A Brief Overview of Oncogenes and Signal Transduction Pathways in Gynecological Cancer.

Lately, cancer has become one of the deadliest diseases in the world (1). World widely, the World Health Organization’s statistics indicate an increase of 18,1 million new cases and 9,6 million deaths from cancer (1). Additionally, by the year 2040, the percentage of people developing cancer will be augmented by 60% and the percentage of cancer deaths will rise up to 70% (1). Scientists define gynecological cancer as a cancer that develops in the female reproductive system (2,3). Gynecological cancer, depending on its exact anatomical position, can be divided into the following categories: 1) Cervical cancer. This type of cancer begins in the tissues of the cervix (4). 2) Ovarian cancer, which begins in the ovaries of the female reproductive system. In 2012, ovarian cancer was the seventh most common cancer and the 8th most common cause of cancer death among the female population worldwide (3). 3) Uterine cancer. This cancer begins in the uterus of the female reproductive system (5). 4) Vaginal cancer that starts in the vagina of the female reproductive system (6). 5) Vulvar cancer. This cancer begins in the vulva of the female reproductive system, which is the outer part of the female genitals (7). Oncogenes and Signal Transduction in Gynecological Cancer of Internal Genitalia This activation takes place in the following ways: 1) Point mutations, which activate an enzyme, 2) deficiencies that remove negative regulatory regions from proteins, and 3) increased expression, due to disruption of promoter expression or the presence of multiple copies of the gene (“amplification”) (10). An alteration in a single allele that leads to oncogene activation, is sufficient to allow cancer to either start or progress and is considered to be the predominant mechanism of carcinogenesis. A proto-oncogene is the inactivated form of an oncogene. The proto-oncogene is essentially a normal gene, often with important functions in controlling cellular signals for cell proliferation, differentiation, motility, or cell survival (10). Signal transduction is the mechanism by which a signal is transmitted from the cellular surface to a cell’s nucleus. Many of the transmissions sent throughout the body, Cervical Cancer Cutaneous carcinoma is the first in frequency (70-80%) followed by adenocarcinoma (10-25%). Adenocarcinoma is the one with the worst prognosis. As for the other histological types of cervical cancer, they are found in very limited percentages, such as small cell carcinoma, which occurs in less than 1% (11). Depending on the degree of differentiation, tumors are subdivided into well (Grade I), intermediate (Grade II), and poor (Grade III) differentiation, and the depth of filtration seems to play a major role. If the filtration depth is less than one-centimeter, five-year survival rate is estimated to be approximately 90%, while if it is greater than one centimeter, it is estimated to be below 80% (12). In 2020, this cancer was the fourth most frequently diagnosed cancer among women worldwide and the fourth leading cause of cancer death (13). According to World Health Organization statistics, in 2018, the number of women diagnosed with cervical cancer worldwide reached 570,000, while the number of deaths from this type of cancer in the same year was 311,000 (14). Cervical cancer is most often diagnosed in women between the ages of 35 and 44, with the median age of diagnosis being 50 years of age. Older women do not seem to realize that the risk of cervical cancer persists as they get older. More than 20% of cervical cancers are found in women over the age of 65, while only 6% of cases involve women older than 85 years. However, this cancer appears to occur rarely in women who had undergone regular screening for cervical cancer before the age of 65 years (15). The most important causative agent for the development of cervical cancer is considered to be the human papillomavirus (HPV) (16). Cervical cancer develops by cervical intraepithelial neoplasia (CIN), caused by HPV (17). Cervical cancer risk factors include: 1) Early age of first sexual intercourse. Women who had their first sexual intercourse before reaching the age of 18, seems to have doubled the risk (18); 2) Immunosuppression, such as seen in women infected with the human immunodeficiency virus (HIV) (19); 3) Large number of sexual partners (20); 4) Existence of a high-risk sexual partners; 5) History of infection with sexually transmitted diseases (21); 6) Active or passive smoking (22); 7) Usage of oral contraceptives (23); 8) Pregnancy and childbirth at a young age (18); 9) Large number of deliveries (24); 10) Racial characteristics (25); 11) Individual history of either vulvar or vaginal intraepithelial lesion or cancer (26); 12) HPV infection (27); 13) Low socio-economic status (28). Usually, the diagnosis