Quantification of Thyroid Cancer and Multinodular Goiter Risk in the DICER1 Syndrome: A Family-Based Cohort Study

Nicholas E Khan, Andrew J Bauer, Kris Ann P Schultz, Leslie Doros, Rosamma M Decastro, Alexander Ling, Maya B Lodish, Laura A Harney, Ron G Kase, Ann G Carr, Christopher T Rossi, Amanda Field, Anne K Harris, Gretchen M Williams, Louis P Dehner, Yoav H Messinger, D Ashley Hill, Douglas R Stewart, Nicholas E Khan, Andrew J Bauer, Kris Ann P Schultz, Leslie Doros, Rosamma M Decastro, Alexander Ling, Maya B Lodish, Laura A Harney, Ron G Kase, Ann G Carr, Christopher T Rossi, Amanda Field, Anne K Harris, Gretchen M Williams, Louis P Dehner, Yoav H Messinger, D Ashley Hill, Douglas R Stewart

Abstract

Context: The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown.

Objective: To quantify the risk of thyroid cancer and MNG in individuals with DICER1 syndrome.

Design: Family-based cohort study.

Setting: National Institutes of Health (NIH) Clinical Center (CC).

Participants: The National Cancer Institute DICER1 syndrome cohort included 145 individuals with a DICER1 germline mutation and 135 family controls from 48 families.

Interventions: Each individual completed a detailed medical history questionnaire. A subset underwent a 3-day evaluation at the NIH CC.

Main outcome measures: The cumulative incidence of MNG (or thyroidectomy) was quantified using the complement of the Kaplan-Meier product limit estimator. We compared the observed number of thyroid cancers in the NCI DICER1 cohort with matched data from the Surveillance, Epidemiology, and End Results (SEER) Program. We performed germline and somatic (thyroid cancer, MNG) DICER1 sequencing.

Results: By the age of 40 years, the cumulative incidence of MNG or thyroidectomy was 75% in women and 17% in men with DICER1 syndrome compared with 8% of control women (P < 0.001) and 0% of control men (P = 0.0096). During 3937 person-years of observation, individuals with DICER1 syndrome had a 16-fold increased risk of thyroid cancer (95% confidence interval, 4.3 to 41; P < 0.05) compared with the SEER rates. Of 19 MNG nodules and 3 thyroid cancers, 16 (84%) and 3 (100%), respectively, harbored germline and somatic pathogenic DICER1 mutations.

Conclusions: We propose a model of thyroid carcinogenesis in DICER1 syndrome. Early-onset, familial, or male MNG should prompt consideration of the presence of DICER1 syndrome.

Copyright © 2017 by the Endocrine Society

Figures

Figure 1.
Figure 1.
Cumulative incidence of MNG for entire DICER1 syndrome cohort. (a) The cumulative incidence of MNG diagnosis censored at thyroidectomy in DICER1 carriers (red) and controls (blue). Shaded areas indicate the 95% pointwise CIs. The cumulative incidence of MNG in women with DICER1 syndrome had reached 50% by age 36 years (95% CI, 25.6 to 60.9). (b) The cumulative incidence for the risk of either MNG diagnosis or thyroidectomy (Table 1).
Figure 2.
Figure 2.
Proposed model of benign thyroid nodules as a premalignant lesion in DICER1 syndrome. Progression to thyroid cancer in association with DICER1 syndrome is hypothesized to be interrupted by a high prevalence of thyroidectomy, performed to remediate symptomatic MNG.

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Source: PubMed

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