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Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate the response to this CFTR modulator therapy. A total of 765 pwCF older than 12 years under LUMA-IVA therapy and with lung function and nutritional measurements available before and after treatment initiation were included. Response to treatment was determined by the change in lung function and nutritional status, from baseline and over the first two years after initiation, and it was assessed by weighted generalized estimating equation models. Gains in lung function and nutritional status were observed after 6 months of treatment (on average 2.11 ± 7.81% for percent predicted FEV1 and 0.44 ± 0.77 kg/m2 for BMI) and sustained over the 2 years. We observed that the more severe patients gained the most in lung function and nutritional status. While females started with a nutritional status more impaired than males, they had a larger response and regained BMI Z-score values similar to men after 2 years of treatment. We observed no association between variants in solute carrier (SLC) genes and the respiratory function response to LUMA-IVA, but the SLC6A14 rs12839137 variant was associated with the nutritional response. Further investigations, including other genomic regions, will be needed to fully explore the inter-individual variability of the response to LUMA-IVA.

// Jianmin Wang 1,* , Antonios Papanicolau-Sengos 2,* , Sreenivasulu Chintala 3,10,* , Lei Wei 1 , Biao Liu 1 , Qiang Hu 1 , Kiersten Marie Miles 2 , Jeffrey M. Conroy 2 , Sean T. Glenn 4 , Manuela Costantini 5,8,9 , Cristina Magi-Galluzzi 6 , Sabina Signoretti 7 , Toni Choueiri 7 , Michele Gallucci 5 , Steno Sentinelli 5 , Vito M. Fazio 8 , Maria Luana Poeta 9 , Song Liu 1 , Carl Morrison 2 and Roberto Pili 3,10 1 Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA 2 Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA 3 Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA 4 Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA 5 Department of Urology, Regina Elena National Cancer Institute of Rome, Rome, Italy 6 Department of Pathology, Cleveland Clinic, Cleveland, OH, USA 7 Department of Pathology and Kidney Cancer Program, Dana Farber, Boston, MA, USA 8 Laboratory of Genetic and Clinical Pathology, University Campus BioMedico of Rome, Rome, Italy 9 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy 10 Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA * These authors have contributed equally to this work Correspondence to: Roberto Pili, email: // Keywords : collecting duct carcinoma, CDKN2A, solute carrier family genes Received : December 04, 2015 Accepted : April 16, 2016 Published : April 28, 2016 Abstract The genetic landscape and molecular features of collecting duct carcinoma (CDC) of the kidney remain largely unknown. Herein, we performed whole exome sequencing (WES) and transcriptome sequencing (RNASeq) on 7 CDC samples (CDC1 -7). Among the 7 samples, 4 samples with matched non-tumor tissue were used for copy number analysis by SNP array data. No recurrent somatic SNVs were observed except for MLL , which was found to be mutated (p.V297I and p.F407C) in 2 samples. We identified somatic SNVs in 14 other cancer census genes including: ATM, CREBBP, PRDM1, CBFB, FBXW7, IKZF1, KDR, KRAS, NACA, NF2, NUP98, SS18, TP53 , and ZNF521 . SNP array data identified a CDKN2A homozygous deletion in 3 samples and SNV analysis showed a non-sense mutation of the CDKN2A gene with unknown somatic status. To estimate the recurrent rate of CDKN2A abnormalities, we performed FISH screening of additional samples and confirmed the frequent loss (62.5%) of CDKN2A expression. Since cisplatin based therapy is the common treatment option for CDC, we investigated the expression of solute carrier (SLC) family transporters and found 45% alteration. In addition, SLC7A11 (cystine transporter, xCT), a cisplatin resistance associated gene, was found to be overexpressed in 4 out of 5 (80%) cases of CDC tumors tested, as compared to matched non-tumor tissue. In summary, our study provides a comprehensive genomic analysis of CDC and identifies potential pathways suitable for targeted therapies.