دورية أكاديمية

Rare inactivating PDE11A variants associated with testicular germ cell tumors.

التفاصيل البيبلوغرافية
العنوان: Rare inactivating PDE11A variants associated with testicular germ cell tumors.
المؤلفون: Pathak, Anand, Stewart, Douglas R., Faucz, Fabio R., Xekouki, Paraskevi, Bass, Sara, Vogt, Aurelie, Xijun Zhang, Boland, Joseph, Yeager, Meredith, Loud, Jennifer T., Nathanson, Katherine L., McGlynn, Katherine A., Stratakis, Constantine A., Greene, Mark H., Mirabello, Lisa
المصدر: Endocrine-Related Cancer; Dec2015, Vol. 22 Issue 6, p909-917, 9p
مصطلحات موضوعية: TESTICULAR cancer, GERM cell tumors, PHOSPHODIESTERASES, MISSENSE mutation, RNA splicing
مستخلص: Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer. Testicular tissue is unique in expressing all four isoforms of PDE11A. In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk. To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls. We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic. Ten missense variants were novel; nine occurred in transcript variant 4 and one in transcript variant 3. Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (PZ0.0037). The latter two novel variants were functionally characterized and shown to be functionally inactivating, resulting in reduced PDE activity and increased cAMP levels. In further analysis of this cohort, we focused on white participants only to minimize confounding due to population stratification. This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk. [ABSTRACT FROM AUTHOR]
Copyright of Endocrine-Related Cancer is the property of Bioscientifica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
قاعدة البيانات: Complementary Index
الوصف
تدمد:13510088
DOI:10.1530/ERC-15-0034