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

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.