TY - JOUR
T1 - A comprehensive analysis of polymorphic variants in steroid hormone and insulin-like growth factor-1 metabolism and risk of in situ breast cancer
T2 - Results from the Breast and Prostate Cancer Cohort Consortium
AU - Barrdahl, Myrto
AU - Canzian, Federico
AU - Gaudet, Mia M.
AU - Gapstur, Susan M.
AU - Trichopoulou, Antonia
AU - Tsilidis, Kostas
AU - van Gils, Carla H.
AU - Borgquist, Signe
AU - Weiderpass, Elisabete
AU - Khaw, Kay Tee
AU - Giles, Graham G.
AU - Milne, Roger L.
AU - Le Marchand, Loic
AU - Haiman, Christopher
AU - Lindström, Sara
AU - Kraft, Peter
AU - Hunter, David J.
AU - Ziegler, Regina G.
AU - Chanock, Stephen J.
AU - Yang, Xiaohong R.
AU - Buring, Julie E.
AU - Lee, I. Min
AU - Kaaks, Rudolf
AU - Campa, Daniele
N1 - Funding Information:
This work was supported by the Australian National Health and Medical Research Council (NHMRC, grant 1088405); VicHealth and Cancer Council Victoria (to MCCS cohort recruitment); NHMRC grants 209057, 251553 and 504711 (to MCCS) and Hellenic Health foundation and Stavros Niarchos Foundation (to EPIC Greece). Infrastructure was provided by Cancer Council Victoria. Cases were ascertained through the Victorian Cancer Registry (VCR) and the Australian Cancer Database (Australian Institute of Health and Welfare). The CPS-II cohort was initiated and is maintained by the American Cancer Society (Atlanta, GA).
Publisher Copyright:
© 2017 UICC
PY - 2018/3/15
Y1 - 2018/3/15
N2 - 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.
AB - 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.
KW - BPC3
KW - Breast cancer in situ
KW - Genetic epidemiology
KW - Single nucleotide polymorphisms
UR - http://www.scopus.com/inward/record.url?scp=85034254307&partnerID=8YFLogxK
U2 - 10.1002/ijc.31145
DO - 10.1002/ijc.31145
M3 - Article
AN - SCOPUS:85034254307
SN - 0020-7136
VL - 142
SP - 1182
EP - 1188
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 6
ER -