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Page 224 Puyana et al. J Transl Genet Genom 2022;6:223-239 https://dx.doi.org/10.20517/jtgg.2021.51

Conclusion: In summary, multiple obesity-associated SNPs contribute to racial/ethnic disparities in obesity of
breast cancer patients; the obesity PRS has application in identifying breast cancer patients with higher genetic risk
for obesity who may benefit from more aggressive weight management, such as bariatric surgery to improve breast
cancer clinical outcomes.

Keywords: Breast cancer, obesity, race, polygenic risk score, c-reactive protein, bariatric surgery

INTRODUCTION
[1,2]
Obesity plays a critical role in the incidence, recurrence, and clinical outcomes of breast cancer . High
[3]
body mass index (BMI) is associated with increased breast cancer incidence and more advanced tumor
stage at diagnosis , particularly in post-menopausal women [1,2,4-8] . This may be due to increased estrogen
[2,4]
[8,9]
production from excess adipose tissue and elevated insulin levels [4,10] . In addition, multiple studies have
shown that women with high BMI experience worse side effects from cancer treatments due to obesity and
related comorbidities [3,11] . Obesity may also increase breast cancer mortality rates [1-3,5,12] . The American
Cancer Society links 11% of breast cancer deaths to overweight or obese status .
[13]

Breast cancer is the most common form of cancer among women in the United States and the second
leading cause of cancer deaths [2,14,15] . Early detection and improved treatments have led to a remarkable
[16]
reduction in the mortality rate of breast cancer ; however, not all women have benefited equally from such
declines. Mortality rates remain highest among African American (AA) women, followed by non-Hispanic
White (NHW), Hispanic White (HW), and women of other races . Although NHW women are more
[17]
likely to be diagnosed with breast cancer, AA women are more likely to die from breast cancer .
[18]

Obesity is a public health crisis - 42.4% of United States adults are obese, and AA adults are
disproportionately affected [19,20] . AA has the highest age-adjusted prevalence of obesity (49.6%) followed by
HW (44.8%), NHW (42.2%), and other races [19,20] . Importantly, obesity is heritable. 47%-80% of inter-
individual variability in BMI has been attributed to genetic factors [21-23] . The anticipation is that individuals
with a genetic predisposition to obesity may require more aggressive treatment methods to achieve a
healthy weight, such as bariatric surgery. Recent genome-wide association studies (GWAS) using large
samples identified single-nucleotide polymorphisms (SNPs) significantly associated with higher BMI .
[24]
SNPs refer to single-base pair changes that constitute the majority of inter-individual genetic variability .
[24]
Over 700 obesity-associated SNPs have been identified [21,25] , and these are hypothesized to play a role in the
hypothalamic control of energy metabolism, satiety pathways, insulin secretion and action, lipid biology,
and adipogenesis . Research surrounding obesity-related SNPs is ongoing, and additional obesity-related
[21]
loci may be discovered .
[24]
While single SNPs alone may have insufficient effect sizes to explain inter-individual variability in body
composition, multiple large studies have posited that the cumulative effects of multiple SNPs associated
with obesity risk factors contribute to an individual’s genetic predisposition to obesity [26-31] . The polygenic
risk score (PRS) describes an approach to aggregating common polygenic variation in complex traits, like
obesity, into a single continuous variable. The PRS for obesity is advantageous in that it accounts for both
the amount of inter-individual variation and the likelihood of developing a trait while reducing the
statistical burden relating to the multiple comparisons when examining a set of SNPs separately but
simultaneously [27,28,32,33] .