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Breast Cancer Risk Linked to Genetics, Treatment Exposures in Childhood Cancer Survivors

NEW YORK (GenomeWeb) – New research suggests that common and rare genetic variants — and past treatment exposures — can all contribute to breast cancer risk in women who survived cancer as a child.

As part of the St. Jude Lifetime Cohort Study, investigators from St. Jude Children's Research Hospital and other centers in the US and Canada used whole-genome sequencing to profile germline variants in more than 1,100 women of European ancestry who survived childhood cancer, searching for germline differences in the 47 women who were subsequently diagnosed with breast cancer.

As reported online this week in the journal Clinical Cancer Research, the team saw ties between breast cancer and the presence of pathogenic or likely pathogenic mutations falling in 11 known breast cancer risk genes. But its analyses also highlighted an over-representation in breast cancer cases diagnosed before the age of 45 in women with a high polygenic risk score (PRS) comprised of 170 common breast cancer risk variants.

"The PRS can identify individuals with high breast cancer risk that do not carry known pathogenic mutations," St. Jude computational biology researcher Zhaoming Wang, the study's first and corresponding author, said 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."

Although the cancers such as breast cancer appear to be more common in individuals who have survived a childhood cancer, the team explained, it is unclear whether these secondary cancers are a consequence of mutagenizing cancer treatments such as chemotherapy or chest irradiation, as suspected, or whether there are genetic contributors as well.

"Our current study attempts to investigate the contributions to the risk of subsequent breast cancer by considering the full picture of breast cancer genetic susceptibility," Wang said, "which includes common genetic variants with small effects (polygenic determinants) in addition to P/LP mutations (monogenic determinants)."

For their analyses, the researchers focused on 1,133 female childhood cancer survivors, including 47 women who were diagnosed with breast cancer at least once between the ages of 24 and 53 years old.

In the women with the top one-fifth of PRS scores, they reported, breast cancer occurred 2.7 times more often than in women falling in the lowest PRS group. But chest irradiation appeared to boost breast cancer risk as well: women with a history of high irradiation as children appeared even more likely to develop breast cancer than those with high scores on the polygenic risk model.

Breast cancer risk rose nearly twenty-twofold in individuals carrying pathogenic or likely pathogenic mutations in breast cancer-related genes such as BRCA1, BRCA2, TP53, and PTEN, the team explained.

"[W]e demonstrate that the rates of subsequent breast cancer are significantly increased for survivors with a higher PRS and/or carrying a [pathogenic/likely pathogenic] mutation, independent of prior chest irradiation and other clinical risk factors," the authors wrote.

In particular, Wang noted that the data "supports the hypothesis that genetic risk factors play a more important role in the development of subsequent breast cancers in younger women," though he cautioned that "this observed age-specific association could be partly due to the smaller sample size of older survivors in our study." 

"Our results indicate that personalized breast cancer surveillance strategies for survivors should incorporate prior exposure to specific anti-cancer treatments, the presence of [pathogenic/likely pathogenic] mutations, and the cumulative presence of small-effect common variants, as represented by a polygenic risk score," he said.