Risk of differential cancer types over age in families with Li-Fraumeni syndrome: a validation study using multi-center cohorts

Shin, S. J.; Dodd, E.; Peng, G.; Bojadzieva, J.; Chen, J.; Amos, C.; Mai, P. L.; Savage, S. A.; Ballinger, M. L.; Thomas, D. M.; yuan, Y.; Strong, L. C.; Wang, W.

doi:10.1101/567727

bioRxiv · 10.1101/567727

Risk of differential cancer types over age in families with Li-Fraumeni syndrome: a validation study using multi-center cohorts

Shin, S. J.·Dodd, E.·Peng, G.·Bojadzieva, J.·Chen, J.·Amos, C.·Mai, P. L.·Savage, S. A.·Ballinger, M. L.·Thomas, D. M.·yuan, Y.·Strong, L. C.·Wang, W.

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Abstract

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome associated with an autosomal dominant mutation inheritance in the TP53 tumor suppressor gene and a wide spectrum of cancer diagnoses. An accurate estimation of the penetrance of different cancer types in LFS is crucial to improve the clinical characterization and management of high-risk individuals of LFS. Our competing risk-based statistical model incorporates the pedigree structure efficiently into the penetrance estimation and corrects for the ascertainment bias. A set of TP53 penetrance for three cancer types (breast, BR/sarcoma, SA/others, OT) involved in LFS is then estimated from 186 pediatric-sarcoma families collected at MD Anderson Cancer Center. The penetrance was then validated on a mixed cohort of clinically ascertained families with cancer (total number of families=668). The age-dependent onset probability distributions of specific cancer types are different. For breast cancer, the TP53 penetrance goes up at an earlier age than the reported BRCA1/2 penetrance. We validated the prediction performance of the penetrance estimates via two independent cohorts combined (BR=85, SA=540, OT=158). We obtained areas under the ROC curves (AUCs) of 0.92 (BR), 0.75 (SA), and 0.81 (OT). Our R package, LFSPRO, provides risk estimates for the diagnosis of breast cancer, sarcoma, other cancers or death before cancer diagnosis in future.\n\nSignificanceCancer-specific penetrance can facilitate clinical characterization of LFS and will contribute to the management of families at high risk of LFS.

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Shin, S. J., Dodd, E., Peng, G., Bojadzieva, J., Chen, J., Amos, C., Mai, P. L., Savage, S. A., Ballinger, M. L., Thomas, D. M., yuan, Y., Strong, L. C., Wang, W.. 2019-03-05. Risk of differential cancer types over age in families with Li-Fraumeni syndrome: a validation study using multi-center cohorts. https://doi.org/10.1101/567727

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