TY - JOUR
T1 - Penetrance estimates over time to first and second primary cancer diagnosis in families with Li-Fraumeni syndrome
T2 - A single institution perspective
AU - Shin, Seung Jun
AU - Dodd-Eaton, Elissa B.
AU - Gao, Fan
AU - Bojadzieva, Jasmina
AU - Chen, Jingxiao
AU - Kong, Xianhua
AU - Amos, Christopher I.
AU - Ning, Jing
AU - Strong, Louise C.
AU - Wang, Wenyi
N1 - Funding Information:
S.J. Shin, E.B. Dodd-Eaton, and W. Wang were supported in part by the Cancer Prevention Research Institute of Texas through grant number RP130090. S.J. Shin was supported in part by National Research Foundation of Korea funded by the Korea government (MSIT) through grant number 2019R1A4A1028134. E.B. Dodd-Eaton and W. Wang were supported in part by the U.S. NCI through grant numbers 1R01 CA183793, 1R01 CA174206, and 2R01 CA158113. W. Wang is supported in part by U.S. NCI grant P30CA016672. F. Gao and J. Chen are supported by U.S. NCI 1R01 CA183793. J. Bojadzieva, X. Kong, and L.C. Strong were supported in part by the U.S. NIH through grant P01CA34936. J. Ning was funded in part by the NCI R01 (R01CA193878) and the Andrew Sabin Family Fellowship. C.I. Amos was supported by the U.S. NCI 1U01CA196386, CA196386S1, and 1R01CA186566. C.I. Amos would also like to thank the CPRIT RR170048 grant and the U.S. NCI U19CA203654 and U19CA203654S1 grants for their additional funding. We thank Dr. Jialu Li for his contribution to this project and Dr. Banu Arun and Jessica Ross for their helpful comments.
Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2020/1/15
Y1 - 2020/1/15
N2 - Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging because of limited data and the difficulty of characterizing the effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach that incorporates a family-wise likelihood to efficiently integrate the pedigree structure, we estimated the penetrance for both first and second primary cancer diagnosis from a pediatric sarcoma cohort at MD Anderson Cancer Center [MDACC, Houston, TX; number of families ¼ 189; single primary cancer (SPC) ¼ 771; and MPC ¼ 87]. Validation of the risk prediction performance was performed using an independent MDACC clinical cohort of TP53 tested individuals (SPC ¼ 102 and MPC ¼ 58). These findings showed that an individual diagnosed at a later age was more likely to be diagnosed with a second primary cancer. In addition, TP53 mutation carriers had a HR of 1.65 (95% confidence interval, 1.1–2.5) for developing a second primary cancer versus SPC. The area under the ROC (AUC) curve for predicting individual outcomes of MPC versus SPC was 0.77. In summary, we provide the first set of penetrance estimates for first and second primary cancer for TP53 germline mutation carriers and demonstrate its accuracy for cancer risk assessment. Significance: These findings present an open-source R package LFSPRO that could be used for genetic counseling and health management of individuals with LFS as it estimates the risk of both first and second primary cancer diagnosis.
AB - Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging because of limited data and the difficulty of characterizing the effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach that incorporates a family-wise likelihood to efficiently integrate the pedigree structure, we estimated the penetrance for both first and second primary cancer diagnosis from a pediatric sarcoma cohort at MD Anderson Cancer Center [MDACC, Houston, TX; number of families ¼ 189; single primary cancer (SPC) ¼ 771; and MPC ¼ 87]. Validation of the risk prediction performance was performed using an independent MDACC clinical cohort of TP53 tested individuals (SPC ¼ 102 and MPC ¼ 58). These findings showed that an individual diagnosed at a later age was more likely to be diagnosed with a second primary cancer. In addition, TP53 mutation carriers had a HR of 1.65 (95% confidence interval, 1.1–2.5) for developing a second primary cancer versus SPC. The area under the ROC (AUC) curve for predicting individual outcomes of MPC versus SPC was 0.77. In summary, we provide the first set of penetrance estimates for first and second primary cancer for TP53 germline mutation carriers and demonstrate its accuracy for cancer risk assessment. Significance: These findings present an open-source R package LFSPRO that could be used for genetic counseling and health management of individuals with LFS as it estimates the risk of both first and second primary cancer diagnosis.
UR - http://www.scopus.com/inward/record.url?scp=85077927513&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-0725
DO - 10.1158/0008-5472.CAN-19-0725
M3 - Review article
C2 - 31719099
AN - SCOPUS:85077927513
SN - 0008-5472
VL - 80
SP - 347
EP - 353
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -