Increased risk of uterine cancer linked to 24 gene variants

By Dr. Liji Thomas, MDFeb 17 2020

The risk of uterine endometrial cancer is increased by 24 gene variants that code for different cellular processes such as cell growth and death, gene regulation, and estrogen metabolism, according to a comprehensive review published in the Journal of Medical Genetics.

Female Reproductive System with nervous system and urinary bladder. 3D Illustration. Credit: Magic mine / Shutterstock

Endometrial cancer

Endometrial cancer is the most common female cancer in industrialized countries. 1 in 35 American women will have this disease at some point in their lives, and the number of women dying of this cancer is increasing by 2% each year, since 2008. This is chiefly because more women are developing this cancer due to factors like a longer lifespan, a lower number of uterus removal surgeries for non-cancer reasons, and a marked increase in the incidence of obesity.

A woman who has most or all of these variants runs a risk of endometrial cancer that is two or three times as high as for a woman without them. The genetic risk, in our present state of knowledge, still makes up only a small number of these cancers, as low as 3% to 5%, mostly as a part of two inherited syndromes called Lynch syndrome and Cowden syndrome. In other words, lifestyle or unknown factors still account for the vast majority of these cases.

Endometrial cancer is of two types, type I, which is typically less aggressive and is picked up early, and type II, which is an insidious but very aggressive form, and is diagnosed later in its course. Type I is made up of endometrioid tumors, arising as a result of estrogen exposure which stimulates the growth of the endometrium. The outcome of this type is very favorable. On the other hand, type II includes different types of tumors that don’t depend on estrogen for their growth and are difficult to treat. The only known risk factor for this is age.

Gene variants and cancer risk

Earlier research has shown that genetic factors that increase the risk of endometrial cancer may be as slight as a change of one DNA nucleotide. These are known as single nucleotide polymorphisms (SNPs) and are common phenomena, with about 4-5 million of them to be found in the genome of any given individual. Such SNPs may occur unpredictably and uniquely or may have a pattern that is observable in many individuals.

SNPs don’t always cause disease or affect normal development. The problem comes when a gene or a regulatory element near a gene has an SNP that changes the way the gene functions because this then can potentially give rise to specific diseases.

Some prior studies have indicated that SNPs might cause some cases of endometrial cancer, but the exact extent of risk estimated showed wide variation. These studies were mostly done before the whole genome association studies were developed. There is no clear understanding of how an individual’s genetic makeup predisposes to endometrial cancer, and therefore no way to make a personalized cancer risk assessment.

The study findings

For this reason, the current study undertook to review all the available studies around this topic published in the period 2007 and 2018. The researchers found 149 studies relevant to this topic.

Their analysis showed 24 SNPs to be common either within or near six different genes. Five of these gene variants were significantly associated with endometrial cancer odds, namely, HNF1B, CYP19A1, SOX4, MYC, KLF, and EIF2AK. Another 19 variants showed a more significant occurrence than could be attributed to chance alone. However, with the SNP that has undergone the most intense study, there was no convincing evidence.

The limitations include the inclusion of mostly European ethnicities in most larger studies and the lack of reference genotypes for other racial origins. To obtain results that are more broadly applicable, more extensive and more inclusive studies need to be performed.

Also, endometrioid tumors make up only about a fifth of all endometrial cancers, which means much more extensive studies need to undertaken to detect gene variants that contribute significantly to the risk of non-endometrioid tumors. On the other hand, most existing studies have examined either endometrioid or mixed histology, even though non-endometrioid tumors carry a far worse prognosis and are responsible for most of the mortality from endometrial cancer. The lack of a standardized and useful classification system for endometrial tumors is also a top priority for future research.

Implications

If all these 24 are present, or most of them, the risk for endometrial cancer goes up two- to threefold. However, this is likely to be only the tip of the iceberg, because almost 200 SNPs have been found to increase the risk of breast cancer. On the other hand, these 24 might be useful, incorporated into a single risk index, to forecast a personalized risk prediction for individual women. This could allow targeted screening and prevention for women at the highest risk of endometrial cancer.