Impact of HFE variants and sex in lung cancer

Autoři: Sang Y. Lee aff001;  Vonn Walter aff002;  Junjia Zhu aff002;  Anna C. Salzberg aff004;  Dajiang J. Liu aff002;  James R. Connor aff001
Působiště autorů: Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America aff001;  Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America aff002;  Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America aff003;  Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226821


The homeostatic iron regulator protein HFE is involved in regulation of iron acquisition for cells. The prevalence of two common HFE gene variants (H63D, C282Y) has been studied in many cancer types; however, the impact of HFE variants, sex and HFE gene expression in lung cancer has not been studied. We determined the prevalence of HFE variants and their impact on cancer phenotypes in lung cancer cell lines, in lung cancer patient specimens, and using The Cancer Genome Atlas (TCGA) database. We found that seven out of ten human lung cancer cell lines carry the H63D or C282Y HFE variant. Analysis of lung cancer specimens from our institute (Penn State Hershey Medical Center) revealed a sex and genotype interaction risk for metastasis in lung adenocarcinoma (LUAD) patients; H63D HFE is associated with less metastasis in males compared to wild type (WT) HFE; however, females with the H63D HFE variant tend to develop more metastatic tumors than WT female patients. In the TCGA LUAD dataset, the H63D HFE variant was associated with poorer survival in females compared to females with WT HFE. The frequency of C282Y HFE is higher in female lung squamous cell carcinoma (LUSC) patients of TCGA than males, however the C282Y HFE variant did not impact the survival of LUSC patients. In the TCGA LUSC dataset, C282Y HFE patients (especially females) had poorer survival than WT HFE patients. HFE expression level was not affected by HFE genotype status and did not impact patient’s survival, regardless of sex. In summary, these data suggest that there is a sexually dimorphic effect of HFE polymorphisms in the survival and metastatic disease in lung cancer.

Klíčová slova:

Adenocarcinoma of the lung – Adenocarcinomas – Gene expression – Lung and intrathoracic tumors – Metastasis – Non-small cell lung cancer – Squamous cell lung carcinoma – Variant genotypes


1. American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available from:

2. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5): 584–594. doi: 10.4065/83.5.584 18452692

3. Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016;5(3): 288–300. doi: 10.21037/tlcr.2016.06.07 27413711

4. Ridge CA, McEriean AM, Ginsberg MS. Epidemiology of lung cancer. Semin Intervent Radiol. 2013;30(2): 93–98. doi: 10.1055/s-0033-1342949 24436524

5. Cook RM, Miller YE, Bunn PA Jr. Small cell lung cancer: etiology, biology, clinical features, staging, and treatment. Curr Probl Cancer. 1993;17(2): 69–141. doi: 10.1016/0147-0272(93)90010-y 8395998

6. Feng H, Wang X, Zhang Z, Tang C, Ye H, Jones L, et al. Identification of Genetic Mutations in Human Lung Cancer by Targeted Sequencing. Cancer Inform. 2015;14: 83–93.

7. El-Telbany A, Ma PC. Cancer genes in lung cancer: racial disparities: are there any? Genes Cancer. 2012;3(7–8): 467–480. doi: 10.1177/1947601912465177 23264847

8. Lovly C, Horn L, Pao W. Molecular Profiling of Lung Cancer. My Cancer Genome (

9. Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13(5): 342–355. doi: 10.1038/nrc3495 23594855

10. Zhang S, Chang W, Wu H, Wang YH, Gong YW, Zhao YL, et al. Pan-cancer analysis of iron metabolic landscape across the Cancer Genome Atlas. J Cell Physiol. 2019; doi: 10.1002/jcp.29017 31240715

11. Pfeifhofer-Obermair C, Tymoszuk P, Petzer V, Weiss G, Nairz M. Iron in the Tumor Microenvironment-Connecting the Dots. Front Oncol. 2018;8: 549. doi: 10.3389/fonc.2018.00549 30534534

12. Thielmann CM, Costa da Silva M, Muley T, Meister M, Herpel E, Muckenthaler MU. Iron accumulation in tumor-associated macrophages marks an improved overall survival in patients with lung adenocarcinoma. Sci Rep. 2019;9(1): 11326. doi: 10.1038/s41598-019-47833-x 31383898

13. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4): 399–408. doi: 10.1038/ng0896-399 8696333

14. Gerhard GS, Paynton BV, DiStefano JK. Identification of Genes for Hereditary Hemochromatosis. Methods Mol Biol. 2018;1706: 353–365. doi: 10.1007/978-1-4939-7471-9_19 29423808

15. Ali-Rahmani F, Schengrund CL, Connor JR. HFE gene variants, iron, and lipids: a novel connection in Alzheimer’s disease. Front Pharmacol. 2014;5: 165. doi: 10.3389/fphar.2014.00165 25071582

16. Connor JR, Lee SY. Chapter 21. Iron and cancer. In: Milner JA, Romagnolo DF, editors. Bioactive Compounds and Cancer; 2010. Humana/Springer Press. Pp. 469–496.

17. Chen J, Chloupkova M. Abnormal iron uptake and liver cancer. Cancer Biol Ther. 2009;8(18): 1699–1708. doi: 10.4161/cbt.8.18.9146 19571663

18. Ellervik C, Birgens H, Tybjaerg-Hansen A, Nordestgaard BG. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology. 2007;46(4): 1071–1080. doi: 10.1002/hep.21885 17828789

19. Hanson EH, Imperatore G, Burke W. HFE gene and hereditary hemochromatosis: a HuGE review, Human Genome Epidemiology. Am J Epidemiol. 2001;154(3): 193–206. doi: 10.1093/aje/154.3.193 11479183

20. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005;352(17): 1769–1778. doi: 10.1056/NEJMoa041534 15858186

21. Steinberg KK, Cogswell ME, Chang JC, Caudill SP, McQuillian GM, Bowman BA, et al. Prevalence of C282Y and H63D mutations in the Hemochromatosis (HFE) gene in the United States. JAMA. 2001;285(17): 2216–2222. doi: 10.1001/jama.285.17.2216 11325323

22. Viola A, Pagano L, Laudati D, D'Elia R, D'Amico MR, Ammirabile M, et al. HFE gene mutations in patients with acute leukemia. Leuk Lymphoma. 2006;47: 2331–2334. doi: 10.1080/10428190600821898 17107905

23. Dorak MT, Burnett AK, Worwood M, Sproul AM, Gibson BE. The C282Y mutations of HFE is another male-specific risk factor for childhood acute lymphoblastic leukemia. Blood. 1999;94: 3957. 10627122

24. Gunel-Ozcan A, Alyilmaz-Bekmez S, Guler EN, Guc D. HFE H63D mutation frequency shows an increase in Turkish women with breast cancer. BMC Cancer. 2006;6: 37. doi: 10.1186/1471-2407-6-37 16503999

25. Liu X, Lv C, Luan X, Lv M. C282Y polymorphism in the HFE gene is associated with risk of breast cancer. Tumour Biol. 2013;34(5): 2759–2764. doi: 10.1007/s13277-013-0833-9 23681799

26. Martinez di Montemuros F, Tavazzi D, Salsano E, Piepoli T, Pollo B, Fiorelli G, Finocchiaro G. High frequency of the H63D mutation of the hemochromatosis gene (HFE) in malignant gliomas. Neurology. 2001;57: 1342.

27. Shi Z, Johnstone D, Talseth-Palmer BA, Evans TJ, Spigelman AD, Groombridge C, et al. Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age. Int J Cancer. 2009;125: 78–83. doi: 10.1002/ijc.24304 19291797

28. Ropero P, Briceño O, López-Alonso G, Agúndez JA, González Fernández FA, García-Hoz F, et al. The H63D mutation in the HFE gene is related to the risk of hepatocellular carcinoma. Rev Esp Enferm Dig. 2007;99: 376–381. doi: 10.4321/s1130-01082007000700002 17973580

29. Shen LL, Gu DY, Zhao TT, Tang CJ, Xu Y, Chen JF. Implicating the H63D polymorphism in the HFE gene in increased incidence of solid cancers: a meta-analysis. Genet Mol Res. 2015;14(4): 13735–13745. doi: 10.4238/2015.October.28.36 26535689

30. Ye Q, Qian BX, Yin WL, Wang FM, Han T. Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls. PLoS One. 2016;11(9): e0163423. doi: 10.1371/journal.pone.0163423 27657935

31. Zhang M, Xiong H, Fang L, Lu W, Wu X, Wang YQ, et al. Meta-Analysis of the Association between H63D and C282Y Polymorphisms in HFE and Cancer Risk. Asian Pac J Cancer Prev. 2015;16(11): 4633–4639. doi: 10.7314/apjcp.2015.16.11.4633 26107216

32. Chen W, Zhao H, Li T, Yao H. HFE gene C282Y variant is associated with colorectal cancer in Caucasians: a meta-analysis. Tumour Biol. 2013;34(4): 2255–2259. doi: 10.1007/s13277-013-0766-3 23553028

33. Jin F, Xiong WJ, Jing JC, Feng Z, Qu LS, Shen XZ. Evaluation of the association studies of single nucleotide polymorphisms and hepatocellular carcinoma: a systematic review. J Cancer Res Clin Oncol. 2011;137(7): 1095–1104. doi: 10.1007/s00432-010-0970-0 21240526

