Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer

Zhaoming Wang; Carmen L. Wilson; John Easton; Andrew Thrasher; Heather Mulder; Qi Liu; Dale J. Hedges; Shuoguo Wang; Michael C. Rusch; Michael N. Edmonson; Shawn Levy; Jennifer Q. Lanctot; Eric Caron; Kyla Shelton; Kelsey Currie; Matthew Lear; Aman Patel; Celeste Rosencrance; Ying Shao; Bhavin Vadodaria; Donald Yergeau; Yadav Sapkota; Russell J. Brooke; Wonjong Moon; Evadnie Rampersaud; Xiaotu Ma; Ti Cheng Chang; Stephen V. Rice; Cynthia Pepper; Xin Zhou; Xiang Chen; Wenan Chen; Angela Jones; Braden Boone; Matthew J. Ehrhardt; Matthew J. Krasin; Rebecca M. Howell; Nicholas S. Phillips; Courtney Lewis; Deokumar Srivastava; Ching Hon Pui; Chimene A. Kesserwan; Gang Wu; Kim E. Nichols; James R. Downing; Melissa M. Hudson; Yutaka Yasui; Leslie L. Robison; Jinghui Zhang

doi:10.1200/JCO.2018.77.8589

Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer

Zhaoming Wang, Carmen L. Wilson, John Easton, Andrew Thrasher, Heather Mulder, Qi Liu, Dale J. Hedges, Shuoguo Wang, Michael C. Rusch, Michael N. Edmonson, Shawn Levy, Jennifer Q. Lanctot, Eric Caron, Kyla Shelton, Kelsey Currie, Matthew Lear, Aman Patel, Celeste Rosencrance, Ying Shao, Bhavin VadodariaDonald Yergeau, Yadav Sapkota, Russell J. Brooke, Wonjong Moon, Evadnie Rampersaud, Xiaotu Ma, Ti Cheng Chang, Stephen V. Rice, Cynthia Pepper, Xin Zhou, Xiang Chen, Wenan Chen, Angela Jones, Braden Boone, Matthew J. Ehrhardt, Matthew J. Krasin, Rebecca M. Howell, Nicholas S. Phillips, Courtney Lewis, Deokumar Srivastava, Ching Hon Pui, Chimene A. Kesserwan, Gang Wu, Kim E. Nichols, James R. Downing, Melissa M. Hudson, Yutaka Yasui, Leslie L. Robison, Jinghui Zhang

Radiation Physics

Research output: Contribution to journal › Article › peer-review

94 Scopus citations

Abstract

Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were $ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.

Original language	English (US)
Pages (from-to)	2078-2087
Number of pages	10
Journal	Journal of Clinical Oncology
Volume	36
Issue number	20
DOIs	https://doi.org/10.1200/JCO.2018.77.8589
State	Published - Jul 10 2018

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1200/JCO.2018.77.8589

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Wang, Z., Wilson, C. L., Easton, J., Thrasher, A., Mulder, H., Liu, Q., Hedges, D. J., Wang, S., Rusch, M. C., Edmonson, M. N., Levy, S., Lanctot, J. Q., Caron, E., Shelton, K., Currie, K., Lear, M., Patel, A., Rosencrance, C., Shao, Y., ... Zhang, J. (2018). Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer. Journal of Clinical Oncology, 36(20), 2078-2087. https://doi.org/10.1200/JCO.2018.77.8589

Wang, Z, Wilson, CL, Easton, J, Thrasher, A, Mulder, H, Liu, Q, Hedges, DJ, Wang, S, Rusch, MC, Edmonson, MN, Levy, S, Lanctot, JQ, Caron, E, Shelton, K, Currie, K, Lear, M, Patel, A, Rosencrance, C, Shao, Y, Vadodaria, B, Yergeau, D, Sapkota, Y, Brooke, RJ, Moon, W, Rampersaud, E, Ma, X, Chang, TC, Rice, SV, Pepper, C, Zhou, X, Chen, X, Chen, W, Jones, A, Boone, B, Ehrhardt, MJ, Krasin, MJ, Howell, RM, Phillips, NS, Lewis, C, Srivastava, D, Pui, CH, Kesserwan, CA, Wu, G, Nichols, KE, Downing, JR, Hudson, MM, Yasui, Y, Robison, LL & Zhang, J 2018, 'Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer', Journal of Clinical Oncology, vol. 36, no. 20, pp. 2078-2087. https://doi.org/10.1200/JCO.2018.77.8589

@article{1962413fd05c4fc18430b899eaea0687,

title = "Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer",

abstract = "Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were $ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.",

author = "Zhaoming Wang and Wilson, {Carmen L.} and John Easton and Andrew Thrasher and Heather Mulder and Qi Liu and Hedges, {Dale J.} and Shuoguo Wang and Rusch, {Michael C.} and Edmonson, {Michael N.} and Shawn Levy and Lanctot, {Jennifer Q.} and Eric Caron and Kyla Shelton and Kelsey Currie and Matthew Lear and Aman Patel and Celeste Rosencrance and Ying Shao and Bhavin Vadodaria and Donald Yergeau and Yadav Sapkota and Brooke, {Russell J.} and Wonjong Moon and Evadnie Rampersaud and Xiaotu Ma and Chang, {Ti Cheng} and Rice, {Stephen V.} and Cynthia Pepper and Xin Zhou and Xiang Chen and Wenan Chen and Angela Jones and Braden Boone and Ehrhardt, {Matthew J.} and Krasin, {Matthew J.} and Howell, {Rebecca M.} and Phillips, {Nicholas S.} and Courtney Lewis and Deokumar Srivastava and Pui, {Ching Hon} and Kesserwan, {Chimene A.} and Gang Wu and Nichols, {Kim E.} and Downing, {James R.} and Hudson, {Melissa M.} and Yutaka Yasui and Robison, {Leslie L.} and Jinghui Zhang",

year = "2018",

month = jul,

day = "10",

doi = "10.1200/JCO.2018.77.8589",

language = "English (US)",

volume = "36",

pages = "2078--2087",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "20",

}

TY - JOUR

T1 - Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer

AU - Wang, Zhaoming

AU - Wilson, Carmen L.

AU - Easton, John

AU - Thrasher, Andrew

AU - Mulder, Heather

AU - Liu, Qi

AU - Hedges, Dale J.

AU - Wang, Shuoguo

AU - Rusch, Michael C.

AU - Edmonson, Michael N.

AU - Levy, Shawn

AU - Lanctot, Jennifer Q.

AU - Caron, Eric

AU - Shelton, Kyla

AU - Currie, Kelsey

AU - Lear, Matthew

AU - Patel, Aman

AU - Rosencrance, Celeste

AU - Shao, Ying

AU - Vadodaria, Bhavin

AU - Yergeau, Donald

AU - Sapkota, Yadav

AU - Brooke, Russell J.

AU - Moon, Wonjong

AU - Rampersaud, Evadnie

AU - Ma, Xiaotu

AU - Chang, Ti Cheng

AU - Rice, Stephen V.

AU - Pepper, Cynthia

AU - Zhou, Xin

AU - Chen, Xiang

AU - Chen, Wenan

AU - Jones, Angela

AU - Boone, Braden

AU - Ehrhardt, Matthew J.

AU - Krasin, Matthew J.

AU - Howell, Rebecca M.

AU - Phillips, Nicholas S.

AU - Lewis, Courtney

AU - Srivastava, Deokumar

AU - Pui, Ching Hon

AU - Kesserwan, Chimene A.

AU - Wu, Gang

AU - Nichols, Kim E.

AU - Downing, James R.

AU - Hudson, Melissa M.

AU - Yasui, Yutaka

AU - Robison, Leslie L.

AU - Zhang, Jinghui

PY - 2018/7/10

Y1 - 2018/7/10

N2 - Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were $ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.

AB - Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were $ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.

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Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer

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