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Endometrial Cancer Study Identifies 24 Variants Linked to Disease Predisposition

NEW YORK – Researchers at the University of Manchester and the University of Cambridge in the UK have identified 24 genetic variants significantly associated with predisposition to endometrial cancer.

In a study published on Monday in the Journal of Medical Genetics, the researchers reported that they identified SNPs in HNF1B, KLF, EIF2AK, CYP19A1, SOX4, and MYC, which are all genes involved in cell survival, estrogen metabolism, and transcriptional control. Nineteen of the variants were reported with genome-wide significance and the other five were reported with suggestive significance.

"Because many of the studies carried out to date have been of variable quality, we felt it was important to understand more fully genetic predispositions to endometrial cancer," University of Manchester Professor Emma Crosbie, the paper's senior author, said in a statement. "Our work, we hope, will facilitate personalized risk assessment so that prevention and screening could be targeted more efficiently."

The researchers undertook a systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. They searched the MEDLINE, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases for endometrial cancer studies published from 2007 to 2019. After various screening efforts, they were left with 149 articles.

They compiled a list of the most robust endometrial cancer-associated SNPs and assessed the applicability of these SNPs with a theoretical polygenic risk score (PRS) calculation. Following data interpretation, they were left with 24 independent SNPs that showed the strongest association with endometrial cancer. These SNPs were located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway.

They then tested the utility of these SNPs as predictive markers by devising a theoretical PRS calculation using data from the published literature. They calculated that using all 24 SNPs, women with a PRS in the top 1 percent of the distribution would be predicted to have a risk of endometrial cancer 3.16 times higher than the mean risk. Using the 19 genome-wide significant SNPs only, women with a PRS in the top 1 percent of the distribution would be predicted to have a risk of endometrial cancer 2.09 times higher than the mean risk.

"This article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer," the authors concluded.

They did note, however, that non-endometrioid cases comprise a small proportion (about 20 percent) of all endometrial cancer cases, and that much larger cohort sizes are needed to detect genuine signals for non-endometrioid tumors. Most of the studies the team evaluated looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect signals with any statistical significance.

"This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumors with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer," the authors wrote. "It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes."