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Puyana et al. J Transl Genet Genom 2022;6:223-239 https://dx.doi.org/10.20517/jtgg.2021.51 Page 233

large, diverse populations are necessary to refine our understanding of how SNPs contribute to genetic
obesity risk.

Consistent with previous studies, our data demonstrate that the PRS is strongly associated with BMI [82,83] .
Indeed, there was a dose-response increase in PRS for each increasing BMI category, and women with a PRS
level 4 had 3.77-fold higher odds of being obese. Comparison of PRS by race/ethnicity aligned with known
racial/ethnic trends in obesity, as PRS for AA women, was found to be significantly greater than HW and
NHW women. Genetic predisposition to obesity varies significantly by race/ethnicity.

The mechanism by which obesity leads to carcinogenesis is multifactorial and not entirely understood;
however, many propose that one causal link may be inflammation. Obesity represents a chronic low-grade
inflammatory state, and there is a known bidirectional link between chronic inflammation and
carcinogenesis [84-87] . Chronic inflammation creates an inflammatory microenvironment that promotes
tumorigenesis [86,88] ; tumor cells, in turn, attract immune cells that produce cytokines and chemokines that
induce carcinogenic DNA mutations in nearby cells [84-87,89] . This inflammatory tumor microenvironment
facilitates the progression of the disease and contributes to poor outcomes [81,84-86,88,90] .

We demonstrate that the PRS is closely associated with blood levels of CRP. CRP is an inflammatory
biomarker that differs by BMI [36-38,91] , making it a suitable biomarker for studying inflammation in this study.
Excess adipose tissue in overweight and obese individuals can release cytokines, stimulate CRP synthesis,
and induce low-grade systemic inflammation [34,91] . Elevated CRP levels may also contribute to leptin
[32]
resistance in obese individuals ; high leptin and CRP levels have been shown to exacerbate pre-existing
systemic inflammation in breast cancer patients and survivors, increasing susceptibility to recurrence
and/or metastasis [34,92] . In our cohort, women with PRS level 4 had 3.77-fold increased odds of being obese
and had exceptionally high CRP levels. These findings support the hypothesis that inflammation links
obesity and breast cancer and additionally suggest that CRP may be implicated.

Considering our understanding of the association between obesity and breast cancer risk, recurrence, and
poor outcomes, weight loss interventions among obese women may represent an effective strategy for breast
cancer prevention and improving outcomes. Initial weight loss recommendations include lifestyle
modifications focused on diet and exercise. Although evidence indicates that multidisciplinary programs
reliably produce and sustain a 5%-10% weight loss, this may not be sufficient to mitigate health risks in
[93]
obese class II and III women, especially among those with a high genetic predisposition to obesity . These
women may instead benefit from more aggressive approaches, like bariatric surgery, to achieve a greater
weight loss than possible with lifestyle modifications alone [94,95] . In our cohort, a high PRS was significantly
associated with bariatric surgery eligibility. Bariatric surgery may be recommended in women who meet
NIH criteria and have a high genetic predisposition to obesity (indicated by above-median PRS) to improve
both breast cancer outcomes and other obesity-associated comorbidities.

In addition to improved quality of life, the known benefits of bariatric surgery include improved glucose
homeostasis, insulin responsiveness, and reduced inflammation - all of which are believed to be protective
against the development of cancer . In addition, the Swedish Obese Subjects study found that bariatric
[96]
[94]
surgery significantly decreased cancer incidence among women . Although literature exploring bariatric
surgery outcomes in breast cancer patients is limited, one large retrospective cohort study demonstrated a
reduced risk of postmenopausal breast cancer in women who underwent bariatric surgery compared to
BMI-matched subjects who did not .
[97]