Genetic Sequence Variations and Breast Cancer Risk

Posted by Ben White on أبريل 19, 2019

By Jillian Harrington, PhD, MB(ASCP), HCLD/TS(ABB), ZRT Laboratory

Single nucleotide variations (SNVs — formerly single nucleotide polymorphisms, SNPs) are the most common genetic variations in individuals. Research shows that some SNVs can help predict an individual’s risk of developing certain diseases, such as breast cancer. This article reviews the current literature on SNVs within the steroid metabolism pathway and their relationship to breast cancer risk.

A Crash Course in Genetics

DNA is comprised of nucleotides — adenine, guanine, thymine or cytosine — that come together on both strands, forming a tightly wound double helix. It takes three nucleotides to provide the necessary code to translate into one amino acid. If one of these nucleotides is replaced by another, a completely different amino acid can form, potentially compromising the function of the resulting protein. This is what an SNV is — a change of one nucleotide in the DNA molecule at one specific location.

SNVs are common and occur about once every 1,000 nucleotides, meaning any one person can have up to 5 million SNVs in their genome. A single SNV can either result in no change to the DNA coding sequence, change the resulting amino acid, or affect gene splicing, binding of transcription factors or gene expression.

SNVs Affecting Steroid Hormone Metabolism

It has long been known that inappropriate estrogen metabolism resulting in high levels of catechol estrogens is considered a risk factor for susceptibility to breast cancer. Some of the most important research focuses on SNVs in the enzymes within the sex steroid hormone pathway and how these may affect the levels of parent estrogens and their metabolites.

Understanding your baseline estrogen levels — including estradiol, estrone and estriol — is an important first step in assessing your hormonal risk profile. Our Comprehensive Female Saliva Hormone Profile (LCMS) measures the free, bioavailable fraction of estradiol, progesterone, testosterone and DHEA using gold-standard LCMS analysis — providing a detailed picture of your hormonal milieu.

CYP11A1: The Starting Point

CYP11A1, the cholesterol side-chain cleavage enzyme, catalyses the conversion of cholesterol to pregnenolone — the initial and rate-limiting step of steroid hormone production. Multiple SNVs associated with CYP11A1 show a cumulative effect on increased breast cancer risk in certain populations, though researchers have yet to fully elucidate the mechanism.

Aromatase (CYP19A1): A Key Therapeutic Target

Aromatase is very well-studied for its important role in the formation of estrogens from androgens. In breast cancer, aromatase inhibitors are commonly used as therapeutic targets to block estrogen formation. Variants in this gene can lead to increased enzyme activity and therefore contribute to increased levels of circulating estrogens. One variant is associated with an increased estrone/androstenedione ratio; another is associated with improved treatment outcomes and increased time to disease progression.

Estrogen Receptor Alpha (ERα) Variations

The estrogen receptor ERα is a ligand-activated nuclear receptor and transcription factor — upon binding to estradiol, it can activate or repress the expression of numerous genes. Since ERα plays a major role in hormone response as well as in breast cell growth and differentiation, it has been a focus in breast cancer prevention and treatment. Many SNVs have been identified in the ERα gene that have positive effects on breast cancer risk, though this may be population-specific.

The Dangers of Catechol Estrogens

Estrone and estradiol are metabolised by three competitive pathways involving irreversible hydroxylation, catalysed by CYP enzymes: CYP1A1, CYP1A2 and CYP1B1. The hydroxylated estrogens (catechol estrogens) have the potential to be cancer-causing due to their ability to cause DNA damage via the formation of superoxide radicals and DNA-damaging adducts. Hydroxylated estradiol (4-OH-E2) is particularly carcinogenic because of its highly reactive nature.

Methylation by the Catechol-O-Methyltransferase (COMT) enzyme adds a protective methyl group to the reactive hydroxyl, inactivating these potentially dangerous metabolites. Variations in COMT can predispose an individual to methylate less effectively, potentially leaving them vulnerable to the ravaging effects of oxidative stress brought on by free radical formation.

When all three of the at-risk SNVs were combined, women were at a 12.2-fold increased risk of breast cancer.

A 2011 case-control study of 530 post-menopausal women with breast cancer found that the combined effects of SNVs in CYP1B1, COMT and MnSOD increased susceptibility to breast cancer incidence. MnSOD is a mitochondrial enzyme that catalyses the conversion of superoxide anion into hydrogen peroxide and molecular oxygen, protecting cells from free radical damage resulting from estrogen metabolism. Concurrent presence of the CYP1B1 + COMT or COMT + MnSOD SNVs each represented a 2-fold increased risk of breast cancer. When all three at-risk SNVs were combined, women were at a 12.2-fold increased risk.

Assessing Methylation and Estrogen Metabolites

Methylation is generally considered to be protective — methylation of the catechol estrogens marks them for safe elimination from the body and prevents their further conversion to even more reactive quinone estrogens. The ability to properly methylate can be evaluated by measuring and assessing the ratio of catechol estrogens (2 and 4-hydroxy-estradiol) to their methylated counterparts (2 and 4-methoxy-estradiol).

If catechol estrogen levels are elevated while methylated estrogens are low, this could indicate an inability to effectively methylate — potentially resulting from genetic variants in COMT which decrease enzyme activity. Determining the levels of estrogen metabolites in urine provides a comprehensive picture regarding methylation ability and potential increased risk of breast cancer. Our Dried Urine Hormone Tests measure estrogen metabolites and hormone levels from a simple at-home urine collection — providing the most complete analysis of estrogen processing and methylation status.

Lifestyle and Dietary Strategies to Reduce Risk

Genetics are only one piece of the puzzle. There are lifestyle and dietary changes that can be implemented to help decrease breast cancer risk:

DIM and indole-3-carbinol (found in cruciferous vegetables) help shift estrogen metabolism to the safer 2-hydroxylation pathway.
Methylation support with vitamin B12, folic acid or SAM-e can help compensate for COMT variants.
Diet: cruciferous vegetables (arugula, broccoli, cabbage, kale), beets, berries and beans are important for maximising methylation.
Lifestyle: reducing stress, getting enough sleep and routine exercise are important for everyone to mitigate disease risk.

For women wanting the most comprehensive hormonal and toxicological picture — including hormones, neurotransmitters and heavy metals that affect oxidative stress — our Women’s All-In-One Test provides a complete picture with specialist interpretation included.