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Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors.

ABSTRACT: Purpose: Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants, we analyzed germline and SMN samples from pediatric cancer survivors.Experimental Design: We performed whole-exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors. To assess the frequency of germline TP53 variants in SMNs, Sanger sequencing was performed to analyze germline TP53 in 37 pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) without any history of a familial cancer predisposition syndrome but known to have developed SMNs.Results: WES revealed TP53 mutations involving p53's DNA-binding domain in both index cases, one of which was also present in the germline. The germline and somatic TP53-mutant variants were enriched in the transcriptomes for both sarcomas. Analysis of TP53-coding exons in germline specimens from the CCSS survivor cohort identified a G215C variant encoding an R72P amino acid substitution in 6 patients and a synonymous SNP A639G in 4 others, resulting in 10 of 37 evaluable patients (27%) harboring a germline TP53 variant.Conclusions: Currently, germline TP53 is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germline TP53 variants at the time a primary cancer is diagnosed may identify patients at high risk for SMN development, who could benefit from modified therapeutic strategies and/or intensive posttreatment monitoring. Clin Cancer Res; 23(7); 1852-61. ©2016 AACR.

SUBMITTER: Sherborne AL

PROVIDER: S-EPMC5570538 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors.

Sherborne Amy L AL Lavergne Vincent V Yu Katharine K Lee Leah L Davidson Philip R PR Mazor Tali T Smirnoff Ivan V IV Horvai Andrew E AE Loh Mignon M DuBois Steven G SG Goldsby Robert E RE Neglia Joseph P JP Hammond Sue S Robison Leslie L LL Wustrack Rosanna R Costello Joseph F JF Nakamura Alice O AO Shannon Kevin M KM Bhatia Smita S Nakamura Jean L JL

Clinical cancer research : an official journal of the American Association for Cancer Research 20160928 7

Purpose: Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants, we analyzed germline and SMN samples from pediatric cancer survivors.Experimental Design: We performed whole-exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising fro ...[more]

PMID: 27683180

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Project description:ImportanceAlthough the increased incidence of second primary malignant neoplasms (SPMs) is a well-known late effect after cancer, few studies have compared survival after an SPM to survival of the same cancer occurring as first primary malignant neoplasm (PM) by age.ObjectiveTo assess the survival impact of SPMs in adolescents and young adults (AYAs) (15-39 years) compared with that of pediatric (<15 years) and older adult (?40 years) patients with the same SPMs.Design, setting, and participantsThis was a population-based, retrospective cohort study of patients with cancer in 13 Surveillance, Epidemiology and End Results regions in the United States diagnosed from 1992 to 2008 and followed through 2013. Data analysis was performed between June 2016 and January 2017.Main outcomes and measuresFive-year relative survival was calculated overall and for each cancer occurring as a PM or SPM by age at diagnosis. The impact of SPM status on cancer-specific death was examined using multivariable Cox proportional hazards regression.ResultsA total of 15?954 pediatric, 125?750 AYAs, and 878?370 older adult patients diagnosed as having 14 cancers occurring as a PM or SPM were included. Overall, 5-year survival after an SPM was 33.1% lower for children, 20.2% lower for AYAs, and 8.3% lower for older adults compared with a PM at the same age. For the most common SPMs in AYAs, the absolute difference in 5-year survival was 42% lower for secondary non-Hodgkin lymphoma, 19% for secondary breast carcinoma, 15% for secondary thyroid carcinoma, and 13% for secondary soft-tissue sarcoma. Survival by SPM status was significantly worse in younger vs older patients for thyroid, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, soft-tissue sarcoma, and central nervous system cancer. Adolescents and young adults with secondary Hodgkin lymphoma (hazard ratio [95% CI], 3.5 [1.7-7.1]); soft-tissue sarcoma (2.8 [2.1-3.9]); breast carcinoma (2.1 [1.8-2.4]); acute myeloid leukemia (1.9 [1.5-2.4]); and central nervous system cancer (1.8 [1.2-2.8]) experienced worse survival compared with AYAs with the same PMs.Conclusion and relevanceThe adverse impact of SPMs on survival is substantial for AYAs and may partially explain the relative lack of survival improvement in AYAs compared with other age groups. The impact of a particular SPM diagnosis on survival may inform age-specific prevention, screening, treatment, and survivorship recommendations.

