Ovarian cancer and DNA repair: DNA ligase IV as a potential key

Table 1 Hypothesis to epithelial ovarian cancer development

Hypothesis	Biological mechanism proposed	Epidemiological evidence
Incessant ovulation[24]	Repetitive ovulation and quickly cellular proliferation in post-ovulation repair creates a propitious environment to carcinogenesis initiation by genetic alteration accumulation as well as inclusion cysts development	Events that suppress ovulation such as pregnancy, lactation and oral contraceptive use are protective factors
	Ovulation inhibition results in gonadotropin and oxidative stress levels reduction, deceleration of ovarian follicle depletion and to a diminished inclusion cysts development in ovarian epithelium
Gonadotropins[91]	Excessive stimulation of ovarian epithelium by FSH and LH conducts to downstream genes activation as well as to stimulation of hormonal production by the ovary (as estrogen) in order to enhance cellular proliferation and consequently to malignant transformation and angiogenesis	Oral contraceptive use and pregnancy are protective. Hyper-gonadotropic conditions are common in infertile, in polycystic ovarian syndrome and in post-menopausal women
	The formation of a protective progestagenic hormonal milieu can stimulate apoptosis in genetically damaged ovarian epithelial cells, preventing tumor development
Hormonal stimulation[92]	High androgen levels are harmful while an increase in progesterone levels is benefic	Protective effect due to multiparity and oral contraceptive use. Harmful effect is associated with higher androgen levels as in polycystic ovarian syndrome women
Inflammation[25]	Ovulation is accomplished by an inflammatory response: redox potential alteration, cellular infiltration, cytokine release that can introduce DNA damage in epithelial cells involved in ovary rupture/repair	Inflammatory gynecological diseases, as endometriosis, can enhance EOC risk. Non-steroid anti-inflammatory drugs can be a protective factor

FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; EOC: Epithelial ovarian cancer.

Table 2 Some studies that evaluate LIG4 polymorphisms role in cancer

Authors	LIG4 SNP identification	Tumor model	Ethinicity	Result
Jakubowska et al[84]	rs1805386	Ovarian and Breast Cancer	Caucasian	The polymorphism was not associated with BRCA1-associated ovarian and breast cancer risk (P = 0.16 and P = 0.97, respectively)
Schildkraut et al[82]	rs10131	Ovarian Cancer	Caucasian	The polymorphism was significantly associated with invasive serous ovarian cancer risk (P < 0.05)
Pearce et al[83]	rs1805386	Ovarian Cancer	Mixed	The polymorphism was initially associated with ovarian cancer risk (P = 0.007) but replication results do not confirm this association
Yin et al[93]	rs1805388	Non-small cell Lung Cancer	Mixed	The polymorphism was significantly associated with the risk of severe radiation pneumonitis in non-small cell lung cancer patients who received radio(chemo)therapy (P < 0.05)
Tseng et al[94]	rs1805388	Non-small cell Lung Cancer	Asian	The polymorphism was significantly associated with lung cancer risk (P = 0.038) especially in smoking patients (P = 0.015), and with high fractional allelic loss (P = 0.016)
de las Peñas et al[89]	rs1805386	Non-small cell Lung Cancer	Caucasian	The polymorphism was not associated with survival in cisplatin/gemcitabine-treated non-small cell lung cancer patients (P = 0.31)
Sakiyama et al[95]	rs2232641	Lung Cancer	Japanese	The polymorphism was significantly associated with a diminish risk to develop lung cancer (P = 0.03)
Sobczuk et al[96]	rs2232641	Breast Cancer	Caucasian	The polymorphism was not associated with breast cancer risk (P > 0.05)
Han et al[97]	rs1805386	Breast Cancer	Mostly Caucasian	No statistically differences in breast cancer risk according LIG4 C299T or T1977C. The polymorphism T1977C was significantly associated with breast cancer risk if the patients had a first degree family history of breast cancer (P = 0.01)
	rs4987182
Goode et al[98]	rs1805386	Breast Cancer	Caucasian	The polymorphism was significantly associated with the breast cancer survival (P = 0.002)
Kuschel et al[99]	rs1805386	Breast Cancer	Caucasian	The polymorphism was significantly associated with a decrease in breast cancer risk (P = 0.04)
Liu et al[100]	rs3093739	Glioma	Asian	The polymorphism was significantly associated with glioma risk (P = 0.009)
Liu et al[101]	rs7325927	Glioblastoma	Caucasian	The polymorphism was significantly associated with glioblastoma survival (P = 0.008)

SNP: Single nucleotide polymorphism.