The Role of Circadian Disruption in Prostate Cancer

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The Role of Circadian Disruption in Prostate Cancer

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The Role of Circadian Disruption in Prostate Cancer Development
Lara G. Sigurdardottir
Thesis for the degree of Philosophiae Doctor
Supervisor: Unnur A. Valdimarsdottir
Advisor: Lorelei A. Mucci Doctoral committee: Unnur A. Valdimarsdóttir, Lorelei A. Mucci, Katja Fall, Eirikur Jonsson and Vilmundur Gudnason
September 2015

Röskun á lífklukku og þróun blöðruhálskirtilskrabbameins
Lára G. Sigurðardóttir
Ritgerð til doktorsgráðu
Umsjónarkennari: Unnur A. Valdimarsdóttir
Leiðbeinandi: Lorelei A. Mucci Doktorsnefnd: Unnur A. Valdimarsdóttir, Lorelei A. Mucci, Katja Fall, Eiríkur Jónsson og Vilmundur Guðnason
September 2015

Thesis for a doctoral degree at the University of Iceland. All right reserved. No part of this publication may be reproduced in any form without the prior permission of the copyright holder.
© Lara G. Sigurdardottir 2015 ISBN 978-9935-9261-0-4 Printing by Háskólaprent. Reykjavik, Iceland 2015

Ágrip
Inngangur: Fjölmargar rannsóknir hafa sýnt fram á að röskun á lífklukku, sem birst getur í svefntruflunum og minnkaðri melatónínframleiðslu, er líklegur áhættuþáttur krabbameins. Þó mikilvægar lífeðlisfræðilegar vísbendingar séu til staðar hafa tengsl þessara þátta við krabbamein í blöðruhálskirtli (BHKK) lítið verið rannsökuð. Því var meginmarkmið þessa doktorsverkefnis að kanna tengsl svefns og styrks melatóníns við þróun BHKK. Að auki þróuðum við aðferð til að mæla rúmmál heilakönguls og könnuðum fylgni þess við melatónín með það að markmiði að nýta aðferðina síðar til að skoða tengsl rúmmáls heilakönguls og áhættu BHKK. Að lokum athuguðum við áreiðanleika skráningar BHKK fyrir rannsóknarhópinn með því að meta gæði krabbameinsskráningar á Íslandi.
Efniviður og aðferðir: Fyrsta rannsóknin var yfirlitsgrein um vísindagreinar með upplýsingum um birtu að næturlagi, svefnvenjur eða næturvaktavinnu (vísbendingar fyrir röskun á lífklukku) og áhættu BHKK. Alls voru 16 rannsóknir sem við gátum stuðst við. Í rannsókn tvö var stuðst við ferilhóp 2102 karlþátttakenda í Öldrunarrannsóknar Hjartaverndar til að skoða hvort karlar með svefntruflanir væru í aukinni áhættu að greinast með BHKK. Við notuðum tilfella-ferilrannsókn innan Öldrunarrannsóknarinnar í rannsókn þrjú til að kanna hvort karlar með lægra gildi 6-súlfatoxymelatóníns (aMT6s) í morgunþvagi væru í aukinni hættu á BHKK, sérstaklega langt gengnum sjúkdómi. Við notuðum lifunargreiningu Cox til að meta hættuhlutfall (HR) með 95% öryggismörkum (95% CI). Í rannsókn fjögur völdum við slembiúrtak með 122 körlum og merktum handvirkt á segulómun þrjá vefjahluta (kirtilvef, belgmein og kalk) heilakönguls. Við notuðum línulega aðhvarfsgreiningu til að reikna tengsl heilakönguls og aMT6s. Loks skoðuðum við í rannsókn fimm hlutfall BHKK greininga í Krabbameinsskrá Íslands sem var byggt á vefjarannsókn eða eingöngu dánarvottorði.
Niðurstöður: Af 16 vísindagreinum fundu 15 samband á milli birtu að
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næturlagi, röskunar á lífklukku eða svefntruflana og aukinnar áhættu á BHKK, þar af voru niðurstöður 10 þeirra tölfræðilega marktækar. Á rannsóknartímabilinu (meðaltal=fimm ár) greindust 135 (6,4%) karlar með BHKK, þar af 26 (19%) með langt gengið krabbamein (stig III/IV við greiningu eða dánarorsök). Karlar sem áttu erfitt með að sofna og vöknuðu að næturlagi voru í aukinni áhættu að greinast með BHKK (HR 2,1; 95% CI: 1,23,7) í samanburði við karla án svefntruflana. Karlar með svefntruflun voru í þrefaldri áhættu að fá langt genginn sjúkdóm í samanburði við karla án svefntruflana (HR 3,2; 95% CI: 1,1-9,7). Auk þess reyndust karlar með svefntruflun vera með lægra gildi aMT6s í þvagi. Karlar með aMT6s undir miðgildi voru í fjórfalt aukinni áhættu að greinast með langt gengið BHKK (HR 4,0; 95% CI: 1,3-13,0), í samanburði við þá sem mældust yfir miðgildi. Stærð heilakönguls var mjög breytileg. Meðalrúmmál kirtilvefs mældist 178 mm3 (spönn 65-503). Karlar sem voru með lítinn heilaköngul mældust með lægra aMT6s-gildi (p<0.001). Úttekt á Krabbameinsskrá Íslands sýndi að 98% tilfella BHKK voru staðfest með vefjagreiningu og örfá tilfelli (0,3%) voru eingöngu staðfest af dánarvottorði.
Ályktun: Rannsóknirnar benda til þess að röskun á lífklukku, mælt með svefntruflun og minnkaðri melatónín framleiðslu, tengist aukinni áhættu á langt gengnu BHKK. Áhrif röskunar á lífklukku á þróun krabbameins, sérstaklega BHKK, er enn vanrannsakað svið. Í ljósi þeirrar staðreyndar að röskun á lífklukku fylgir oft örri þróun tæknivæðingar, er gríðarlega mikilvægt er að skoða þetta samband frekar í framtíðinni. Ef þessi tengsl verða staðfest í fleiri rannsóknum þá geta opnast nýir möguleikar til forvarna gegn BHKK.