is made during a preventive screening with a Pap test, followed by cytological examination colposcopy and biopsy of the cervix (29). The clinical profile of women with cervical cancer depends directly on the extent and exact anatomical location of the lesion. In early stages, the patient is usually asymptomatic and the diagnosis may occur randomly (30). Symptoms in advanced stages of the disease include: 1) Posterior sternal pain (31); 2) increased vaginal secretions (6); 3) a foul-smelling vaginal secretion (32); 4) Vaginal bleeding (either spontaneously or after sexual intercourse) (33); 5) inguinal lymph nodes enlargement (34); 6) Weakness - fatigue – exhaustion; 7) Anemia; 8) Weight loss (35); 9) Ureteral obstruction; leading to oliguria or anuria in advanced stages of the disease (36). The management of cervical cancer depends on the stage and extent of the disease. Treatment options include chemotherapy, radiotherapy and surgery (cone resection, radical cervical resection, hysterectomy - partial, radical or modified) (37). In developing countries, where Pap smear availability is limited, cervical cancer is the second leading cause of morbidity and cancer death among women compared to developed countries. It is estimated that if screening for cervical cancer was performed in accordance with international recommendations, the prevalence of this disease could be reduced to >4 per 100,000 cases per year (27). • About 85% of the research samples were infected with HPV. • Amplification of the 3q26.3 chromosome was found in the majority of samples of gynecological cancer tissues of the cervix. • An increased number of Researchers concluded that PIK3CA is one of the oncogenes responsible for cervical carcinogenesis (39). According to Yu-Li and Wang (2015), another oncogene responsible for initiating cervical carcinogenesis is HCCR. This oncogene is involved in the development of cervical cancer, by inhibiting the function of the tumor suppressor gene • 77% of the samples were infected with HPV. • The PIK3CA oncogene appeared amplified by 43% on the samples. • There were other amplified oncogenes in the samples, such as: • Increased expression of c-erbB2 and c-myc proteins was observed in tumors with the corresponding gene amplification. • Most amplified oncogenes were found mainly in tumors that were infected with HPV (mainly Riou Ovarian Cancer Malignant ovarian tumors are epithelial in 90% of the cases. Epithelial tumors may show various degrees of histological differentiation and are considered to be aggressive (45). In recent years, knowledge about the histological origin of ovarian cancer has changed dramatically. The disease was initially thought to originate from the ovarian epithelial cell lining, but in the light of new evidence, it seems that ovarian cancers originate from other structures (including the fallopian tube and endometrium) (46). These new data are important for both prevention and detection of cancer. They should also be taken into account when conducting clinical trials and experimental studies, especially with regard to the search for new diagnostic markers and new therapeutic targets (46). According to the latest data, ovarian cancer, although it is not the most common gynecological cancer, it has high rate of mortality (47). In 2012, 239,000 new cases of ovarian cancer were diagnosed worldwide, leading to 152,000 deaths. Ovarian cancer is the 7th most common cancer in women worldwide and ranks 5th in prevalence in developed countries (48). The exact cause of ovarian cancer has not yet been scientifically established, but there are some factors that have been well known to be implicated in increasing the risk (47). These factors include: 1) A positive medical family history of ovarian cancer, breast cancer and /or colorectal cancer (without polyps); 2) Age over 50 years; 3) HPV infection; 4) Smoking; 5) Sedentary life; 6) Obesity; and 7) Endometriosis (47). In the early stages of the disease, women usually show complete absence of clinical signs and symptoms (47). The diagnosis is based on hereditary and personal history, clinical examination, abdominal and/or vaginal ultrasound (depending on the estimated size of the tumor), possibly the color Doppler, and plasma CA 125 levels (49). In advanced stages symptoms may appear, including: A possible palpable mass during a typical gynecological examination; 2) Constipation; 3) Feeling of bloating; 4) Dizziness - nausea – vomiting; 5) Weakness, fatigue and exhaustion; 6) Anorexia and weight loss; 7) Anemia; 8) Swelling of the lower extremities; 9) elevated core body temperature (50). Therapeutic approaches include chemotherapy and surgery (depending on the extent of the disease) (51). In addition, there is evidence that the same oncogene may appear amplified in other types of cancer, such as endometrial, gastric, and salivary gland cancers (54). The HER-2/neu proto-oncogene