Abstract
Simple SummaryEndometrial cancer is the leading female reproductive tract cancer in developed countries. Discovering new biomarkers is critical for understanding the etiology this cancer and identifying women with a higher risk of this cancer from the general population. Several blood protein biomarkers have been linked to endometrial cancer in previous studies, but these studies have assessed only a limited number of biomarkers usually among a small number of participants. The current study aimed at identifying novel circulating protein biomarkers of endometrial cancer by using the largest available dataset to date. Our finding suggested nine proteins to be associated with endometrial cancer risk, and five of the identified associations showed suggestive associations with risk of non-endometrioid EC, a much more lethal subtype. If validated by additional studies, our findings may contribute to understanding the pathogenesis of endometrial tumor development and facilitating the risk assessment of endometrial cancer.Endometrial cancer (EC) is the leading female reproductive tract malignancy in developed countries. Currently, genome-wide association studies (GWAS) have identified 17 risk loci for EC. To identify novel EC-associated proteins, we used previously reported protein quantitative trait loci for 1434 plasma proteins as instruments to evaluate associations between genetically predicted circulating protein concentrations and EC risk. We studied 12,906 cases and 108,979 controls of European descent included in the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium, and the UK Biobank. We observed associations between genetically predicted concentrations of nine proteins and EC risk at a false discovery rate of <0.05 (p-values range from 1.14 × 10−10 to 3.04 × 10−4). Except for vascular cell adhesion protein 1, all other identified proteins were independent from known EC risk variants identified in EC GWAS. The respective odds ratios (95% confidence intervals) per one standard deviation increase in genetically predicted circulating protein concentrations were 1.21 (1.13, 1.30) for DNA repair protein RAD51 homolog 4, 1.27 (1.14, 1.42) for desmoglein-2, 1.14 (1.07, 1.22) for MHC class I polypeptide-related sequence B, 1.05 (1.02, 1.08) for histo-blood group ABO system transferase, 0.77 (0.68, 0.89) for intestinal-type alkaline phosphatase, 0.82 (0.74, 0.91) for carbohydrate sulfotransferase 15, 1.07 (1.03, 1.11) for D-glucuronyl C5-epimerase, and 1.07 (1.03, 1.10) for CD209 antigen. In conclusion, we identified nine potential EC-associated proteins. If validated by additional studies, our findings may contribute to understanding the pathogenesis of endometrial tumor development and identifying women at high risk of EC along with other EC risk factors and biomarkers.
Highlights
Endometrial cancer (EC) is a leading gynecological malignancy in developed countries [1]
The instruments used for VCAM-1, MHC class I polypeptide-related sequence B (MICB), blood group ABO system transferase (BGAT), intestinal-type alkaline phosphatase, and ST4S6 only had one SNP; whereas two SNPs were used as the instrument to predict the circulating level of RA51D, desmoglein-2, glucuronyl C5-epimerase (GLCE), and DC-SIGN
COJO conditional analysis showed that associations between those eight predicted proteins and EC risk generally remained the same after conditioning on known EC risk variants identified in previous genome-wide association studies (GWAS) (Table 1)
Summary
Endometrial cancer (EC) is a leading gynecological malignancy in developed countries [1] It is one of the few cancer types with a rapidly increasing incidence and mortality as the rate of obesity continues to grow worldwide [2]. Endometrioid adenocarcinomas represent more than 70% of cases Tumors of this type are usually lowgrade and diagnosed at an early stage. The less common non-endometrioid tumors are typically more aggressive and often diagnosed at an advanced stage. The prognosis of EC remains generally good, it worsens dramatically when diagnosed at an advanced stage, with a median survival time of less than 12 months [1,3]. The discovery of potential non-invasive biomarkers would be especially important for identifying women with a high risk of EC [4,5]. Many protein candidates in blood or vagina samples have been reported as possible
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