Cancer occurrence in Turner syndrome and the effect of sex hormone substitution therapy

in European Journal of Endocrinology
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  • 1 Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
  • 2 Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark
  • 3 Medical Genetics Unit, Massachusetts General Hospital for Children, Boston, Massachusetts, USA
  • 4 Department of Clinical Genetics, Aarhus University, Aarhus, Denmark
  • 5 Department of Public Health, Aarhus University, Aarhus, Denmark

Correspondence should be addressed to M H Viuff; Email: metteviuff@clin.au.dk
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Objective

Although the overall risk of cancer is not increased in Turner syndrome, the pattern of cancer occurrence differs from the general population. We aim to describe the cancer morbidity pattern in Turner syndrome and evaluate the effect of long-term hormone replacement therapy (HRT).

Design

Nationwide epidemiological study.

Methods

1156 females with Turner syndrome diagnosed during 1960–2014, were linked with data from the Danish National Patient Registry. Statistics Denmark randomly identified 115 578 female controls. Stratified Cox regression was used to analyze cancer morbidity, mortality and effect of HRT.

Results

Overall risk of cancer was not elevated (hazard ratio 1.04 (95% CI: 0.80–1.36)). The risk of skin cancer and benign skin neoplasms was two-fold increased, while the risk of breast cancer was decreased (hazard ratio 0.4 (0.2–0.9)). Turner syndrome (45,X) had a two- to five-fold increased risk of benign CNS tumors, colon and rectal cancers, benign skin neoplasms and skin cancer. Turner syndrome women with a 45,X/46,XX karyotype had an increased risk of tongue cancer. HRT had no impact on the risk of any cancer investigated in this study.

Conclusions

The lack of one X chromosome might play a role in skin neoplasms, CNS tumors, colon and rectal cancers. The risk of breast cancer is lower than in the general population. Long-term HRT during the premenopausal age range seems not to exert a cancerous effect in Turner syndrome. Increased vigilance concerning specific types of cancer in Tuner syndrome harboring a 45,X karyotype is needed.

 

     European Society of Endocrinology

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  • 1

    Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF & Jacobs PA Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncology 2008 9 2392 46. (https://doi.org/10.1016/S1470-2045(0870033-0)

    • Search Google Scholar
    • Export Citation
  • 2

    Gravholt CH, Juul S, Naeraa RW & Hansen J Morbidity in Turner syndrome. Journal of Clinical Epidemiology 1998 51 1471 58. (https://doi.org/10.1016/S0895-4356(9700237-0)

    • Search Google Scholar
    • Export Citation
  • 3

    Hasle H, Olsen JH, Nielsen J, Hansen J, Friedrich U & Tommerup N Occurrence of cancer in women with Turner syndrome. British Journal of Cancer 1996 73 1156115 9. (https://doi.org/10.1038/bjc.1996.222)

    • Search Google Scholar
    • Export Citation
  • 4

    Viuff M, Skakkebaek A, Nielsen MM, Chang S & Gravholt CH Epigenetics and genomics in Turner syndrome. American Journal of Medical Genetics, Part C 2019 181 6875. (https://doi.org/10.1002/ajmg.c.31683)

    • Search Google Scholar
    • Export Citation
  • 5

    Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, Lin AE, Mauras N, Quigley CA & Rubin K et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. European Journal of Endocrinology 2017 177 G1G70. (https://doi.org/10.1530/EJE-17-0430)

    • Search Google Scholar
    • Export Citation
  • 6

    Cools M, Looijenga LHJ, Wolffenbuttel KP & T’Sjoen G Managing the risk of germ cell tumourigenesis in disorders of sex development patients. Endocrine Development 2014 27 1851 96. (https://doi.org/10.1159/000363642)

    • Search Google Scholar
    • Export Citation
  • 7

    Gravholt CH, Dollerup OL, Duval L, Mejlgaard E, Stribolt K, Vang S, Laursen BE, Knudsen M, Thorsen K & Hersmus R et al. A rare case of embryonal carcinoma in a patient with Turner syndrome without Y chromosomal material but mutations in KIT, AKT1, and ZNF358 demonstrated using exome sequencing. Sexual Development 2017 11 26226 8. (https://doi.org/10.1159/000484398)

