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Whole-Genome Sequencing May Help Identify Young Childhood Cancer Survivors at High Risk for Breast Cancer

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Key Points

  • Young childhood cancer survivors with high polygenic risk scores had 2.7 times greater risk of developing subsequent breast cancer compared to survivors in the lowest quintiles.
  • Survivors who carried pathogenic or likely pathogenic mutations, such as BRCA1, had 21.8 times increased risk for subsequent breast cancer compared with those survivors who did not have pathogenic or likely pathogenic mutations.
  • The polygenic risk score can be utilized with the rare mutations in clinical settings to enhance the identification of high-risk survivors for screening to enable the early detection and prevention of subsequent breast cancer.

Female survivors of childhood cancer, especially those treated with chest irradiation, have a substantially higher risk of developing breast cancer later in life. As a result, current clinical screening of this high-risk population relies primarily on the radiation dose and volume to the chest/breast tissue used to treat prior childhood cancer. A study aimed at assessing the genetic contributions to subsequent breast cancer risk among female childhood cancer survivors has found that those with a high polygenic risk score and/or carrying pathogenic or likely pathogenic mutations had 2.7 times the risk of developing breast cancer compared to survivors with a low polygenic risk score. The findings could inform personalized breast cancer risk and surveillance and early intervention in female cancer survivors. The study by Wang et al is published in Clinical Cancer Research.

Study Methodology

The researchers analyzed whole-genome sequencing data on 1,133 female cancer survivors of European ancestry enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) and germline mutations in breast cancer disposition genes were classified for pathogenicity. A polygenic risk score (PRS) was constructed for each survivor using 170 established common risk variants.

Relative rate (RR) and 95% confidence interval (CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression.

The median age of the survivors at their follow-up was 35.4 years.

Study Results

Of the 1,133 survivors analyzed, 47 were diagnosed with one or more subsequent breast cancers (median age at subsequent breast cancer was 40.3 years; range = 24.5–53.0). Adjusting for attained age, age at primary diagnosis, chest irradiation, doses of alkylating agents and anthracyclines, and genotype eigenvectors, RRs for survivors with PRS in the highest vs lowest quintiles were 2.7 (95% CI = 1.0–7.3), 3.0 (95% CI = 1.1–8.1), and 2.4 (95% CI = 0.1–81.1) for all survivors and survivors with and without chest irradiation, respectively.

Similar associations were observed after excluding carriers of pathogenic/likely pathogenic mutations in breast cancer predisposition genes. Notably, the PRS was associated with the subsequent breast cancer rate under the age of 45 years (RR = 3.2; 95% CI = 1.2–8.3).

“Genetic profiles comprised of small-effect common variants and large-effect predisposing mutations can inform personalized breast cancer risk and surveillance/intervention in female childhood cancer survivors,” concluded the study authors.

“The PRS can identify individuals with high breast cancer risk that do not carry known pathogenic mutations,” said lead study author Zhaoming Wang, PhD, Associate Member in the Department of Epidemiology and Cancer Control at St. Jude Children’s Research Hospital, in a statement. “Our results indicate that both polygenic determinants and large-effect rare mutations (monogenic determinants) contribute to the risk of subsequent breast cancer independently.”

Dr. Wang is the corresponding author of this study.

Funding for this study was provided by the American Lebanese Syrian Associated Charities and the National Institutes of Health. The study authors declared no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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