Project description:ImportanceDetailed data describing the epidemiology of second malignant neoplasms (SMN) are needed for survivors of adolescent and young adult (AYA) cancer to inform the development of age-appropriate survivorship care guidelines.ObjectiveTo describe the incidence, risk factors, and mortality for SMN in survivors of AYA cancer.Design, setting, and participantsThis retrospective matched cohort study included 10 574 two-year survivors diagnosed with cancer between January 1, 1990, and December 31, 2012, at age 15 to 39 years in an integrated health care delivery system in Southern California. A comparison cohort without a history of cancer was individually matched 13:1 to survivors of AYA cancer by age, sex, and calendar year. Data analysis was completed in July 2018.ExposuresSecondary malignant neoplasm risk factors of interest included age, stage, and calendar year at first cancer diagnosis; sex; race/ethnicity; radiation therapy; and chemotherapy.Main outcomes and measuresDiagnoses of SMN were ascertained using cancer registries from the National Cancer Institute Surveillance, Epidemiology, and End Results Program through December 31, 2014. Poisson regression was used to evaluate the association between cancer survivor status and developing SMN and risk factors for SMN, while risk of all-cause mortality by SMN status was examined in Cox regression.ResultsA total of 10 574 survivors of AYA cancer (6853 [64.8%] female; median [range] age, 33 [15-39] years; 622 with SMN) and 136 683 participants in the comparison cohort (88 513 [64.8%] female; median [range] age, 33 [15-39] years; 3437 with first cancer) were included. In survivors of AYA cancer, 20-year cumulative incidence of SMN was 12.5%. The incidence rate ratio (IRR) of developing SMN in survivors of AYA cancer was 2.6 (95% CI, 2.4-2.9) compared with the comparison cohort. Survivors of breast cancer, melanoma, and testicular cancer had substantially elevated risk for SMN of the same organ (IRR, 5.6 [95% CI, 4.6-6.8], 11.2 [95% CI, 7.3-17.2], and 16.2 [95% CI, 6.8-38.4], respectively). Among survivors of AYA cancer, older age (IRR for age 30-39 years, 1.79 [95% CI, 1.21-2.65]), female sex (IRR, 1.31 [95% CI, 1.09-1.57]), white race/ethnicity (IRR for Asian race, 0.61 [95% CI, 0.43-0.87]), advanced stage at first cancer diagnosis (IRR for stage II, 1.29 [95% CI, 1.11-1.65]), and use of radiotherapy (IRR, 1.50 [95% CI, 1.26-1.79]) were associated with increased risk of SMN. Survivors of AYA cancer who developed SMN had an all-cause mortality rate 7.2 (95% CI, 6.1-8.5) times greater than survivors without SMN.Conclusions and relevanceThis study suggests that SMN risk is elevated in survivors of AYA cancer and varies across survivor subgroups. Survival following SMN may be significantly compromised. These data may form the basis for identifying individuals at high risk, as well as informing screening for SMN.

Project description:ImportanceRadiotherapy is a common treatment for rectal cancer, yet the risk of second gynecological malignant neoplasms (SGMNs) in patients with rectal cancer undergoing radiotherapy have not been adequately studied.ObjectiveTo investigate the association between radiotherapy and the risk of individual types of SGMN in patients with rectal cancer and assess survival outcomes.Design, setting, and participantsA large population-based cohort study was designed to identify the risk of SGMNs in patients with rectal cancer diagnosed from January 1973 to December 2015. The statistical analysis was conducted from September 2019 to April 2020. The study was based on the 9 cancer registries of Surveillance, Epidemiology, and End Results database. A total of 20 142 female patients with rectal cancer in localized and regional stage were included.ExposureReceipt of neoadjuvant radiotherapy for rectal cancer.Main outcomes and measuresThe development of an SGMN defined as any type of GMN occurring more than 5 years after the diagnosis of rectal cancer. The cumulative incidence of SGMNs was estimated by Fine-Gray competing risk regression. Poisson regression was used to evaluate the radiotherapy-associated risk for SGMNs in patients undergoing radiotherapy vs patients not undergoing radiotherapy. The Kaplan-Meier method was used to assess the survival outcomes of patients with SGMNs.ResultsOf 20 142 patients, 16 802 patients (83.4%) were White and the median age was 65 years (interquartile range, 54-74 years). A total of 5310 (34.3%) patients were treated with surgery and radiotherapy, and 14 832 (65.7%) patients were treated with surgery alone. The cumulative incidence of SGMNs during 30 years of follow-up was 4.53% among patients who received radiotherapy and 1.53% among patients who did not. In competing risk regression analysis, undergoing radiotherapy was associated with a higher risk of developing cancer of the uterine corpus (adjusted hazard ratio, 3.06; 95% CI, 2.14-4.37; P < .001) and ovarian cancer (adjusted hazard ratio, 2.08; 95% CI, 1.22-3.56; P = .007) compared with those who did not receive radiotherapy. The dynamic radiotherapy-associated risks (RR) for cancer of the uterine corpus significantly increased with increasing age at rectal cancer diagnosis (aged 20-49 years: adjusted RR, 0.79; 95% CI, 0.35-1.79; P = .57; aged 50-69 years: adjusted RR, 3.74; 95% CI, 2.63-5.32; P < .001; aged ≥70 years: adjusted RR, 5.13; 95% CI, 2.64-9.97; P < .001) and decreased with increasing latency since rectal cancer diagnosis (60-119 months: adjusted RR, 3.22; 95% CI, 2.12-4.87; P < .001; 120-239 months: adjusted RR, 2.72; 95% CI, 1.75-4.24; P < .001; 240-360 months: adjusted RR, 1.95; 95% CI, 0.67-5.66; P = .22), but the dynamic RR for ovarian cancer increased with increasing latency since rectal cancer diagnosis (60-119 months: adjusted RR, 0.70; 95% CI, 0.26-1.89; P = .48; 120-239 months: adjusted RR, 2.26; 95% CI, 1.09-4.70; P = .03; 240-360 months: adjusted RR, 11.84; 95% CI, 2.18-64.33; P = .004). The 10-year overall survival among patients with radiotherapy-associated cancer of the uterine corpus was significantly lower than that among matched patients with primary cancer of the uterine corpus (21.5% vs 33.6%; P = .01).Conclusions and relevanceRadiotherapy for rectal cancer was associated with an increased risk of cancer of the uterine corpus and ovarian cancer. Special attention should be paid to reduce radiotherapy-associated SGMNs and improve their prognosis.

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Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors.

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Somatic and Germline <i>TP53</i> Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors.

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