Turner syndrome: fertility, familial clustering, and cancer risk.

study questionIs there an increased risk of reproductive or colon cancer in women with Turner syndrome and their family members? SUMMARY ANSWER: Our data suggest that there is an increased risk for sigmoid colon cancer in women with Turner syndrome and an increased prostate cancer risk in second- and third-degree male relatives. WHAT IS KNOWN ALREADY: Turner syndrome has been associated with lower risk of breast cancer, but increased risk of gonadoblastoma and colon cancer in some, but not all studies. There is also evidence for a genetic predisposition to sex chromosome aneuploidy, which may indicate a predisposition to Turner syndrome and the associated cancer risk in family members. STUDY DESIGN, SIZE, DURATION: The study was a retrospective case-control study of women with Turner syndrome diagnosed from 1995 to 2021, their relatives, and population subjects from Utah. PARTICIPANTS/MATERIALS, SETTING,

methodsWomen with Turner syndrome were identified using International Classification of Disease (ICD) codes in electronic medical records from two major Utah healthcare systems and reviewed for accuracy. Women with Turner syndrome were linked to genealogy in the Utah Population Database. Cancer diagnoses (breast, ovarian, endometrial, colon, testicular, and prostate) were determined for women with Turner syndrome and their relatives using the Utah Cancer Registry. Live births to women with Turner syndrome were identified by linked birth certificates. The relative risk of cancer in women with Turner syndrome and in relatives was estimated by comparison to population rates matched by age, sex, and birthplace. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 289 women with Turner syndrome. Sigmoid colon cancer was increased in women with Turner syndrome (OR [95% CI] 24.2 [2.9, 87.4]; P = 0.0032). There were 233 women with Turner syndrome who had at least three generations of genealogical data. There was an increased risk of Turner syndrome in first- (OR [95% CI] 18.08 [2.19, 65.32]; P = 0.0057) and second-degree relatives (9.62 [1.17, 34.74]; P = 0.019), although numbers were very small. There was an increased risk of prostate cancer in second- (1.8 [1.4, 2.2]; P < 0.001) and third-degree relatives (1.3 [1.1, 1.5]; P < 0.001). There was no increased risk of colon cancer in relatives. LIMITATIONS, REASONS FOR CAUTION: Based on the small number of sigmoid colon cancer cases, it is possible that our data have overestimated the colon cancer risk. Limitations include the identification of Turner syndrome by a diagnosis code in one of the two major health systems in Utah. The population is largely northern European with 9.3% of the women self-identified as Hispanic and 2.4% as Native American or multiple races. The results may not be generalizable to other populations. WIDER IMPLICATIONS OF THE

findingsOur data suggest that women with Turner syndrome may need early screening for colon cancer. Additional studies are needed to identify risk factors for sex chromosome aneuploidy and cancer risk in women with Turner syndrome and their male relatives. STUDY FUNDING/COMPETING INTEREST(S): The work in this publication was supported by R56HD090159 and R01HD099487 (C.K.W.). We also acknowledge partial support for the Utah Population Database through grant P30 CA2014 from the National Cancer Institute. The Utah Cancer Registry is funded by the National Cancer Institute's SEER Program, Contract No. HHSN261201800016I, the US Centers for Disease Control and Prevention's National Program of Cancer Registries, Cooperative Agreement No. NU58DP007131, with additional support from the University of Utah and Huntsman Cancer Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.