Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

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A Role for Common Genomic Variants in the Assessment of Familial Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2012.41.7469 ◽

2012 ◽

Vol 30 (35) ◽

pp. 4330-4336 ◽

Cited By ~ 50

Author(s):

Sarah Sawyer ◽

Gillian Mitchell ◽

Joanne McKinley ◽

Georgia Chenevix-Trench ◽

Jonathan Beesley ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Familial Breast Cancer ◽

Brca2 Mutation ◽

Mutation Screening ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Genomic Variants ◽

Risk Distribution

Purpose Genome-wide association studies have identified common genomic variants associated with increased susceptibility to breast cancer. In the general population, the risk associated with these known variants seems insufficient to inform clinical management. Their contribution to the development of familial breast cancer is less clear. Patients and Methods We studied 1,143 women with breast cancer who had completed BRCA1 and BRCA2 mutation screening as a result of a high risk for hereditary breast cancer. Genotyping of 22 breast cancer–associated genomic variants was performed. A polygenic risk score (PRS), calculated as the sum of the log odds ratios for each allele, was compared with the same metric in 892 controls from the Australian Ovarian Cancer Study. The clinical features associated with the high and low ends of the polygenic risk distribution were compared. Results Women affected by familial breast cancer had a highly significant excess of risk alleles compared with controls (P = 1.0 × 10−16). Polygenic risk (measured by the PRS) was greater in women who tested negative for a BRCA1 or BRCA2 mutation compared with mutation carriers (P = 2.3 × 10−6). Non-BRCA1/2 women in the top quartile of the polygenic risk distribution were more likely to have had early-onset breast cancer (< 30 years of age, odds ratio [OR]= 3.37, P = .03) and had a higher rate of second breast cancer (OR 1.96, P = .02) compared with women with low polygenic risk. Conclusion Genetic testing for common risk variants in women undergoing assessment for familial breast cancer may identify a distinct group of high-risk women in whom the role of risk-reducing interventions should be explored.

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Exercise lowers estrogen and progesterone levels in premenopausal women at high risk of breast cancer

Journal of Applied Physiology ◽

10.1152/japplphysiol.00319.2011 ◽

2011 ◽

Vol 111 (6) ◽

pp. 1687-1693 ◽

Cited By ~ 29

Author(s):

D. A. Kossman ◽

N. I. Williams ◽

S. M. Domchek ◽

M. S. Kurzer ◽

J. E. Stopfer ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Menstrual Cycle ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Luteal Phase ◽

Premenopausal Women ◽

High Risk Women ◽

Estrogen Exposure ◽

Hormone Exposure

Experimental and clinical data support a role for estrogens in the development and growth of breast cancer, and lowered estrogen exposure reduces breast cancer recurrence and new diagnoses in high-risk women. There is varied evidence that increased physical activity is associated with breast cancer risk reduction in both pre- and postmenopausal women, perhaps via lowered estrogen levels. The purpose of this study was to assess whether exercise intervention in premenopausal women at increased breast cancer risk reduces estrogen or progesterone levels. Seven healthy premenopausal women at high risk for breast cancer completed a seven-menstrual-cycle study. The study began with two preintervention cycles of baseline measurement of hormone levels via daily first-morning urine collection, allowing calculation of average area under the curve (AUC) hormone exposure across the menstrual cycle. Participants then began five cycles of exercise training to a maintenance level of 300 min per week at 80–85% of maximal aerobic capacity. During the last two exercise cycles, urinary estradiol and progesterone levels were again measured daily. Total estrogen exposure declined by 18.9% and total progesterone exposure by 23.7%. The declines were mostly due to decreased luteal phase levels, although menstrual cycle and luteal phase lengths were unchanged. The study demonstrated the feasibility of daily urine samples and AUC measurement to assess hormone exposure in experimental studies of the impact of interventions on ovarian hormones. The results suggest value in exercise interventions to reduce hormone levels in high-risk women with few side effects and the potential for incremental benefits to surgical or pharmacologic interventions.