    • Search Google Scholar
    • Export Citation
  • 8

    Gravholt CH, Fedder J, Naeraa RW & Muller J Occurrence of gonadoblastoma in females with Turner syndrome and Y chromosome material: a population study. Journal of Clinical Endocrinology and Metabolism 2000 85 31993 202. (https://doi.org/10.1210/jcem.85.9.6800)

    • Search Google Scholar
    • Export Citation
  • 9

    Rojek A, Obara-Moszynska M, Kolesinska Z, Rabska-Pietrzak B & Niedziela M Molecular detection and incidence of Y chromosomal material in patients with Turner syndrome. Sexual Development 2017 11 2542 61. (https://doi.org/10.1159/000484880)

    • Search Google Scholar
    • Export Citation
  • 10

    Berglund A, Viuff MH, Skakkebaek A, Chang S, Stochholm K & Gravholt CH Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study. Orphanet Journal of Rare Diseases 2019 14 16. (https://doi.org/10.1186/s13023-018-0976-2)

    • Search Google Scholar
    • Export Citation
  • 11

    Ji J, Zoller B, Sundquist J & Sundquist K Risk of solid tumors and hematological malignancy in persons with Turner and Klinefelter syndromes: a national cohort study. International Journal of Cancer 2016 139 75475 8. (https://doi.org/10.1002/ijc.30126)

    • Search Google Scholar
    • Export Citation
  • 12

    Cancer CGoHFiB. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019 394 115911 68. (https://doi.org/10.1016/S0140-6736(1931709-X)

    • Search Google Scholar
    • Export Citation
  • 13

    Bosze P, Toth A & Torok M Hormone replacement and the risk of breast cancer in Turner’s syndrome. New England Journal of Medicine 2006 355 25992 600. (https://doi.org/10.1056/NEJMc062795)

    • Search Google Scholar
    • Export Citation
  • 14

    Swerdlow AJ, Cooke R, Beckers D, Borgstrom B, Butler G, Carel JC, Cianfarani S, Clayton P, Coste J & Deodati A et al. Cancer risks in patients treated with growth hormone in childhood: the SAGhE European cohort study. Journal of Clinical Endocrinology and Metabolism 2017 102 166116 72. (https://doi.org/10.1210/jc.2016-2046)

    • Search Google Scholar
    • Export Citation
  • 15

    Viuff MH, Berglund A, Juul S, Andersen NH, Stochholm K & Gravholt CH Sex hormone replacement therapy in Turner syndrome: impact on morbidity and mortality. Journal of Clinical Endocrinology and Metabolism 2020 105 468478. (https://doi.org/10.1210/clinem/dgz039)

    • Search Google Scholar
    • Export Citation
  • 16

    Kildemoes HW, Sorensen HT & Hallas J The Danish National Prescription Registry. Scandinavian Journal of Public Health 2011 39 3841. (https://doi.org/10.1177/1403494810394717)

    • Search Google Scholar
    • Export Citation
  • 17

    Freriks K, Timmermans J, Beerendonk CCM, Verhaak CM, Netea-Maier RT, Otten BJ, Braat DDM, Smeets DFCM, Kunst DHPM & Hermus ARMM et al. Standardized multidisciplinary evaluation yields significant previously undiagnosed morbidity in adult women with Turner syndrome. Journal of Clinical Endocrinology and Metabolism 2011 96 E1517E15 26. (https://doi.org/10.1210/jc.2011-0346)

    • Search Google Scholar
    • Export Citation
  • 18

    Naess EE, Bahr D & Gravholt CH Health status in women with Turner syndrome: a questionnaire study on health status, education, work participation and aspects of sexual functioning. Clinical Endocrinology 2010 72 6786 84. (https://doi.org/10.1111/j.1365-2265.2009.03715.x)

