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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 225

Inflammation may mediate the association between obesity and breast cancer. C-reactive protein (CRP) is a
sensitive, nonspecific biomarker of acute and chronic inflammatory states synthesized in hepatocytes in
[34]
response to inflammation and tissue damage . Elevated CRP levels have been associated with high
[35]
cholesterol, blood pressure, fat percentage , obesity [36-38] , and insulin resistance [39-41] . There is a known
association between inflammation and cancer, though studies of CRP and cancer report conflicting
findings. A 2009 meta-analysis demonstrated that elevated CRP levels were associated with increased cancer
risk , and high CRP levels have been shown to correlate with a more advanced disease stage and worse
[42]
[43]
prognosis . However, a more recent review found an association between high CRP and cancer incidence
and survival only for ovarian cancer and hepatocellular carcinoma, respectively .
[44]
Several studies report an association between elevated CRP levels and breast cancer risk in postmenopausal
women [45-51] and women within the highest quartile of CRP [52,53] , linking chronic low-grade inflammation to
obesity and breast cancer. High CRP levels have also been associated with reduced disease-free survival and
overall survival in women with breast cancer [54-56] . However, multiple studies did not find an association
between CRP and breast cancer risk or mortality [57-59] . The mechanism of inflammation in cancer
development and progression is complex, and it is unclear whether CRP levels reflect the specific
inflammatory pathways involved . Study inconsistencies may also be driven by confounders such as
[44]
lifestyle factors, differences in population characteristics, or differences in study design [51,59] .

In summary, it is necessary to examine the molecular mechanisms of obesity and its impact on racial/ethnic
disparities in breast cancer diagnosis and prognosis as well as other health conditions to develop effective,
long-term weight management strategies that may improve survival - particularly in high-risk underserved
minority populations. This study evaluates genetic predisposition to obesity by first developing a PRS
composed of 35 externally-validated SNPs associated with obesity risk. We then assess the association of our
PRS with obesity and race/ethnicity in a diverse sample of women with breast cancer to evaluate its utility in
identifying a high-risk population who may benefit from aggressive weight-loss interventions, such as
bariatric surgery. We also compared the obesity PRS by race/ethnicity as well as the association between the
obesity PRS and CRP levels and bariatric surgery eligibility.

METHODS
Study design
We conducted a cross-sectional study using two prospective clinic-based studies of breast cancer patients to
evaluate the impact of genomics and exposures on breast cancer radio-sensitivity from 2008 to 2015 at the
University of Miami Miller School of Medicine. These studies recruited women diagnosed with breast
carcinoma stages 0-III, scheduled to receive adjuvant radiation therapy (RT) on the intact breast or chest
wall from the radiation oncology department at the Sylvester Comprehensive Cancer Center and Jackson
Memorial Hospital in Miami, FL. Patients were older than 18 years old and self-reported AA or white race,
Hispanic or non-Hispanic ethnicity was recruited before RT and followed for up to one year after treatment.
Patients with prior radiation or concurrent chemotherapy were excluded from the study.

As of October 2014, 397 post-lumpectomy and 116 post-mastectomy breast cancer patients were enrolled.
These two studies were pooled for analysis purposes into a post-surgery RT group of 513 women. Every
study participant completed a self-administered study entry questionnaire that included information on
demographics, reproductive history, presence of other medical conditions, smoking history, and family
history of breast cancer. Whole blood (25-30 mL) was collected from each patient at baseline and at the time
of the last RT.