Lindsay M. Morton, PhD
Chest radiotherapy to treat a childhood cancer is a well-established risk factor for developing breast cancer in adulthood, and now a study has unearthed two specific genetic variants which may be used to more precisely stratify which survivors may face the highest risk.
The specific variants were found to increase breast cancer risk only in women who received 10 or more Gy of chest radiotherapy, reported Lindsay M. Morton, PhD, a senior investigator with the National Cancer Institute’s Radiation Epidemiology Branch, at the 2016 AACR Annual Meeting held April 16-20 in New Orleans.
A variant at position q41 on chromosome 1 was associated with nearly a 2-fold increase in risk, Morton said, and one at position q23 on chromosome 11 was associated with a nearly 3-fold increased risk for each copy of the risk alleles. These variants did not increase breast cancer risk in survivors who had not received radiotherapy to the chest as part of their cancer treatment, however.
Morton said the findings, if elucidated and confirmed in subsequent studies, have the potential to impact cancer and survivorship care for the nation’s growing number of childhood cancer survivors, currently estimated to number 420,000—particularly the women among them.
“This is the first study that provides evidence that germline genetics outside the context of high-risk syndromes can modify the risk for breast cancer in childhood cancer survivors treated with chest radiation therapy,” said Morton. “In addition, for patients who have already been treated, the results could be used to identify the survivors who have the highest risks of developing breast cancer and therefore might benefit the most from screening.”
Morton and colleagues conducted genomic DNA analyses of more than 3400 blood or saliva samples drawn from 2 large groups of childhood cancer survivors who had been followed for a median 25 years: the Childhood Cancer Survivor Study, which includes children diagnosed with cancer between 1970 and 1986 from 26 participating institutions, and the St. Jude Lifetime Cohort, which includes children diagnosed between 1962 and 2001, all of whom were treated at St. Jude’s. Morton said the two cohorts were data-rich, because germline DNA had been collected and access to the survivors’ medical treatment records were available.
Of the 207 breast cancer cases diagnosed across the 2 cohorts, the majority (65%) had Hodgkin lymphoma as their first primary childhood cancer, 10% had leukemia, and the remaining had a mix of other childhood cancer types.
Nearly 17 million high-quality genotyped or imputed variants were available across both of the study cohorts, and investigators compared the genotypes for survivors who developed breast cancer with those who did not.
“About two-thirds of the cases had at least 10 Gy of radiation to their breasts during the course of their childhood cancer radiotherapy,” Morton noted. She added that the median age of breast cancer diagnosis in the population was 39. “These are breast cancer cases that are being seen at a much younger age than you would see in the general population.”
Morton explained the mechanisms behind the two single nucleotide polymorphisms (SNPs, or “snips”) found to be implicated in increasing breast cancer risk in the ≥10 Gy group. The chromosome 1 marker, PROX1, is involved in embryonic development, cellular proliferation, and migration, and alterations are present in about 13% of breast tumor cells, Morton said. The chromosome 11 marker, TAGLN, is involved in cellular migration and is overexpressed in breast tumors compared with normal breast tissue.
“Our top association was for a marker on chromosome 1q41 … there was a very significant difference in the genotype distribution at this particular location among the childhood cancer survivors who developed breast cancer compared with those who did not,” said Morton. “The relative risk for developing breast cancer was nearly 2-fold for each copy of the risk allele … but there was no effect on risk among childhood cancer survivors who had not received chest radiotherapy.”
Similar results were seen for the marker on chromosome 11q23, Morton noted, but “unlike the chromosome 1 snip, which was a relatively common one, the chromosome 11 snip was a relative rare marker,” only present in 2% to 3% of controls. This snip conferred about a 2.6-fold increased risk for breast cancer, again restricted to those childhood cancer survivors who had received at least 10 Gy of radiation to the breast, Morton continued.
Morton cautioned that, because they were generated in a “discovery” study, these early findings will require replication before evaluation in the clinic. “The road ahead will be long, winding, and a little bit of an uphill climb,” she said.