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Genetic predisposition for subsequent neoplasms common in pediatric cancer survivors
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Twelve percent of childhood cancer survivors harbored mutations that significantly increased their risk for developing subsequent neoplasms, according to a study presented at the American Association of Cancer Research Annual Meeting.
“The remarkable advances realized over the past 4 decades in the treatment and survival of pediatric cancer patients is one of the most notable success stories within the cancer field,” Leslie Robison, PhD, chair of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital in Memphis, Tennessee, said in a press release. “However, childhood cancer survivors are at increased risk for subsequent neoplasms, largely considered to be therapy related.”
Many forms of childhood cancer have cure rates of more than 80%, resulting in more than 400,000 long-term survivors of childhood cancer in the United States.
St. Jude’s research team, led by Robison and Zhaoming Wang, PhD, chair of the department of computational biology at St. Jude, explored the role of germline mutations in increased risk for secondary cancers, such as nonmelanoma skin cancer, meningioma, thyroid cancer and breast cancer.
Researchers analyzed data from 2,988 participants (53% male) who had survived childhood cancer for 5 years or longer. Of these individuals, 1,629 had leukemia/lymphoma, 332 had central nervous system tumors and 1,027 had other solid tumors.
Median follow-up was 28 years (range, 6-55).
A total of 1,117 subsequent neoplasms occurred in 434 survivors, 93 of whom were diagnosed with two or more histologically distinct subsequent neoplasms.
Overall, 25.5% of the survivors developed a subsequent neoplasm by age 45 years, most commonly basal cell carcinoma (542 cases in 153 survivors), meningioma (201 cases in 100 survivors), thyroid cancer (64 cases and survivors) and breast cancer (58 cases in 50 survivors).
Median age at subsequent neoplasm was 38.2 years and median time to first subsequent neoplasm was 29.2 years.
Moreover, 12% of the survivors carried a pathogenic or likely pathogenic mutation in one of the 156 genes associated with an increased risk for cancer. The most common mutations were in the genes of RB1, NF1, BRCA2, BRCA1 and TP53.
Results confirmed the association between cancer predisposition genes and specific diagnoses, include RB1 mutations in 32 of 41 of bilateral and seven of 57 unilateral retinoblastoma survivors. Out of 22 NF1 mutations, 20 occurred 332 CNS survivors; all four SUFU mutations occurred in medulloblastoma survivors; and all five WT1 mutations occurred in Wilms tumor survivors.
Among 1,326 survivors who had never received radiotherapy in childhood treatments, 54 developed 62 subsequent neoplasms. Fifteen of these (24.2%) occurred in survivors who carried a pathogenic or likely pathogenic mutation, who researchers found were nearly six times more likely to develop a subsequent neoplasm than survivors without these mutations (OR = 5.6; 95% CI, 2.6-12).
Further, the chance of developing two or more distinct histologic types of subsequent neoplasms increased by nearly 24-fold for survivors who did not receive radiotherapy but who harbored these mutations (OR = 23.6; 95% CI, 5.4-102.7).
Among 1,662 survivors who were exposed to radiotherapy, those with pathogenic or likely pathogenic mutations were twice as likely to develop two or more distinct histologic types of subsequent neoplasms than those who did not carry a mutation (OR = 2.3; 95% CI, 0.9-6).
“While these mutations put survivors or their children at higher risk for cancer in the future, they do not mean cancer is inevitable,” Wang said. “As we identify and understand more about germline mutations in cancer predisposition genes, we expect to find that genetics plays an even more substantial role in the life-long cancer risk of some survivors.”
Based on their findings, researchers estimate that more than 32,000 of the more than 400,000 childhood cancer survivors in the United States are at risk for second or third cancers because they carry mutations in known cancer predisposition genes.
“Our findings have immediate implications for the growing population of long-term survivors of childhood cancer,” said Robison, adding that a limitation of the study was its exclusion of childhood cancer survivors who had died of subsequent neoplasms or other chronic conditions related to pediatric cancer therapy.
“We are recommending that survivors of childhood cancer who develop specific types of subsequent neoplasms receive genetic counseling,” Robison said. “In addition, we believe that these findings will contribute to future decisions relating to recommendations for personalized therapeutic approaches based on genetic profiles for children who are newly diagnosed with cancer.” – by Chuck Gormley
Reference:
Wang Z, et al. Abstract 2306. Presented at: AACR Annual Meeting; April 1-5, 2017; Washington, D.C.
Disclosure: The American Lebanese Syrian Associated Charities and the NCI funded this study. The researchers report no relevant financial disclosures.
Perspective
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Survivors of childhood cancer are an important — and often overlooked — population of patients that continues to grow exponentially with improved cure rates. Childhood cancer survivors are vulnerable to a variety of medical complications, especially secondary neoplasms. The identification of a subset of childhood cancer survivors with germline variants at significant risk for secondary neoplasms independent of radiotherapy exposure gives this study great clinical relevance. The cumulative incidence of reported secondary neoplasms is like that previously reported by the Childhood Cancer Survivorship Study (CCSS). However, the current study may be subject to selection bias, especially because it includes patients with RB1 mutations that are known to increase the risk for secondary neoplasms; the CCSS did not include these patients.
One area to better understand is the finding of typically adult-onset cancer genes (eg, BRCA1, BRCA2) and the extent to which cancer treatment may have accelerated the risk for cancer in these patients. An omission from this study are reports of cancer family history, another important aspect of CPS diagnosis. It would be interesting to examine if a significant cancer family history in this high-risk cohort also correlated with increased secondary neoplasms. Regardless, this study contributes significant clinical and genomic data in an often-understudied population of patients, hopefully serving as a springboard for future research.
Reference:
Friedman DL, et al. J Natl Cancer Institute. 2010;doi:10.1092/jnci/djg238.
Luke Maese, DO
University of Utah
Joshua D. Schiffman, MD
University of Utah
Huntsman Cancer Institute
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