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Estrogen metabolism, lifetime methylation disorders, and breast cancer

Problems of Endocrinology ◽

10.14341/probl10070 ◽

2019 ◽

Vol 65 (3) ◽

pp. 161-173

Author(s):

Natalia B. Chagay ◽

Ashot M. Mkrtumyan

Keyword(s):

Breast Cancer ◽

Epigenetic Modification ◽

The Body ◽

Individual Risk ◽

Estrogen Metabolism ◽

Suppressor Genes ◽

Estrogen Exposure ◽

Increased Risk ◽

Endogenous Estrogen

Oncogenesis can be caused by an increase in the activity of genes responsible for initiating tumor growth in stem or progenitor cells, as well as a reduction in the functioning of suppressor genes. Endogenous estrogen exposure is associated with an increased risk of breast cancer in both pre- and postmenopausal women. The most important step in the understanding of the pathogenesis of breast cancer was the development of the theory of the switching of estrogen’s effect from hormonal to genotoxic, in which the main culprits of carcinogenesis are not chemical metabolites of estrogens, but their derivatives, corresponding to chemical procarcinogens according to their damaging characteristics. The origin of these substances and the formation of estrogen genotoxicity lies in the disruption of the inactivation process of catechol estrogens in methylation reactions. The main epigenetic modification of the human genome is the methylation of cell DNA molecules. DNA methylation does not alter the primary sequence of nucleotides, but is necessary for the functional suppression of certain genes. The phenomenon of hypomethylation-hypermethylation underlies the long-term silencing of various genes, including tumor suppressor genes. Nutrition and a lifestyle associated with smoking and the consumption of excessive quantities of alcohol determine estrogen metabolism and the availability of methyl groups in the body, as well as epigenetic changes in the DNA of the genome. The assessment of individual risk of breast cancer on the basis of an assay for the expression and methylation of the COMT gene responsible for estrogen metabolism seems relevant.

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Abstract CT111: Green tea extract supplementation, estrogen metabolism and breast cancer risk in postmenopausal women at high risk of breast cancer

10.1158/1538-7445.am2015-ct111 ◽

2015 ◽

Author(s):

Hamed Samavat ◽

Renwei Wang ◽

Anna Wu ◽

Jian-Min Yuan ◽

Mindy Kurzer

Keyword(s):

Breast Cancer ◽

High Risk ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Postmenopausal Women ◽

Green Tea ◽

Green Tea Extract ◽

Estrogen Metabolism ◽

Tea Extract

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Mutation analysis and characterization of HSD17B2 sequence variants in breast cancer cases from French Canadian families with high risk of breast and ovarian cancer

Journal of Molecular Endocrinology ◽

10.1677/jme-07-0101 ◽

2008 ◽

Vol 40 (4) ◽

pp. 161-172 ◽

Cited By ~ 11

Author(s):

Marie Plourde ◽

Caroline Manhes ◽

Gilles Leblanc ◽

Francine Durocher ◽

Martine Dumont ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Cancer Susceptibility ◽

Susceptibility Gene ◽

Germline Mutations ◽

Breast Cancer Susceptibility Gene ◽

Sequence Variants ◽

Sequencing Analysis ◽

French Canadian ◽

Estrogen Exposure

Estrogen exposure is a risk factor for breast cancer. Given that HSD17B2 gene encodes an enzyme that catalyses estradiol inactivation, it appears as a good candidate breast cancer susceptibility gene. This study was designed to screen for HSD17B2 germline mutations potentially involved in breast cancer predisposition. Our re-sequencing analysis did not identify any deleterious germline mutations, and therefore mutations in HSD17B2 do not explain the clustering of breast cancer cases in non-BRCA1/2 high-risk French Canadian families. However, six sequence variants were identified, including two novel missense variants. Expression assays revealed that p.Ala111Asp and p.Gly160Arg did not alter the catalytic properties of 17β-hydroxysteroid dehydrogenase type 2 enzyme, although p.Ala111Asp appears to affect protein stability resulting in significant decreases in the protein levels, providing valuable information on structure–function relationship.

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