Estrogen is well-recognized to play an important role in the development and progression of breast and endometrial cancers. Endometrial and breast cancers are considered to be ‘estrogen-dependent tumors,’ as they share common risk factors, such as early age at menarche, late age at menopause, nulliparity, late age at first birth, long-term postmenopausal hormone use, and increased body mass index (for postmenopausal breast cancer), that have been shown to influence the levels and duration of exposure to sex steroid hormones.
Genetic factors are also likely to play a major role in the development of endometrial cancer. Endometrial cancer is part of the hereditary cancer syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), which is attributable to the inheritance of rare, highly penetrant mutated DNA repair genes 1, 2
. Given the small percentage (2-5%) of endometrial cancers attributable to this hereditary cancer syndrome, other genetic models may play a role in the development of endometrial cancer. Women with a family history of endometrial cancer have their risk increased by 1.5 to 3-fold 3-5
suggesting that family history is an important risk factor in the population. Variation in genes involved in steroid hormone metabolism influence the levels of estrogen and progesterone and thus may be associated with an increased risk of endometrial cancer.
Several genome-wide association studies (GWAS) have identified novel risk alleles for breast cancer 6-9
. Easton et al. 6
initially scanned 408 breast cancer cases with a strong family history of breast cancer and 400 controls for 266,722 SNPs followed by a second stage in which 12,711 SNPs were genotyped in 3,990 breast cancer cases and 3,916 controls. A confirmation phase followed in which 30 of the highest ranking SNPs that achieved a combined P
< 0.00002 (based on either the Cochran-Armitage or a 2 degree freedom test) were genotyped in 21,860 cases and 22,578 controls to reveal five novel, independent loci with strong evidence of an association for breast cancer (P
). Four of these loci contained possible causative genes (FGFR2, TNRC9, MAP3K1, LSP1
). The fifth polymorphism (rs13281615) lies on chromosome 8q24 and is correlated with SNPs in a 110kb linkage disequilibrium (LD) block that has no known genes6
. Hunter et al.7
genotyped 528,173 SNPs in 1,145 breast cancer cases and 1,142 controls and identified four SNPs in intron 2 of the FGFR2
gene, which were significantly associated with sporadic postmenopausal breast cancer risk. This association was replicated in an additional 1,776 cases and 2,072 controls from breast cancer case-control studies nested within three prospective cohorts 7
. Stacey et al.8
genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals and 11,563 controls and then tested the ten highest ranking SNPs in five replication sets. Two SNPs (rs3803662 (TNRC9
) and rs13387042) were consistently associated with estrogen receptor-positive breast cancer 8
. The rs13387042 SNP is on chromosome 2q35, and the LD block containing this polymorphism has no known genes or human RNAs 8
. A recent scan of 6,145 breast cancer cases and 33,016 controls observed a significant association with the previously identified FGFR2
and estrogen receptor-positive breast cancer 9
. Stacey et al
and Easton et al. 6
both identified the rs3803662 (TNRC9
) SNP, and Hunter et al.7
and Easton et al. 6
identified the same principal locus in FGFR2,
as the two respective SNPs have an r2
of 1.0 (rs1219648 and rs2981582) in the HapMap CEU samples. Taken together, the genome-wide association studies have revealed, with some consistencies, a number of SNPs that are associated with breast cancer risk.
We reasoned that genetic variants that are associated with breast cancer, a hormone-related disease, would also be associated with endometrial cancer, another hormone-related disease. Therefore, we conducted a nested case-control study within the Nurses’ Health Study and the Women’s Health Study to investigate the associations between these seven newly identified breast cancer risk alleles and endometrial cancer risk, using 692 invasive endometrial cancer cases and 1,723 matched controls.