Quantification of Thyroid Cancer and Multinodular Goiter Risk in the DICER1 Syndrome: A Family-Based Cohort Study.
The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown.



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



Family-based cohort study.



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



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



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



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.



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.



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.
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20850.
Nicholas E
NE
Khan
The Thyroid Center, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Andrew J
AJ
Bauer
Cancer and Blood Disorders, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404.|International Pleuropulmonary Blastoma Registry, Minneapolis, Minnesota 55404.|International Ovarian and Testicular Stromal Tumor Registry, Minneapolis, Minnesota 55404.
Kris Ann P
KAP
Schultz
Food and Drug Administration, Silver Spring, Maryland 20993.
Leslie
L
Doros
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20850.
Rosamma M
RM
Decastro
Radiology & Imaging Sciences Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
Alexander
A
Ling
Section of Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Maya B
MB
Lodish
Westat, Inc., Rockville, Maryland 20850.
Laura A
LA
Harney
Westat, Inc., Rockville, Maryland 20850.
Ron G
RG
Kase
Westat, Inc., Rockville, Maryland 20850.
Ann G
AG
Carr
Division of Pathology and Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037.
Christopher T
CT
Rossi
Division of Pathology and Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037.
Amanda
A
Field
Cancer and Blood Disorders, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404.|International Pleuropulmonary Blastoma Registry, Minneapolis, Minnesota 55404.|International Ovarian and Testicular Stromal Tumor Registry, Minneapolis, Minnesota 55404.
Anne K
AK
Harris
Cancer and Blood Disorders, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404.|International Pleuropulmonary Blastoma Registry, Minneapolis, Minnesota 55404.
Gretchen M
GM
Williams
Washington University in St. Louis, St. Louis, Missouri 63130.
Louis P
LP
Dehner
Cancer and Blood Disorders, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404.|International Pleuropulmonary Blastoma Registry, Minneapolis, Minnesota 55404.
Yoav H
YH
Messinger
Division of Pathology and Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037.
D Ashley
DA
Hill
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20850.
Douglas R
DR
Stewart
D018263:Adenocarcinoma, Follicular / Q000453:epidemiology* / Q000235:genetics / Q000601:surgery; D000293:Adolescent; D000328:Adult; D002277:Carcinoma / Q000453:epidemiology* / Q000235:genetics / Q000601:surgery; D002291:Carcinoma, Papillary; D016022:Case-Control Studies; D015331:Cohort Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005190:Family; D005260:Female; D018095:Germ-Line Mutation; D006044:Goiter, Nodular / Q000000981:diagnostic imaging / Q000453:epidemiology* / Q000235:genetics / Q000601:surgery; D006801:Humans; D015994:Incidence; D008297:Male; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D015995:Prevalence; D043244:Ribonuclease III / Q000235:genetics*; D012306:Risk; D017422:Sequence Analysis, DNA; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000453:epidemiology* / Q000235:genetics / Q000601:surgery; D013965:Thyroidectomy / Q000706:statistics & numerical data; D014463:Ultrasonography; D055815:Young Adult
C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases