Childhood Cancer Survivors Found to Have Inherited Mutations Increasing Risk of the Disease

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Michael Walsh is a member of the research team at MSK’s Robert and Kate Niehaus Center for Inherited Cancer Genomics, which is using the latest in gene sequencing technologies to discover the inherited causes of cancer.

Summary

Pediatric cancer survivors are at an increased risk of developing a subsequent cancer. A new study shows that many of these patients carry inherited mutations in genes associated with cancer risk. Further research should clarify the relationship between these mutations and the occurrence of secondary cancers in this patient group.

With more than 400,000 pediatric cancer survivors alive in the United States today, there is an urgent need to understand who among them is at greater risk of developing a second cancer. Memorial Sloan Kettering has played a leadership role in this type of long-term follow-up care and monitoring, establishing a Long-Term Follow-Up Program for children and teenagers and a separate initiative for Adult Survivors of Pediatric Cancer to manage the health of these patients and screen them for new cancers.

A new study led by a team at St. Jude Children’s Research Hospital analyzed a large group of over 430 childhood cancer survivors and found that 25.5% developed a subsequent neoplasm (a growth that may be benign or cancerous) by age 45. The most common forms of these growths were non-melanoma skin cancer, meningioma (a type of brain tumor), thyroid cancer, and breast cancer.

Further, 12% of survivors had a germline, or inherited, mutation in one of 156 known genes associated with an increased risk of cancer, most commonly RB1, NF1, BRCA2, BRCA1, and TP53. Results were presented at the 2017 American Association for Cancer Research Annual Meeting.

We spoke with Michael Walsh, an MSK geneticist and pediatric oncologist, to learn more and to put the findings into context.

What is new with this study?

This is showing that there’s an enrichment of second cancers in patients with a germline predisposition to cancer. Researchers are describing the frequency of cancer predisposition gene mutations described in childhood cancer survivors.

It’s important to understand that correlation is not the same as causation. This group of patients was looked at for mutations in cancer predisposition genes. That does not necessarily mean that those cancer predisposition genes are driving the subsequent cancers. It means they’re at risk for other cancers, but we can’t say that risk is independent from whatever caused their pediatric cancer.

An RB gene mutation, we know, is linked with retinoblastoma, so that is an underpinning for pediatric cancer. We know that mutations in BRCA1 or BRCA2 are linked with breast cancer, which we are seeing more of in these patients in their adult years. But we can’t say that mutations in BRCA1 or BRCA2 are driving the pediatric cancers.

What is a key takeaway from this study — for both parents of current pediatric patients but also adult survivors of childhood cancer?

For anyone who is reading this study and is concerned about his or her personal or family history of cancer, I recommend first talking to a genetic counselor. A genetic counselor can discuss personalized screening recommendations, help you assess your individual risk of cancer, review the latest advances in cancer genetics and more.

For those who do test positive for a mutation that increases the risk of cancer, there are steps that can be taken. These individuals may need to undergo additional screening or consider reducing their risk through surgery. Again, though, seeing a genetic counselor would be the first step.

What research still needs to be done in this area?

We still need to know the link between cancers and mutations. So we may know that yes, a child has cancer and he or she has a mutation in a predisposition gene, but can we conclude that that mutation is predisposing that child to that cancer?

We also need to consider how frequently some of these gene mutations occur in an adult population. For instance, in this data set, 13 patients had a BRCA2 mutation. Would we have expected that kind of frequency based on family history alone? Would we have expected that kind of frequency in comparing against adult control datasets? These are questions that need to be answered.

Editors Note: Dr. Walsh is a member of the research team at MSK’s Robert and Kate Niehaus Center for Inherited Cancer Genomics, which is using the latest in gene sequencing technologies to discover the inherited causes of cancer. Under the leadership of Kenneth Offit, Chief of the Clinical Genetics Service, the Niehaus Center is using data from the MSK-IMPACT™ test — which looks for cancer genes in patients’ tumor samples as well as in their normal tissue — in addition to other advanced genomic techniques.  The ultimate goal is to develop new approaches for prevention as well as earlier detection and treatment of cancer.