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Int J Cancer. 2018 Mar 15;142(6):1182-1188. doi: 10.1002/ijc.31145. Epub 2017 Nov 17.

A comprehensive analysis of polymorphic variants in steroid hormone and insulin-like growth factor-1 metabolism and risk of in situ breast cancer: Results from the Breast and Prostate Cancer Cohort Consortium.

Author information

1
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Epidemiology Research Program, American Cancer Society, Atlanta, GA.
4
Hellenic Health Foundation, Athens, Greece.
5
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
6
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
7
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
8
Clinical Trial Unit, Skåne University Hospital, Lund, Sweden.
9
Division of Oncology and Pathology, Clinical Sciences, Lund, Lund University, Sweden.
10
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
11
Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
12
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
13
Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
14
Department of Public Health and Primary Care, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
15
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia.
16
Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, VIC, Australia.
17
Faculty of Medicine, Monash University, Melbourne, VIC, Australia.
18
Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI.
19
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
20
Department of Epidemiology, University of Washington; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
21
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA.
22
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Pike Bethesda, MD.
23
Core Genotyping Facility, Frederick National Laboratory for Cancer Research, Gaithersburg, MD.
24
Divisions of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
25
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
26
Department of Biology, University of Pisa, Pisa, Italy.

Abstract

We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and insulin-like growth factor 1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was carried out using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (ORhom  = 3.05, 95%CI = 1.72-5.44, Phom  = 1.47 × 10-4 ), MAST2-rs12124649 (ORhom  = 1.73, 95% CI =1.18-2.54, Phom  = 5.24 × 10-3 ), and INSR-rs10500204 (ORhom  = 1.96, 95% CI = 1.44-2.67, Phom =1.68 × 10-5 ) were associated with increased risk of BCIS; however, only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with the risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (ORhom  = 1.78, 95% CI = 1.30-2.44, Phom  = 3.23 × 10-4 ). The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further.

KEYWORDS:

BPC3; breast cancer in situ; genetic epidemiology; single nucleotide polymorphisms

PMID:
29114882
PMCID:
PMC6610718
DOI:
10.1002/ijc.31145
[Indexed for MEDLINE]
Free PMC Article

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