CHILDHOOD CANCER SURVIVORS GENETICS

Almost 12% of childhood cancer survivors have genetic mutations that put them – or their children – at risk for future cancers, according to the first large-scale whole-genome sequencing study in this patient population.

The study, presented here at the American Association for Cancer Research (AACR) 2017 Annual Meeting, highlights the previously underappreciated role that genetics plays in second neoplasms (SNs), study investigator Les Robison, PhD, told Medscape Medical News.

"To date, the overwhelming evidence for SN risk has implicated therapeutic exposures," explained Dr Robison, from St. Jude Children's Research Hospital, in Memphis, Tennessee.

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," he said.

In light of their findings, the researchers recommend enhanced genetic screening and counseling for such patients.

"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," said Dr Robison.

The analysis included 3007 childhood cancer survivors enrolled in the St. Jude's Lifetime Cohort study.

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 coinvestigator Zhaoming Wang, PhD, also from St. Jude's, who presented the findings.

The 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 pediatric 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).

"We feel that at this point, our data are able to identify the high-risk groups within the pediatric cancer survivor population (ie, 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 counseling unless there are other indications, such as a family history or indications of a genetic syndrome," said Dr Robison.

Asked to comment on the findings, John M. Maris, MD, who was not involved in the research, told Medscape Medical News: "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."

Dr Maris, who is professor of pediatrics at the University of Pennsylvania's Perelman School of Medicine, in Philadelphia, added: "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."

This study was funded by the American Lebanese Syrian Associated Charities and by the National Cancer Institute. The authors have disclosed no relevant financial relationships. Dr Maris has had relationships with Novartis and GlaxoSmithKline.

American Association for Cancer Research (AACR) 2017 Annual Meeting. Abstract 3001, presented April 3, 2017.