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Uterine Leiomyoma, Breast Cancer Cross-Trait Analysis Uncovers Genetic Ties

NEW YORK — A new study has found that uterine leiomyoma (UL) and breast cancer have a shared genetic basis and pointed to a possible causal link between UL and estrogen receptor-positive (ER+) breast cancer.

Previous epidemiological and other studies have suggested that UL, also known as fibroids, which are benign tumors, and breast cancer have a shared etiology and that women with UL may have an increased risk of developing breast cancer.

Using data from previously performed genome-wide association studies, researchers from Sichuan University in China conducted a global genetic correlation analysis between UL and breast cancer. As they reported in the American Journal of Human Genetics on Thursday, they found a significant genetic correlation between UL and breast cancer, particularly ER+ breast cancer. They additionally uncovered genetic loci that contribute to risk of both UL and breast cancer, including nine novel loci, and found that genetically predicted UL had a causal effect on the development of ER+ breast cancer.

"Our findings highlight an intrinsic link underlying these two complex female diseases and shed new light on the biological mechanisms; these findings might provide important directions for future therapeutic strategy as well as risk prediction," co-senior author Xia Jiang from Sichuan University and colleagues wrote in their paper.

For their analysis, the researchers combined data from a 2019 GWAS meta-analysis of UL that encompassed 8.7 million variants in 35,474 women with UL and 267,505 without the condition, as well as from a 2020 GWAS meta-analysis of 10.8 million variants in 133,384 women with breast cancer and 113,789 controls. They further examined data from a 2017 study of 69,501 women with ER+ breast cancer, 21,468 women with ER- breast cancer, and 105,974 women without breast cancer.

By using linkage disequilibrium score regression, the researchers uncovered a significant positive genetic correlation between UL and breast cancer overall and an even stronger correlation between UL and ER+ breast cancer. The correlation between UL and ER- breast cancer, however, was not significant.

They further homed in on certain genomic regions that were linked to this correlation, including at 22q13.1. This region includes TNRC6B and CBX7, genes that have been linked to tumorigenesis and poor prognosis in ovarian cancer, respectively.

At the gene level, they further uncovered 29 loci shared between UL and all types of breast cancer, 17 shared between UL and ER+ breast cancer, and 14 that UL and ER- breast cancer had in common. Some of these shared loci were located near known oncogenes like TERT, TNRC6B, and TP53.

After excluding SNPs in linkage disequilibrium, the researchers teased out nine novel pleiotropic loci between UL and breast cancer. The most significant one was near CDKN1A, which encodes a cell cycle regulator, followed by one near PTPN11, which encodes a member of the protein tyrosine phosphatase family.

A Mendelian randomization analysis additionally indicated that a genetic liability for UL was significantly associated with an increased risk of breast cancer. This, the researchers noted, was restricted to ER+ breast cancer, and a genetic liability for breast cancer was not associated with UL.

"We found evidence supporting a significant genetic correlation of UL with BC and with its ER+ subtype," Jiang and colleagues wrote.

They noted, though, that their study has limitations, including its reliance on data from individuals of European ancestry, the inability to analyze sex chromosomes, and decreased statistical power for the ER- breast cancer subgroup.

"Larger and more powerful GWASs for UL and [breast cancer] are needed to establish definitively (or rule out) a potential causal link," the researchers added. "Future longitudinal studies as well as experimental work are also warranted to investigate the biological mechanism underlying the observed genetic relationship."