Women with higher risk scores that consisted of having
certain genetic variants most strongly linked to breast cancer had an
associated higher risk of breast cancer. These scores were also highly
predictive of estrogen receptor-positive disease, according to a study in the
The Journal of the American Medical Association.
“Findings from genome-wide association studies (GWAS), together
with analyses of specific candidate polymorphisms [gene variations], have
identified a number of variants that are definitely or probably associated with
breast cancer risk. There is also increasing evidence that some genetic factors
have different effects on different subtypes of breast cancer,” the
authors wrote in a press release.
Gillian K. Reeves, PhD, of the Cancer Epidemiology Unit, University of
Oxford, U.K., and colleagues conducted a study to analyze breast cancer risk,
overall and by tumor subtype, in relation to 14 individual single-nucleotide
polymorphisms (SNPs;) and a polygenic (relating to an inheritable character
that is controlled by several genes at once) risk score. The study included
10,306 women with breast cancer (average age at diagnosis, 58 years) and 10,393
women without breast cancer, who in 2005-2008 provided blood samples for
genotyping. The researchers estimated the per-allele odds ratio (OR) for
individual SNPs and the cumulative incidence of breast cancer to age 70 years
in relation to a polygenic risk score based on the 4, 7, or 10 SNPs most
strongly associated with risk.
The researchers found that the OR for breast cancer were greatest for
the SNPs FGFR2-rs2981582 and TNRC9-rs3803662 and, for these 2 SNPs, were
significantly greater for estrogen receptor (ER)-positive than for ER-negative
disease, both in the data of this study and in meta-analyses of other published
data. The next strongest association was for 2q-rs13387042, for which the
per-allele OR was significantly greater for bilateral than unilateral disease
and for lobular than ductal tumors.
“When the effects of the 7 SNPs most strongly associated with
overall breast cancer risk in these data were combined using a polygenic risk
score, the cumulative risk of breast cancer to age 70 years among women in the
top fifth was twice that in the bottom fifth (8.8% vs. 4.4%). Both the relative
and, particularly, the absolute difference was much greater for ER-positive
disease (7.4% vs. 3.4%) than for ER-negative disease (1.4% vs. 1.0%),” the
authors wrote. “In this large study including 10,306 women with breast
cancer and 10,393 without the disease, we confirm that some of the more
important common genetic variants for breast cancer have different effects on
different tumor types.”
“Certain established risk factors for breast cancer have similar,
or even greater, effects on breast cancer incidence than the differences seen
here between women in the highest vs. the lowest fifth of polygenic risk score.
Indeed, our estimate of the cumulative incidence of breast cancer to age 70
years in women in the top fifth for polygenic risk score (8.8%) is similar to
that for women in developed countries with one first-degree relative with
breast cancer (9.1%), and considerably less than that for women with 2 affected
first-degree relatives (15.4%). Furthermore, no interactions have been found
between the effects of the genes investigated here and the other risk factors
for breast cancer. Hence, as others have suggested, subdividing women on the
basis of their polygenic risk is, at this stage, not a useful tool for
population-based breast cancer screening programs but may be useful for
understanding disease mechanisms,” the researchers concluded.
