Indicators of microbial-rich environments and the development of papillary thyroid cancer in the California Teachers Study
Introduction
Thyroid cancer is currently the 5th most commonly diagnosed cancer in United States (US) women [1]. Substantial increases in incidence have been observed in US women and men across all ethnic groups [1], [2], [3]. With an average annual percent increase (AAPI) of 6.6% per year between 1996 and 2010 (compared to an AAPI of 2.5% between 1981 and 1996), incidence rates for thyroid cancer are increasing faster than those for any other cancer in women [1]. Improvements in diagnostic technology account for only a portion of the observed increase [2], [4], [5], [6]. Thus identifying new risk factors for thyroid cancer and understanding temporal changes in both established and new risk factors represent an increasingly important public health priority. At this time, the only well-established risk factors for the papillary (including the papillary/follicular variant) form of thyroid cancer (which comprises 80% of all thyroid cancer) are ionizing radiation, history of proliferative benign thyroid disease (BTD) (e.g., goiter and thyroid nodules), and family history of thyroid cancer or proliferative BTD [7], [8], [9]. However, these exposures have relatively low prevalence in the US [8], [10]. More recent studies have found obesity to increase risk [11], [12], [13] and the several years following a full-term pregnancy to be a period of high risk [14], [15]. Little research has focused on immunologic correlates of thyroid carcinogenesis despite the fact that half of all autoimmune diseases in women involve the thyroid [16]. These autoimmune diseases result from hyperactive cell-mediated immune responses against self-tissue [17], and women with autoimmune diseases such as systemic lupus erythematosus (SLE), are at significantly higher risk of developing thyroid cancer [18].
Given the rapid increase, environmental exposures relevant to immune function represent an understudied set of possible risk factors for thyroid cancer. During the last century we have seen unprecedented increases in persons living in more sterile environments and less crowded housing conditions, resulting in diminished exposure to a diversity of microbes [19]. This reduction in exposure to microbial-rich environments, especially when it occurs in early life, has been linked to hyperactive immune responses to allergens (e.g., atopic disease) in children and is thought to be detrimental to establishing the appropriate immune “calibration” or “priming” that may be needed for lifelong healthy immune function [19], [20], [21], [22]. This set of circumstances has been termed the “hygiene hypothesis.” Exposure to microbial-rich environments has been associated with lower risk of other cancers (e.g., daycare and childhood leukemia, occupational exposures to endotoxin-rich agricultural and textile environments and lung cancer [23], [24]) and it is plausible that similar exposures could be related to thyroid cancer development. Here we investigate the association between early life self-reported exposures to microbial-rich environments and papillary thyroid cancer risk in a large, prospective cohort of female California teachers.
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Materials and methods
The California Teachers Study (CTS) cohort, established in 1995–1996, includes 133,479 active and retired female public school teachers, administrators, and other professionals [25]. Participants initially completed a self-administered baseline questionnaire addressing health and medical history, lifestyle, diet, and other behaviors. The fourth follow-up questionnaire, completed in 2005–2006, included questions on exposures related to microbial and infectious exposures throughout the lifespan.
Results
The average age of women in the analytic cohort was 62 (±0.1) years at the time they completed the 2005–2006 questionnaire; 88% were non-Latina white, 29% were overweight (BMI 25–29.9 kg/m2), and 18% were obese (BMI >30 kg/m2). Only 1.4% reported having a family history of thyroid cancer in a first degree relative, but almost 15% had a family history of BTD, and 10% reported a personal history of benign thyroid disease. Women in the analytic cohort who were diagnosed with papillary thyroid cancer
Discussion
To the best of our knowledge, this is the first study addressing the association between papillary thyroid cancer development and events that could reflect immunologically relevant microbial exposures during specific periods of life. We examined two types of factors culled from the literature regarding their association with atopic disease: those presumably reflecting exposure to a wide diversity of microbes and microbial byproducts and endotoxins (i.e., living within close proximity to hoofed
Grant support
This study was supported by grants R21 CA152839 (PI: C. Clarke) and R01 CA77398 (PI: L. Bernstein) from the National Cancer Institute. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract HHSN261201000036C awarded to the
Conflict of interest
None of the authors report a conflict of interest.
Authorship contribution
CC, PR, IOG, EL, YL, LB, PHR designed and conducted the research, prepared the manuscript and have responsibility for content; JY and LM analyzed data. All authors read and approved the final manuscript.
Acknowledgments
The authors would like to thank the CTS Steering Committee who are responsible for the formation and maintenance of the cohort within which this study was conducted and Dr. David Nelson for statistical consultation.
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