According to the first large-scale whole-genome sequencing study on Childhood Cancer Survivors, approximately 12% of them have genetic mutations that put them or their children at risk for future cancers.
Previous studies include Second Primary Cancers in Survivors of Childhood Cancer, published in The Lancet in 2009, a registry-based report about a Nordic cohort of 47 697 childhood cancer survivors reported that “The overall risk of second primary cancers was 2·3-fold greater than that in the general population. In two large cohorts of 14 581 individuals who had survived for 5 years or more (USA, Childhood Cancer Survivor Study) and 16 541 who had survived for 3 years or more (UK, population-based study), the risk was reported to be 6·4-fold2 and 5·8-fold3 greater, respectively, than that in the general population.”
The findings from St. Jude Children’s Research Hospital’s latest whole genome sequencing of cancer survivors study was recently presented at the American Association for Cancer Research (AACR) 2017 Annual Meeting, and highlights the previously under-appreciated role that genetics plays in second neoplasms (SNs).
Dr Robison, from St. Jude Children’s Research Hospital, in Memphis, Tennessee, gave the following statement:
To date, the overwhelming evidence for SN risk has implicated therapeutic exposures.
While it has previously been recognized that genetic predisposition is an important risk factor in selected subgroups – for example, retinoblastoma patients with an RB1 mutation ― the contribution of mutations in cancer predisposition genes across the full population of childhood cancer survivors has not been studied.
Information obtained from a detailed family history, genetic-focused physical examination, and/or germline genetic testing can be used to advise on possible future risks of cancer, recommendations for appropriate screening and risk reduction, potential cancer risks for other family members, and family planning.
The analysis included 3007 childhood cancer survivors enrolled in the St. Jude’s Lifetime Cohort study, and in light of the findings, researchers recommend enhanced genetic screening and counselling for such patients. The mean age of the patients was 36 years. They had been treated between 1962 and 2010 and had survived childhood cancer for at least 5 years.
Whole-genome sequencing performed on 156 genes associated with elevated cancer risk, including 60 cancer predisposition genes, found that 11.5% of the cohort had a pathogenic or likely pathogenic mutation.
A total of 448 patients had already been diagnosed with a subsequent cancer (SC). Of these patients, 93 had been diagnosed with more than one, noted co-investigator Zhaoming Wang, PhD, also from St. Jude’s, who presented the findings.
Researchers estimate that “more than 32,000 of the more than 400,000 childhood cancer survivors in the US are at risk for second or even third cancers because they carry mutations in known cancer predisposition genes.”
Although such mutations do not always lead to cancer, survivors who carried high-risk mutations and had also received radiation therapy for paediatric cancer had more than an 11-fold increased risk of developing secondary breast cancer or sarcoma compared to frequency-matched community control persons (P < .001) and more than a fourfold increased risk for thyroid cancer (P = .02).
Survivors with high-risk mutations who had not received prior radiation had a sevenfold increased risk for breast cancer (P = .004) and a 4.6-fold increased risk for any SN (P < .001).
Among survivors with high-risk mutations, risk for multiple SNs was increased 11.5-fold among patients who had undergone radiation therapy (P = .002); it was increased 2.5-fold for patients who had not received radiation (P = .04).
Dr Robison went on to say: “We feel that at this point, our data are able to identify the high-risk groups within the paediatric cancer survivor population (i.e., those with an SN without radiation and those with specific types of SN that occur within a radiation field).
Given that approximately 80% of cases do not have a mutation, we feel that at this point we cannot recommend that all patients receive genetic counselling unless there are other indications, such as a family history or indications of a genetic syndrome,”
Dr John M. Maris, MD, professor of paediatrics at the University of Pennsylvania’s Perelman School of Medicine, in Philadelphia, who was not involved in the study but was asked to comment, said:
“This is a very important study that further refines our understanding of why children develop cancer in the first place, but also why survivors may be at increased risk for a subsequent new malignancy.
The fact that 11.5% of survivors may be at a significantly increased risk is sobering, but even more worrisome is that this study may be the proverbial tip of the iceberg, as they have not yet analyzed the majority of the genome, so we will be looking forward to follow-up reports from this group.”