34. Osborne NJ, Gurrin LC, Allen KJ, Constantine CC, Delatycki MB, McLaren CE, et al. HFE C282Y homozygotes are at increased risk of breast and colorectal cancer. Hepatology. 2010;51: 1311–1318. doi: 10.1002/hep.23448 20099304

35. Lv YF, Chang X, Hua RX, Yan GN, Meng G, Liao XY, et al. The risk of new-onset cancer associated with HFE C282Y and H63D mutations: evidence from 87,028 participants. J Cell Mol Med. 2016;20(7): 1219–1233. doi: 10.1111/jcmm.12764 26893171

36. Jin F, Qu LS, Shen XZ. Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis. J Exp Clin Cancer Res. 2010;29: 18. doi: 10.1186/1756-9966-29-18 20196837

37. Xiao-Bing H, Lu Z, Hong G, Ping L, Guanghui L, Hongming L, et al. Meta analysis on relationship between distributions of C282Y and H63D alleles and genotypes and hepatocellular carcinoma. Minerva Med. 2016 [Epub ahead of print]

38. Gannon PO, Medelci S, Le Page C, Beaulieu M, Provencher DM, Mes-Masson AM, et al. Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis. Int J Cancer. 2011;128: 2326–2334. doi: 10.1002/ijc.25577 20669231

39. Lee SY, Slagle-Webb B, Sheehan JM, Zhu J, Muscat JE, Glantz M, et al. HFE polymorphisms affect survival of brain tumor patients. J Neurooncol. 2015;122(1): 97–104. doi: 10.1007/s11060-014-1681-1 25491948

40. Lee SY, Zhu J, Salzberg AC, Zhang B, Liu DJ, Muscat JE, et al. Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data. PLoS One. 2017;12(3): e0174778. doi: 10.1371/journal.pone.0174778 28358914

41. Lee SY, Patton SM, Henderson RJ, Connor JR. Consequences of expressing mutants of the hemochromatosis gene (HFE) into a human neuronal cell line lacking endogenous HFE. FASEB J. 2007;21(2): 564–576. doi: 10.1096/fj.06-6397com 17194693

42. Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, et al. TCGAbiolinks: An R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 2016;44(8): e71 doi: 10.1093/nar/gkv1507 26704973

43. Silva CT, Colaprico A, Olsen C, D'Angelo F, Bontempi G, Ceccarelli M, et al. TCGA Workflow: Analyze cancer genomics and epigenomics data using Bioconductor packages. F1000Res. 2016;5: 1542. doi: 10.12688/f1000research.8923.2 28232861

44. Mounir M, Lucchetta M, Silva TC, Olsen C, Bontempi G, Chen X, et al. New functionalities in the TCGAbiolinks package for the study and integration of cancer data from GDC and GTEx. PLoS Comput Biol. 2019;15(3): e1006701. doi: 10.1371/journal.pcbi.1006701 30835723

45. R Core Team. (2018) R: A language an environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.

46. Therneau T. (2015) A package for survival analysis in S. version 2.38.

47. Ali-Rahmani F, Grigson PS, Lee S, Neely E, Connor JR, Schengrund CL. H63D mutation in hemochromatosis alters cholesterol metabolism and induces memory impairment. Neurobiol Aging. 2014;35(6): 1511.e1–12.

48. Liu Y, Lee SY, Neely E, Nandar W, Moyo M, Simmons Z, et al. Mutant HFE H63D protein is associated with prolonged endoplasmic reticulum stress and increased neuronal vulnerability. J Biol Chem. 2011;286(15): 13161–13170. doi: 10.1074/jbc.M110.170944 21349849

49. Lee SY, Liu S, Mitchell RM, Slagle-Webb B, Hong YS, Sheehan JM, et al. HFE polymorphisms influence the response to chemotherapeutic agents via induction of p16INK4A. Int J Cancer. 2011;129(9): 2104–2114. doi: 10.1002/ijc.25888 21190189

50. Mrowczynski OD, Madhankumar AB, Slagle-Webb B, Lee SY, Zacharia BE, Connor JR. HFE genotype affects exosome phenotype in cancer. Biochim Biophys Acta Gen Subj. 2017;1861(8): 1921–1928. doi: 10.1016/j.bbagen.2017.05.014 28527894

51. Nixon AM, Neely E, Simpson IA, Connor JR. The role of HFE genotype in macrophage phenotype. J Neuroinflammation. 2018;15(1): 30. doi: 10.1186/s12974-018-1057-0 29391061

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