Author reply

Abstract

Our report concerned peculiarities in the epidemiologic distribution of thyroid carcinoma, which occurs excessively among Japanese but not white patients with Werner syndrome (WS). In addition to the difference by race, there are differences by age (younger patients), gender (fewer females), and cell type (much more follicular) in WS patients compared with a registry for thyroid carcinoma in the general population of Japan. All four follicular thyroid tumors studied had germline mutations in the C-terminal region, and the single papillary tumor studied was in the N-terminal region, possibly a genotype-phenotype relation. Based on three studies that were unavailable to us at the time of our study because the reports were not yet published, Dr. Monnat states that “ …many (and perhaps all) WS-associated WRN mutations are likely to be functionally equivalent null alleles.” Therefore, it is “unlikely that a different spectrum of WRN mutations alone explains the elevated risk of thyroid carcinoma in Japanese WS patients.” The speed of progress in molecular genetics rapidly can change the interpretation of durable clinical data, a foundation of our study. Until the functions of wild and mutant WRN proteins are understood fully, we keep open the possibility that different mutations may cause different phenotypes. The recently announced website for WRN mutations cited by Monnat should speed the resolution of these and other questions from clinical data regarding WS. Yuichi Ishikawa M.D.*, Haruo Sugano M.D.*, Robert W. Miller M.D. , Makoto Goto M.D. , * Department of Pathology, The Cancer Institute, Tokyo, Japan, Genetic Epidemiology Branch, National Cancer Institute, Bethesda, Maryland, Tokyo Metropolitan, Otsuka Hospital, Tokyo, Japan