Lykilorð: Lífklukka, svefn, melatónín, krabbamein, krabbameinsskrá.

heilaköngull,

blöðruhálskirtils-

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Abstract
Background and Aims: Numerous studies have shown that circadian disruption, which may be marked by sleep disturbances and inhibited melatonin production, is probably carcinogenic to humans. Although important biological evidence exists, the association between circadian disruption and prostate cancer remains an underexplored field. Therefore, the aim of this thesis was to examine the association between sleep and melatonin levels in relation to prostate cancer risk and progression. In addition, to develop a method to measure the pineal gland volume in relation to melatonin with a future aim to explore the association of pineal gland volume and prostate cancer risk. Finally, we sought ascertainment of prostate cancer registration for the study groups by evaluating the quality of the Icelandic Cancer Registry (ICR).
Materials and Methods: In aim one, we conducted a systematic review of the literature to evaluate the association between light-at-night, sleep patterns or shift work (as proxies for circadian disruption) and prostate cancer risk, with 16 studies fulfilling our eligibility criteria. In aim two, we utilized a cohort of 2,102 men from the AGES-Reykjavik study with information on sleep problems from a baseline questionnaire to evaluate whether men with sleep disruption were at increased risk of prostate cancer. Using a casecohort design within the AGES-Reykjavik cohort, aim three explored wether men with lower levels of first morning void urinary 6-sulfatoxymelatonin (aMT6s) had an increased risk of prostate cancer, particularly advanced disease. We used weighted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). In aim four, we manually labelled separately the three components (parenchyma, cyst and calcification) of the pineal gland from magnetic resonance images (MRI) of the brain in a random sample of 122 men. We then used multivariable linear regression to calculate the association of pineal volume and aMT6s. Finally,
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in our fifth aim we evaluated the proportion of prostate cancer diagnoses in the Icelandic cancer registry that were verified morphologically or based on death certificate only.
Results: Of the 16 previously published studies, 15 were indicative of a positive association between circadian disruption, sleep loss and prostate cancer risk; 10 of which were statistically significantly associated. Over the study period (mean five years), 135 (6.4%) men were diagnosed with prostate cancer, of whom 26 (19%) had advanced disease (stage III/IV at diagnosis or death from prostate cancer). The men who reported difficulty falling asleep and woke up during the night were at increased risk of prostate cancer (HR 2.1; 95% CI: 1.2-3.7), compared with men without sleep problems. The risk of advanced disease was also stronger, with men who reported sleep problems at a threefold increased risk compared to men without sleep problems (HR 3.2; 95% CI: 1.1-9.7). Furthermore, men who reported sleep problems had lower levels of urinary aMT6s. Men with levels of urinary aMT6s below the median were at a fourfold increased risk of advanced prostate cancer (HR 4.0; 95% CI: 1.3-13.0), compared to men with levels above the median. The pineal gland varied in size with a mean parenchyma volume of 178 mm3 (range 65-503). Smaller pineal volumes were associated with lower levels of aMT6s levels (p<0.001). Assessment of the ICR showed that 98% of the prostate cancer diagnoses verified morphologically and few based only on death certificate (0.3%).
Conclusion: These studies indicate that circadian disruption, as measured by sleep disruption and lower melatonin levels, is associated with an increased risk of advanced prostate cancer. The effect of circadian disruption on cancer risk, particularly prostate cancer, is an understudied area. In light of the fact that circadian disruption often accompanies ever-evolving technology, it is of utmost importance to explore this field in future research. If these findings are confirmed, they may have implications for future prevention of prostate cancer.
Keywords: Circadian, sleep, melatonin, pineal, prostate, cancer, registration.
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Acknowledgements
It was curiosity about the functioning of the human body that originally got me to apply for medical school. Many years later while pursuing a degree in surgery I realized that my passion lay in preventive medicine. I came across an interview with my mentor, Unnur A. Valdimarsdottir. She was building up the department of Public Health Sciences at the University of Iceland. At that time my father-in-law, professor Gudjon Magnusson, inspired me to apply. So, I decided that surgery could wait. With the intent of signing up for a master’s degree I instead found myself heading toward a PhD degree, before I knew it.
During this time I have learned about good research methods, thinking critically and the importance of extensive collaboration. I have also discovered an important virtue, the virtue of patience. In PhD things take an expected time plus unexpected additional time plus yet more extra time that it was not supposed to. Although coming to this destination, I still have another journey ahead of me. There are more questions to answer.
I have been immensely fortunate to be able to learn from top of the world scientists and mentors. I would like to thank my advisors Unnur A. Valdimarsdottir and Lorelei A. Mucci who have widened my perspective and helped me over every obstacle. I am ever grateful for the invaluable contribution of the sleep guys, Charles A. Czeisler, Eva Schernhammer, Erin Flynn-Evans and Steven W. Lockley, and the prostate group Meir J. Stampfer, Jennifer R. Rider, David Havelick and last but not least Sarah C. Markt, who is not only a great collaborator but also a dear friend. Sebastien Haneuse gets thanks for biostatistics challenges.
The team at the Icelandic Heart Association has proven extremely helpful in every possible situation: Thor Aspelund, Guðný Eiríksdóttir, Lars Forsberg, Bryndís Óskarsdóttir, Sigurdur Sigurdsson, and Vilmundur Guðnason.
My sincere gratitude to the staff at the Icelandic Cancer Registry for providing data and always being ready to assist: Laufey Tryggvadottir, Gudridur H. Ólafsdóttir and Elínborg Ólafsdóttir. My special thanks to Ragnheiður Haraldsdóttir at the Icelandic Cancer Society, for her encouragement and support.
I would like to thank my Doctoral Committee for thoughtful guidance in the final steps: Unnur A. Valdimarsdóttir, Lorelei A. Mucci, Katja Fall, Eiríkur Jónsson and
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Vilmundur Guðnason. I would also like to thank the Ph.D. Evaluation Committee for accepting this thesis for public defense: Eric B. Rimm, Helga M. Ögmundsdóttir and Eva Johansson.
To my public health colleagues and friends: I am grateful for your inspiration, countless discussions, and always being ready to assist. I was fortunate to meet Ph.D. students Edda Björk and Jóhanna Eyrún in the beginning and we have shared the highs and lows of graduate studies. I would also like to thank Þrúður, Halldóra, Hildur Guðný, Ragnhildur G., Agnes, Védís, Ragna, Maríanna, Álfheiður, Ólöf Elsa, Emma, Sigríður H., Dóra, Helga, Arna, Chris, Gunnar, Sigurður Y., and Vilhjálmur R. You have all helped me, whether you know it or not.
I am thankful for the financial support of RANNIS (the Icelandic Research Fund) and the Harvard Catalyst Award (CTSA; awards UL1 RR 025758 and KL2 RR 025757) from the National Center for Research Resources, a part of the National Institutes of Health. The studies were also funded in part by the US National Institute on Aging contract N01-AG-1-2100, the Intramural Researh Program of the National Institute on Aging, the Icelandic Cancer Society, and the Icelandic Heart Association.
I thank all my friends that have stood by me, in one way or another. Having them around makes life so much more fun. And my dear mother, Ebba Rannveig, who has at all times believed in me, supported me and encouraged me to push on – I am lucky to have you - and her husband, Steingrímur, for always being ready to help out with the kids. I would also like to thank my father, Sigurður Rúnar, and his wife, Hulda, who have always been very kind and helpful. Then, I would like to thank my generous mother-in-law, Sigrún.
At last, my endless love and gratitude to my three sons that have taught me more about love and the meaning of life than I ever would have imagined. Flóki, Nökkvi and Fróði, you light up my life. I hope that we have made some good memories during our sometimes-limited time together. Without my husband I would not have met my boys and this thesis is dedicated to him. He is my anchor in life, who makes sure that I do not float away with my never-ending and sometimes unrealistic new ideas. My dear husband and soul mate, Halldór Fannar, my love for you is eternal.
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Prostate CancerCircadian DisruptionRiskAssociationAim