    • Search Google Scholar
    • Export Citation
  • 19

    Gravholt CH, Vestergaard P, Hermann AP, Mosekilde L, Brixen K & Christiansen JS Increased fracture rates in Turner’s syndrome: a nationwide questionnaire survey. Clinical Endocrinology 2003 59 8996. (https://doi.org/10.1046/j.1365-2265.2003.01807.x)

    • Search Google Scholar
    • Export Citation
  • 20

    Amelot A, Lemaistre G, Cornu P, Kalamarides M & Peyre M Multiple meningiomas in patients with Turner syndrome. Acta Neurochirurgica 2015 157 62162 3. (https://doi.org/10.1007/s00701-015-2360-5)

    • Search Google Scholar
    • Export Citation
  • 21

    Pier DB, Nunes FP, Plotkin SR, Stemmer-Rachamimov AO, Kim JC, Shih HA, Brastianos P & Lin AE Turner syndrome and meningioma: support for a possible increased risk of neoplasia in Turner syndrome. European Journal of Medical Genetics 2014 57 2692 74. (https://doi.org/10.1016/j.ejmg.2014.03.005)

    • Search Google Scholar
    • Export Citation
  • 22

    Fang H, Disteche CM & Berletch JB X inactivation and escape: epigenetic and structural features. Frontiers in Cell and Developmental Biology 2019 7 219. (https://doi.org/10.3389/fcell.2019.00219)

    • Search Google Scholar
    • Export Citation
  • 23

    Zhu JJ, Maruyama T, Jacoby LB, Herman JG, Gusella JF, Black PM & Wu JK Clonal analysis of a case of multiple meningiomas using multiple molecular genetic approaches: pathology case report. Neurosurgery 1999 45 4094 16. (https://doi.org/10.1097/00006123-199908000-00049)

    • Search Google Scholar
    • Export Citation
  • 24

    Andersen L, Friis S, Hallas J, Ravn P, Schroder HD & Gaist D Hormone replacement therapy increases the risk of cranial meningioma. European Journal of Cancer 2013 49 330333 10. (https://doi.org/10.1016/j.ejca.2013.05.026)

    • Search Google Scholar
    • Export Citation
  • 25

    Ruttledge MH, Sarrazin J, Rangaratnam S, Phelan CM, Twist E, Merel P, Delattre O, Thomas G, Nordenskjold M & Collins VP et al. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nature Genetics 1994 6 18018 4. (https://doi.org/10.1038/ng0294-180)

    • Search Google Scholar
    • Export Citation
  • 26

    Riemenschneider MJ, Perry A & Reifenberger G Histological classification and molecular genetics of meningiomas. Lancet Neurology 2006 5 104510 54. (https://doi.org/10.1016/S1474-4422(0670625-1)

    • Search Google Scholar
    • Export Citation
  • 27

    Lee S, Karas PJ, Hadley CC, Bayley V JC, Khan AB, Jalali A, Sweeney AD, Klisch TJ & Patel AJ The role of merlin/NF2 loss in meningioma biology. Cancers 2019 11 1633. (https://doi.org/10.3390/cancers11111633)

    • Search Google Scholar
    • Export Citation
  • 28

    Herrera-Ornelas L, Ochi H, Petrelli N, Mittelman A & Sandberg AA Nonfamilial Turcot’s syndrome associated with Turner’s syndrome, multiple carcinomas of the tongue, and cancer of the colon. Journal of Surgical Oncology 1984 27 25125 4. (https://doi.org/10.1002/jso.2930270412)

    • Search Google Scholar
    • Export Citation
  • 29

    Levine ME, Lu AT, Chen BH, Hernandez DG, Singleton AB, Ferrucci L, Bandinelli S, Salfati E, Manson JE & Quach A et al. Menopause accelerates biological aging. PNAS 2016 113 932793 32. (https://doi.org/10.1073/pnas.1604558113)

