Pd45-05 Cancer Predisposing Genes Germline Alterations in Patients With Sporadic Kidney Cancer
Year: 2020
Type: article
Study design: Observational Study
Abstract: INTRODUCTION AND OBJECTIVE: Hereditary kidney cancer cases represents less than 5% of all renal cell carcinoma (RCC) cases.Germline testing is recommended in patient with early onset (age 46 y) and family history of the disease.Recent data suggest that familial contribution may be as high as 58%.To address this discrepancy, we sought to identify other genes beyond the known kidney cancer predisposing genes by evaluating the prevalence of germline mutations in 450 reported cancer predisposing genes (CPGs) in a cohort of sporadic RCC patients.METHODS: We reviewed the records of all patients with sporadic RCC (no family history, n[511) within our institutional MyCode-DiscovEHR cohort (n[92,455).Corresponding Whole Exome Sequencing data was analyzed, and variant pathogenicity accessed employing ACMG guidelines for all 450 CPGs.RESULTS: In our cohort, we had 387 patients with clear cell (ccRCC), 74 papillary (pRCC), 27 chromophobe (chRCC), 11 mixed and 12 other RCCs.The mean age of onset of RCC in the entire cohort was 61.65 years (SD, 11.24).One hundred and forty-seven (29%) of 511 patients with sporadic RCC cancer had either predicted loss-offunction variants (pLOF) or ClinVar pathogenic or likely pathogenic (CP/LP; ! 1 gold star review status) germline mutation.Germline alterations were found in 99 of 450 cancer predisposing genes tested.Germline mutations accounted for 27.4%, 35.1%, 25.9%, 27.3%, 41.7% in ccRCC, pRCC, chRCC, mixed, and other RCC respectively.The top altered genes include CHEK2 (5.4%), MUTYH (5.4%), SERPINA1 (4%), ATM (3.4%), PDE11A (3.4%), PYGM (3.4%), TYR (2.7%), TYRP1 (2.7%), BRCA2 (2%) and COL4A3 (2%).28 of 147 patients (19%) had germline alteration in more than one CPG.5.2% of patients also had homozygous or compound heterozygous mutations (Cys282Tyr, His63Asp, Ser65Cys) in homeostatic iron regulator (HFE) gene associated with hemochromatosis also known to increases cancer risk.There were 6% of patients with copy number variation in these CPGs.There was no difference in the age of onset among CPG germline positive vs negative sporadic RCC patients.CONCLUSIONS: This study identified germline alterations in almost 100 CPGs in patient with sporadic kidney cancer.Overall 37% (29% pLOF þ CP/LP; 5.2% HFE; 6% CNVs) of sporadic RCCs patients had germline variations.Therefore, pending functional and clinical validation, these additional genes may represent an expanded repertoire of RCC predisposing genes.
Source: The Journal of Urology
Institution: Regeneron (United States)
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3022222478