Abstract PO-147: Kidney iron overload in African American renal cancer patients with the ferroportin Q248H mutation
Authors: Brooks Samira , Vocke Cathy , Zhang Deliang , Gordeuk Victor , Rouault Tracey , Linehan Marston 
Published: December 2020

Iron plays a role in cellular replication, metabolism, and growth. Although iron is needed, the imbalance of iron in the body can result in adverse health effects, including cancer. Interestingly, cancer cells have frequently been observed to express increased levels or activity of proteins that are associated with iron metabolism.

Ferroportin (FPN), the only known mammalian cell iron exporter, is essential for iron homeostasis. Germline mutations in FPN occur more frequently in African and African American populations. A glutamine to histidine amino acid substitution at position 248 (Q248H) is the first and most prevalent gain-of-function mutation observed in FPN, with an allele frequency range of 2.2% to 13.4% in African and African Americans. However, it is unknown whether FPN Q248H is involved in cancer-associated reprogramming of iron metabolism, especially in individuals of African descent where the FPN Q248H mutation is enriched. The Q248H mutation traditionally renders FPN resistant to degradation. As a result, iron release is increased and aberrant uptake of iron across epithelial barriers of tissues can occur to cause iron overload, a risk factor for cancer. We hypothesize that patients with FPN Q248H have improper regulation of iron and thus increased unbound iron that will result in subsequent systemic and kidney-specific iron overload. We leveraged the repository of kidney cancer patients and banked samples of the Urologic Oncology Branch at the NIH to determine the association of FPN Q248H with kidney cancer. In our study, Black males with kidney cancer that expressed FPN Q248H had earlier onset of cancer compared to those without the variant. There were higher iron levels (p&lt;0.01) and transferrin saturation (p=0.01), a measure for blood iron transport, in serum form Black males with FPN Q248H compared to Black males without. Additionally, serum levels of the iron storage protein ferritin were elevated in association with FPN Q248H. In the kidney, both normal and tumor tissue had distinct levels of iron, as well as protein expression of ferritin and FPN between patients with and without FPN Q248H. In all, these results highlight a potential novel mechanism for global iron-associated cancer risk populations. This work will provide a foundation for future studies that include pre-cancer individuals and other cancer outcomes where the relationship between FPN Q248H and iron overload can be further examined to expand our knowledge of cancer risk.

Citation Format: Samira Brooks, Cathy Vocke, Deliang Zhang, Victor Gordeuk, Tracey Rouault, Marston Linehan. Kidney iron overload in African American renal cancer patients with the ferroportin Q248H mutation [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-147.