Search

Renal cell cancer (RCC) is not a single disease but is made up of a number of cancers, each with a unique histology, biology, clinical course and response to therapy. Alterations in at least 16 hereditary genes have been attributed to the risk of developing RCC. In this study, we describe the prevalence and spectrum of germline variants among these genes and highlight correlations between germline genotype with tumor phenotype. Using the Geisinger MyCode cohort, we sequenced the whole exomes of 42,933 subjects. Subjects were divided into those with a renal cancer diagnosis, other cancer diagnosis and no cancer diagnosis. We analyzed the DNA sequences of 16 hereditary renal cancer genes from each of these groups. The damaging mutations was determined by following ACMG guidelines. Among the 42,933 subjects in the Geisinger MyCode cohort, 168 were diagnosed with RCC. None of these subjects had a family history of RCC. Clear cell RCC (ccRCC) was the most predominant histology (77%), followed by Type 1 papillary RCC (7%), chromophobe RCC (6%), and Type 2 papillary RCC (5%). Mutations in all the predisposing genes were identified in all the renal cancer subtypes but only a subset were deemed damaging. The top 2 ccRCC predisposing genes with damaging or likely damaging mutations were TSC2 (8%) and SDHD (4%). While TSC2 damaging variants were also found in the other histologies, novel TSC2 variants were differentially associated with high grade and metastatic disease in ccRCC as compared to those with low grade or non-metastatic disease. The genes harboring damaging or likely damaging variants in Type 1 and Type 2 papillary RCC were MET and FH respectively. Predisposing RCC germline mutations were found in a significant number of subjects with sporadic RCC. Family history was unhelpful in predicting the affected subjects. Knowledge of these mutations would be beneficial in counseling patients and their families as well as improving our understanding of the disease to direct patient care. Citation Format: Heinric Williams, Raghu Metpally, Mahmoud Mohamed, Sarath Krishnamurthy, Sertac Kip, David J. Carey, Aris Baras, John Overton. Germline mutations in renal cancer predisposing genes: Analysis of the Geisinger MyCode population. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2557.

Background: Hereditary hemochromatosis (HH), one of the most common single gene disorders that alter the body's ability to regulate iron, causes excess iron deposition in liver, heart, pancreas, joints and pituitary gland, with resultant cirrhosis, cancer, diabetes, heart and joint diseases over time. HH can be effectively treated, but if untreated, the increased iron storage can lead to severe organ damage, and death. Therefore, early identification and treatment is imperative. Most severe cases of HH result from a common mutation in the HFE gene (C282Y), but other HFE mutations have also been identified (H63D and S65C), associated with milder disease. Caucasians of northern European descent are at highest risk, and there is ∼1 million people in the US with these mutations, and 10% of Caucasians are carriers. Some individuals are asymptomatic due to the low penetrance, and variable genotype-phenotype correlations. Aims: To determine the prevalence of known HFE mutations, identify potential novel variants, and compare the clinical & laboratory findings with HH genotypes for genotype-phenotype correlations. Materials and Methods: Through the collaboration of Geisinger Health System with the Regeneron, 31,058 MyCode biobank participants were evaluated for HFE gene mutations by analyzing exome sequence data from peripheral blood. Results: Compared to controls, significant differences were noted in males with C282Y/C282Y, C282Y/H63D, and H63D/H63D genotypes for ferritin, serum iron, iron binding capacity (IBC), and transferrin saturation (TS), while C282Y and H63D carriers did not show a significant difference for ferritin, but did for other parameters when compared to non-carriers. Slight differences were noted in females when compared to males, with TS also being significant in C282Y/S65C, H63D/S65C, and S65C/WT females, but not ferritin in C282Y/C282Y or IBC in H63D/H63D individuals. Cirrhosis, hepatocellular carcinoma (HCC), and oral cancers were more prevalent in the C282Y/C282Y genotype. HCC, esophagus and urinary cancers were higher in those with H63D/H63D, while, non-melanoma skin cancers were more prevalent in H63D/WT, and uterine and urinary cancers were more prevalent in the S65C/WT genotype. The patients diagnosed with ICD-9 code of HH were significantly lower than the prevalence of these genotypes, indicating a potential issue of underdiagnosis, or misdiagnosis. One short coming of our evaluation is that the results have not been confirmed by assessment of the medical charts. Conclusion: This large scale genomic study allowed us to identify carriers of HH-associated genetic variants, and uncover potential deficiencies in the current screening algorithm. This will enable the implementation of processes to promote precision medicine, minimize misdiagnosis/underdiagnosis, and maximize outcomes in the management of HH patients. Citation Format: Mehmet Tahir Aslan, Anita Mathew, Ferit Akova, Raghu Metpally, David J. Carey, Heinric Williams, Marc S. Williams, John Overton, Aris Baras, Adam M. Cook, Ryan D. Colonie, Nefize Sertac Kip. Decoding >30 thousand individuals to analyze the most common genetic disorder: Hereditary hemochromatosis (HH). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5222.