Abstract 5222: Decoding >30 thousand individuals to analyze the most common genetic disorder: Hereditary hemochromatosis (HH)

Background: Hereditary hemochromatosis (HH), one of the most common single gene disorders that alter the body9s 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.