Page 19 - TD-2-1

Tumor Discovery Cancer progression in PCOS

4. Mechanism of cancer progression in A recent study has identified several PCOS-related
polycystic ovary syndrome genes (PRGs), based on literature review and genomics
analysis, that showed significant genomic alterations in
Many reports exploring PCOS and the risk of cancer endometrial, ovarian, and breast cancers . Interestingly,
[94]
have been published. Hyperinsulinemia, high estrogen these PRGs included several cancer driver genes, such as
level, and chronic inflammation are some of the factors PTEN, ESR1, and TP53 in case of endometrial cancer, PTEN
associated with normal PCOS progression [35,37] , and there and TP53 for ovarian cancer, and ERBB2, NCOR1, ESR1,
is an evidence that these chronic conditions may be TP53, PTEN, and AKR1C3 for breast cancer . Among
[94]
contributing factors to oncogenesis and cancer progression these identified genes, the tumor suppressor gene PTEN
in PCOS [85,86] . Hyperinsulinemia directly initiates and showed the highest number of mutations in endometrial
regulates the initiation of cancer development, while cancer . Therefore, it is presumable that mutations in the
[94]
inflammation affects various pro-tumorigenic pathways cancer driver genes that are included in PRGs might drive
that ultimately lead to angiogenesis and carcinogenesis, PCOS patients toward cancer progression (Figure 2).
thus promoting cancer cell development in certain
sites [87,88] . Recent evidence has suggested that the effect of Based on clinical behavior and morphological feature,
sympathetic hyperactivity is also a risk factor for cancer endometrial cancer can be generically divided into
progression in PCOS women. Sympathetic hyperactivity two distinct categories: Type I endometrial carcinoma,
leads to the secretion of norepinephrine, in which increased which is an estrogen-related malignancy with a favorable
norepinephrine acts as a biochemical switch for tumor prognosis; and Type II endometrial carcinoma, which is
angiogenesis [85,89-91] . Besides that, low progesterone level is not related to estrogen and carries a poor prognosis .
[95]
directly associated with the development of endometrial Studies have found increased endometrial expression of
cancer, and many studies have supported that low insulin signaling-related genes, such as IGF1, IGFBP1, and
progesterone level is an indication of hyperandrogenism, PTEN, both in PCOS and endometrial cancer patients [86,94] .
thus providing a link between the two [92,93] (Figure 2). PTEN, KRAS, CTNNB1, and PIK3CA mutations are

Figure 2. Proposed mechanism of cancer progression in polycystic ovary syndrome (PCOS). Chronic conditions such as hyperinsulinemia, high estrogen
level, sympathetic hyperactivity, low progesterone level, hyperandrogenism, and chronic inflammation in PCOS might be the contributing factors to cancer
progression. The chronic condition in PCOS might cause significant genomic alterations in the cancer driver genes that are included in PCOS-related
genes, such as PTEN, TP53, IGF1, IGFBP1, HSD17B4, PDGFRA, and more, thus raising the possibility of developing cancer.

Table 2. Prevalence of non‑reproductive cancer in polycystic ovary syndrome patients

Type of Location Total Cancer type Number of Adjusted HR/RR/SIR/ References
study participant (non‑reproductive) cancer patients OR (95% CI value)
Cohort Denmark 12,070 Lung 9 1.1 (0.5 – 2.0) [69]
Colon 11 2.1 (1.1 – 3.8)
Thyroid 8 1.5 (0.7 – 3.0)
Kidney 6 3.9 (1.4 – 8.4)
Brain 18 2.2 (1.3 – 3.5)
Melanoma 22 0.9 (0.5 – 1.3)
Retrospective USA 2,560 Melanoma 5 1.17 (0.45 – 3.02) [79]
cohort Thyroid 5 2.68 (1.24 – 10.63)

Lymphatic 5 1.99 (0.64 – 4.64)
HR: Hazard ratio; OR: Odds ratio; RR: Relative risk; SIR: Standardized incidence ratio

Volume 2 Issue 1 (2023) 6 https://doi.org/10.36922/td.328