March 04, 2019
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Genetic factors influence breast cancer risk after radiotherapy for Hodgkin lymphoma

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Genetic factors influence the risk for breast cancer in women who received radiotherapy for Hodgkin lymphoma, according to results of a case-only analysis published in Blood.

“Women who are treated at young ages with chest radiotherapy for Hodgkin lymphoma have a 5 to 20 times increased risk [for] breast cancer compared with the general population,” Annemieke W.J. Opstal-van Winden, PhD, epidemiologist at Netherlands Cancer Institute, and colleagues wrote. The risk [for] radiotherapy-induced breast cancer rises with increasing radiation dose and volume, but not all female Hodgkin lymphoma survivors treated with a high-dose, high-volume radiotherapy develop breast cancer. However, variation in risk may also be due to genetic factors. The high risk [for] breast cancer in this population provides an excellent opportunity to investigate the genetic basis for differential sensitivity to radiation carcinogenesis.”

The analysis by Opstal-van Winden and colleagues included 327 patients with breast cancer who underwent chest radiotherapy for Hodgkin lymphoma (median age at diagnosis, 45 years; range, 24-76) and 4,671 patients with first primary breast cancer (median age at diagnosis, 46 years; range, 22-84). Overall, researchers looked at 211,155 germline single nucleotide polymorphisms for gene-radiation interaction on breast cancer risk.

Nine SNPs had statistically significant interaction with radiotherapy on breast cancer risk, and one of those in the PVT1 oncogene achieved the Bonferroni threshold for statistical significance.

In the second step of the study, researchers conducted a nested case-control analysis that included the chest-irradiated patients with breast cancer and 491 chest-irradiated patients without breast cancer who served as Hodgkin lymphoma controls.

Median interval between Hodgkin lymphoma and diagnosis of breast cancer was 24 years (range, 9-46). Median follow-up for Hodgkin lymphoma controls was 30 years (range, 9-49).

Most Hodgkin lymphoma cases and controls (87%) received mantle field irradiation. Another 11% underwent mediastinal radiotherapy without axillary node radiotherapy.

About 50% of the patients with breast cancer after Hodgkin lymphoma, as well as 60% of the Hodgkin lymphoma controls, received chemotherapy and radiotherapy for Hodgkin lymphoma.

Researchers evaluated polygenic risk scores based on the nine radiotherapy-interacting SNPs.

Results showed that patients in the highest tertile of the radiotherapy-interaction polygenic risk score had a risk for breast cancer 1.6 times higher than patients in the lowest tertile.

Further, patients in the highest decile of the breast cancer polygenic risk score had a fourfold increased risk for radiotherapy-induced breast cancer than patients in the lowest decile.

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The risk for breast cancer increased 1.4-fold per standard deviation of the breast cancer polygenic risk score, which is similar to the effect size found in the general population.

The study populations for the analysis of the radiotherapy-interaction polygenic risk score were not independent, which researchers cited as a limitation to this study.

“These results indicate that the effects of radiation exposure and common susceptibility variants, summarized in the polygenic risk score, combine approximately multiplicatively,” Opstal-van Winden and colleagues wrote. “Given the high absolute breast cancer risk in radiation-exposed women, these results have important implications for their management.” – by John DeRosier

Disclosures: The Dutch Cancer Society funded this study. The researchers report no relevant financial disclosures.