft model of renal cell carcinoma (RCC) and its application to the evaluation of an experimental drug. Tumor samples from 94 patients were implanted in the kidney of mice without additives or disaggregation. Tumors from 35 patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at high frequency, and stable engraftment of primary tumors in mice correlated with decreased patient survival suggesting that tumor growth in mice may reveal the acquisition by the tumor of an ability to thrive at distant sites and metastasize. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and over 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing mice, tumorgrafts were able to act on the host causing paraneoplastic syndromes. In studies simulating drug exposures in patients, RCC tumorgraft growth was inhibited by sunitinib and sirolimus (into which temsirolimus is converted in humans), but not by erlotinib, which was used as a control. Dovitinib, a drug in clinical development, showed greater activity than sunitinib and sirolimus. The routine incorporation of models recapitulating the molecular genetics and drug sensitivities of human tumors into preclinical programs has the potential to improve oncology drug development.

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Poor dietary habits and inadequate nutrient intakes are of concern in the elderly. The nutritional characteristics of those who survive to become the oldest are not well defined. Our goal was to describe dietary habits, nutrient intakes and nutritional risk of community-dwelling, rural Iowans, 79 y of age and older. Subjects were interviewed (n = 420) using a standardized format on one occasion in their homes and instructed to complete 3-d diet records (n = 261) after the in-home interview. Standardized interviews assessed demographic information, cognitive function and dietary habits (Nutrition Screening Initiative Checklist). Adequate nutrient intake was defined as consumption of the nutrient's estimated average requirement, 67% adequate intake or 67% recommended dietary allowance. Mean age was 85.2 y, 57% lived alone and 58% were widowed. Subjects completing 3-d diet records were younger, more cognitively intact and less likely to be at nutritional risk than subjects not completing diet records. The percentage of subjects with inadequate intakes of selected nutrients was 75% for folate, 83% for vitamin D and 63% for calcium. Eighty percent of subjects reported inadequate intakes of four or more nutrients. Diet variety was positively associated with the number of nutrients consumed at adequate intakes (r = 0.498), total energy (r = 0.522) and dietary fiber (r = 0.421). Our results suggest that rural, community-dwelling old have inadequate intakes of several nutrients. Recommendations to increase diet variety and consume a nutrient supplement may be necessary for elderly people to achieve adequate nutrient intakes.

Significance Despite the discovery of the von Hippel–Lindau ( VHL ) gene in 1993, and that inactivating germ-line mutations of VHL cause multiple kidney lesions, including clear-cell renal cell carcinoma (ccRCC), Vhl inactivation in the mouse does not lead to ccRCC and a mouse model has been lacking. We discovered that the BRCA1-associated protein-1 ( BAP1 ) two-hit tumor suppressor gene is mutated in ccRCC, and one BAP1 allele is frequently somatically codeleted with VHL in tumors. In the mouse, Vhl and Bap1 are on different chromosomes. We show that SIX homeobox 2 ( Six2 ) -Cre;Vhl F/F ;Bap1 F/ + mice develop premalignant lesions and malignant ccRCC resembling VHL syndrome. More broadly, differences in tumor predisposition across species may result from differences in the location of two-hit tumor suppressor genes across the genome.