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Page 184 Berger. J Transl Genet Genom 2023;7:183-5 https://dx.doi.org/10.20517/jtgg.2023.23

which are resistant to high-fat-diet-induced weight gain, the chromatin changes characteristic of cancer
were not identified. The authors concluded that the pro-carcinogenic epigenetic changes were due to
[3]
obesity rather than diet itself .

Exploration of DNA methylation in high-fat diet-fed C57Bl6J mice showed epigenetic changes supportive of
long-chain fatty acid oxidation and downregulation of feedback inhibitors of pro-proliferative signaling
[4]
pathways in older mice . Obesity-associated upregulated genes in aged mice were associated with cell cycle,
DNA replication and repair, and chromatin organization. It is noteworthy that these changes were
[4]
reversible, following long-term (28 weeks) but not short-term (5 weeks) weight loss .
Focusing their analysis on the proteome, Comertpay and Gov applied a machine learning approach to a
[5]
high-throughput gene expression dataset from patients with breast cancer to study obesity-associated
protein networks, interactions and differentially expressed genes. They identified 19 downregulated and 4
upregulated genes in obese compared to non-obese women with breast cancer, indicating significant
activation of cancer-associated pathways, including RAF-independent MAPK 1/3 activation, collagen
degradation, bladder cancer, cytochrome P450 metabolism, and hedgehog. These observations may be
useful for risk assessment of disease progression in patients with breast cancer and approaches to precision
medicine .
[5]

In a tri-racial ethnic population of breast cancer patients, Puyana et al. used 35 externally validated, single
nucleotide polymorphisms to determine whether racial/ethnic differences in Polygenic Risk Score (PRS)
contribute to obesity and inflammatory biomarkers in patients with breast cancer . They identified an
[6]
obesity PRS that correlated with body mass index and CRP levels that were associated with eligibility for
bariatric surgery. Although little is known about the impact of bariatric - metabolic surgery on
obesity-influenced outcomes in patients with breast cancer, the authors suggested that PRS could be
employed to inform the application of bariatric - metabolic surgery in patients with breast cancer to
[6]
improve obesity-related effects on recurrence, metastasis, and mortality .

These reports provide insights into selected aspects of the broad spectrum of genetic, epigenetic, and
proteomic data available for obesity-associated cancers that may be potentially useful as targets for
therapeutic intervention and/or as biomarkers for monitoring cancer predisposition, prognosis, and
preventive strategies. At the same time, their diversity is somewhat reminiscent of the Buddhist parable of
the group of blind men asked to describe an elephant by touching different parts to examine the animal.
Each man described the elephant based on their limited experience: leg, trunk, ear, and tusk, but no one
could provide a comprehensive description of the entire animal. Practically speaking, no one would know
how to deal with the elephant based solely on their limited encounters. By analogy to the parable, what is
clearly needed is a coordinated, comprehensive, multi-omic assessment of obesity-associated cancer,
genetics, epigenetics, and proteomic characteristics over a time course to gain a deeper understanding of
how these factors influence cancer incidence, progression, and control, and to shed light on potential
therapeutic targets within these different aspects. In addition, more detailed information on the genetic,
epigenetic and proteomic consequences of exercise, bariatric - metabolic surgery and new classes of weight
loss pharmaceutical agents will further enhance our comprehension and strategies pertaining to obesity-
associated cancers. And by the way, what do we know about genetics, epigenetics and proteomics of obesity
associated cancers in the elephant, the largest land mammal, with the greatest fat mass.