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. 2021 Jan;147(1):183-194.
doi: 10.1007/s00432-020-03401-9. Epub 2020 Sep 29.

BRAFV600E, hypothyroidism, and human relaxin in thyroid carcinogenesis

Brenda Y Hernandez  1 , Mobeen Rahman  2 , Lenora W M Loo  3 , Owen T M Chan  3 , David Horio  4 , Shane Morita  4 , Gillian Bryant-Greenwood  4
Affiliations

BRAFV600E, hypothyroidism, and human relaxin in thyroid carcinogenesis

Brenda Y Hernandez et al. J Cancer Res Clin Oncol. 2021 Jan.

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. BRAFV600E prevalence was significantly higher in tumors expressing TSH, TSHR, T3R, and RXFP1 and lower in tumors expressing T4. The proportion of BRAFV600E 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 BRAFV600E in thyroid carcinogenesis. BRAFV600E mutation is increasing in papillary thyroid cancers and may be contributing to the rising incidence of this malignancy.

Keywords: BRAFV600E; Cancer; Human relaxin 2; Hypothyroidism; Thyroid.

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Conflict of interest statement

The authors have no conflict of interest.

Figures

Fig. 1
Fig. 1
Protein expression in classic papillary carcinoma (×400)
Fig. 2
Fig. 2
Correlation of protein marker expression (Spearman correlation, r, p < 0.05) in thyroid tumor (T) and adjacent non-tumor (NT)
Fig. 3
Fig. 3
BRAFV600E status by thyroid and relaxin marker expression
Fig. 4
Fig. 4
Secular changes in marker expression in classical papillary thyroid cancer, 1983–1994 to 1995–2004 (p < 0.05)
See this image and copyright information in PMC

References

    1. Bernstein L, Miu A, Monroe K, Henderson B, Ross R (1995) Cancer incidence among Filipinos in Los Angeles County, 1972–1991. Int J Cancer 63:345–348 - PubMed
    1. Bialek J, Kunanuvat U, Hombach-Klonisch S, Spens A, Stetefeld J, Sunley K, Lippert D, Wilkins JA, Hoang-Vu C, Klonisch T (2011) Relaxin enhances the collagenolytic activity and in vitro invasiveness by upregulating matrix metalloproteinases in human thyroid carcinoma cells. Mol Cancer Res 9(6):673–687. 10.1158/1541-7786.MCR-10-0411 - PubMed
    1. Binder C, Hagemann T, Husen B, Schulz M, Einspanier A (2002) Relaxin enhances in-vitro invasiveness of breast cancer cell lines by up-regulation of matrix metalloproteases. Mol Hum Reprod 8(9):789–796 (Epub 2002/08/30 PubMed PMID: 12200455) - PubMed
    1. Binder C, Simon A, Binder L, Hagemann T, Schulz M, Emons G, Trumper L, Einspanier A (2004) Elevated concentrations of serum relaxin are associated with metastatic disease in breast cancer patients. Breast Cancer Res Treat 87(2):157–166. 10.1023/B:BREA.0000041622.30169.16(Epub 2004/09/21; PubMedPMID: 15377840) - PubMed
    1. Biondi B (2010) Thyroid and obesity: an intriguing relationship. J ClinEndocrinolMetab 95(8):3614–3617. 10.1210/jc.2010-1245(Epub 2010/08/06; PubMedPMID: 20685890) - PubMed

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