    • Search Google Scholar
    • Export Citation
  • 30

    Kveiborg M, Gravholt CH & Kassem M Evidence of a normal mean telomere fragment length in patients with Ullrich-Turner syndrome. European Journal of Human Genetics 2001 9 877879. (https://doi.org/10.1038/sj.ejhg.5200722)

    • Search Google Scholar
    • Export Citation
  • 31

    Trabert B, Sherman ME, Kannan N & Stanczyk FZ Progesterone and breast cancer. Endocrine Reviews 2020 41 3203 44. (https://doi.org/10.1210/endrev/bnz001)

    • Search Google Scholar
    • Export Citation
  • 32

    Larizza D, Albanesi M, De Silvestri A, Accordino G, Brazzelli V, Maffe GC & Calcaterra V Neoplasia in Turner syndrome. The importance of clinical and screening practices during follow-up. European Journal of Medical Genetics 2016 59 2692 73. (https://doi.org/10.1016/j.ejmg.2016.03.005)

    • Search Google Scholar
    • Export Citation
  • 33

    El-Mansoury M, Barrenas ML, Bryman I, Hanson C, Larsson C, Wilhelmsen L & Landin-Wilhelmsen K Chromosomal mosaicism mitigates stigmata and cardiovascular risk factors in Turner syndrome. Clinical Endocrinology 2007 66 7447 51. (https://doi.org/10.1111/j.1365-2265.2007.02807.x)

    • Search Google Scholar
    • Export Citation
  • 34

    Handler MZ, Derrick KM, Lutz RE, Morrell DS, Davenport ML & Armstrong AW Prevalence of pilomatricoma in Turner syndrome: findings from a multicenter study. JAMA Dermatology 2013 149 5595 64. (https://doi.org/10.1001/2013.jamadermatol.115)

    • Search Google Scholar
    • Export Citation
  • 35

    Pinheiro I, Dejager L & Libert C X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. BioEssays 2011 33 791802. (https://doi.org/10.1002/bies.201100047)

    • Search Google Scholar
    • Export Citation
  • 36

    Dunford A, Weinstock DM, Savova V, Schumacher SE, Cleary JP, Yoda A, Sullivan TJ, Hess JM, Gimelbrant AA & Beroukhim R et al. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nature Genetics 2017 49 101 6. (https://doi.org/10.1038/ng.3726)

    • Search Google Scholar
    • Export Citation
  • 37

    Trolle C, Nielsen MM, Skakkebaek A, Lamy P, Vang S, Hedegaard J, Nordentoft I, Orntoft TF, Pedersen JS & Gravholt CH Widespread DNA hypomethylation and differential gene expression in Turner syndrome. Scientific Reports 2016 6 34220. (https://doi.org/10.1038/srep34220)

    • Search Google Scholar
    • Export Citation
  • 38

    Gravholt CH, Viuff MH, Brun S, Stochholm K & Andersen NH Turner syndrome: mechanisms and management. Nature Reviews Endocrinology 2019 15 6016 14. (https://doi.org/10.1038/s41574-019-0224-4)

    • Search Google Scholar
    • Export Citation
  • 39

    Lin AE, Prakash SK, Andersen NH, Viuff MH, Levitsky LL, Rivera-Davila M, Crenshaw ML, Hansen L, Colvin MK & Hayes FJ et al. Recognition and management of adults with Turner syndrome: from the transition of adolescence through the senior years. American Journal of Medical Genetics Part A 2019 179 19872033. (https://doi.org/10.1002/ajmg.a.61310)

    • Search Google Scholar
    • Export Citation
  • 40

    Tuke MA, Ruth KS, Wood AR, Beaumont RN, Tyrrell J, Jones SE, Yaghootkar H, Turner CLS, Donohoe ME & Brooke AM et al. Mosaic Turner syndrome shows reduced penetrance in an adult population study. Genetics in Medicine 2019 21 8778 8 6. (https://doi.org/10.1038/s41436-018-0271-6)

    • Search Google Scholar
    • Export Citation