BRAF V600E , hypothyroidism, and human relaxin in thyroid carcinogenesis
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ORIGINAL ARTICLE – CANCER RESEARCH
BRAFV600E, hypothyroidism, and human relaxin in thyroid carcinogenesis Brenda Y. Hernandez1 · Mobeen Rahman2 · Lenora W. M. Loo1 · Owen T. M. Chan1 · David Horio3 · Shane Morita3 · Gillian Bryant‑Greenwood3 Received: 1 May 2020 / Accepted: 19 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose BRAFV600E, a major driver of thyroid cancer, evaluated in the context of thyroid hormones and human relaxin. Methods Immunohistochemical expressions of BRAFV600E, TSH, TSH receptor (TSHR), T4, T3 receptor (T3R), RLNH2, and its receptor, RXFP1, were evaluated in thyroid tumors from a retrospective U.S. population of 481 cancer cases diagnosed in 1983–2004. Results BRAFV600E was expressed in 52% of all thyroid tumors; expression of other markers ranged from 25% for T4 to 98% for RLNH2. Tumors predominantly exhibited hypothyroid-like conditions characterized by elevated TSH and TSHR and reduced T4. B RAFV600E prevalence was significantly higher in tumors expressing TSH, TSHR, T3R, and RXFP1 and lower in tumors expressing T4. The proportion of B RAFV600E mutation in classic papillary tumors significantly increased from 56 to 72% over the 21-year period of diagnoses, while expression of RXFP1, TSH, TSHR, and T3R decreased in non-tumor. Racial/ethnic differences were observed in thyroid hormone marker expression. Non-tumor expression of TSH, TSHR, and T3R were each associated with shorter overall survival, but did not remain significant after adjustment for demographic and clinical factors. Conclusions Our study provides the first evidence of the potential interaction of BRAFV600E mutation, relaxin, and thyroid hormones in thyroid carcinogenesis. Moreover, our results suggest that hypothyroidism, influenced by RLNH2 activity, may underlie the development of the majority of thyroid cancers and mediate the role of B RAFV600E in thyroid carcinogenV600E esis. BRAF mutation is increasing in papillary thyroid cancers and may be contributing to the rising incidence of this malignancy. Keywords BRAFV600E · Hypothyroidism · Human relaxin 2 · Thyroid · Cancer
Introduction Thyroid cancer incidence has steadily increased in the United States over the past several decades (Howlader et al. 2015). It is the fifth most common cancer in women with threefold higher incidence in females compared to males (Howlader et al. 2015; Ryerson et al. 2016). Racial and * Brenda Y. Hernandez [email protected] 1
University of Hawaii Cancer Center, University of Hawaii, 701 Ilalo Street, Honolulu, Hawaii 96813, USA
2
Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
3
John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA
ethnic disparities have been observed in the U.S. with excess risk observed among Asians, especially Filipinos (Bernstein et al. 1995; Haselkorn et al. 2000; Rossing et al. 1995; Goodman et al. 1988; Gomez et al. 2013). The rising incidence and populat
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