encodes a 185 kDa transmembrane receptor protein with endogenous tyrosine kinase activity, which acts as an epidermal growth factor (53). According to Berchuck Amplification of the Increased degree of nuclear atypia and mitotic count is linked with the presence of Another oncogene whose amplification has been shown to be involved in the development of ovarian cancer is PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3-kinase) (59). Finally, a group of researchers tried to correlate the enhancement of the GIP2 oncogene expression, with the development of ovarian cancer, but did not find a significant correlation (60). Uterine Cancer Rarely, cancer of the uterine body comes from histological elements other than the endometrium. There are two types of uterine cancer: Type 1. This type is more frequently found and accounts for 80% of endometrial cancers. It is related to postmenopausal and concurrently obese women. Type 2. This type is associated with a poor prognosis, and it usually refers to younger women with a slimmer body type (5). According to 2018 statistics, endometrial cancer is the 6th most common cancer among the female population worldwide, while in relation to the total population it is ranked in the 15th place (61). Factors, either exogenous or endogenous, that increase uterine exposure to estrogen are associated with increased risk of endometrial adenocarcinoma development (62). Another risk factor that triples the risk of endometrial cancer is polycystic ovarian syndrome (63). Other factors include: 1) Early menarche; 2) Delayed menopause; 3) neglected women (the risk for them is up to twice as high); 4) Exogenous administration of estrogen; 5) Treatment for breast cancer with tamoxifen (risk increases up to twice); 6) Thyroid disease; 7) Elevated body mass index; 8) Advanced age; 9) Diabetes mellitus;10) Lynch syndrome; 11) HPV infection; 12) Positive medical family history of endometrial, ovarian, colon or breast cancer (64). Early endometrial cancer diagnosis leads to more positive outcomes. The most common initial symptom is postmenopausal hemorrhage or spotting, although may also occur in reproductive ages (65). The diagnosis is confirmed by obtaining endometrial biopsy after dilation and curettage or uterine ablation (65). Other symptoms that may appear include: 1) Low hematocrit; 2) Weakness - fatigue – exhaustion; 3) Abdominal - pelvic pain (65). Surgery is defined as treatment for endometrial cancer, and the surgical technique is determined by the stage of the disease at the time of diagnosis (65). Giannakis Jiang Vaginal Cancer Vaginal cancer is mainly due to epidermal carcinoma (90% of cases) and adenocarcinoma (5% of cases). Other rarer types are melanoma (2% of cases), sarcoma (2% of cases) and wart carcinoma (1% of cases) (71). This type of gynecological cancer is not so common (1-2% of gynecological cancers) and is usually a metastasis from another primary site. Older women in menopause have a higher risk of developing the disease than younger women with childbearing potential (72). The exact cause of vaginal cancer has not been determined yet. There are various theories about the origin of this cancer but none is fully scientifically substantiated (72). The following factors have been implicated: 1) Multiple sexual partners; 2) Young age during the first sexual intercourse; 3) Smoking; 4) Excessive alcohol consumption; 5) HPV infection (73). The initial diagnosis is based on a careful examination of the vagina and cytological smears, while the final diagnosis is made by biopsy (72). In the early stages, the disease is asymptomatic and thus difficult to detect. In more advanced stages symptoms may appear such as: 1) Vaginal bleeding; 2) Bleeding or pain during sexual intercourse; 3) Bad smelling vaginal secretions; 4) Increased vaginal secretions; 5) Intense vaginal itching that does not subside; 6) Urinary discomfort (72). The main treatment options for vaginal cancer are radiation therapy, surgery, and chemotherapy if metastases are present (74). Vulvar Cancer About 90% is due to epidermal carcinoma, while the rest is due to wart carcinoma, melanoma, basal cell carcinoma or sarcoma (75). Vulvar cancer belongs to the category of rare gynecological cancers as it represents 4% of gynecological tumors (75). The pathogenesis of vulvar cancer refers to dysplasia that usually arises from the HPV or from vulvar dermatitis, such as sclerosis of the vulva (75). Risk factors include: 1) Smoking; 2) Positive personal medical history of sexually transmitted diseases; 3) Immunosuppression; 4) Increased body weight; 5) Diabetes mellitus; 6) Hypertension (76). For the diagnosis of vulvar cancer, it is necessary to perform a biopsy. Other additional examinations that are usually performed include pelvic magnetic tomography, abdominal CT scan (disease staging), groin ultrasound (lymph nodes evaluation) and various blood tests (75). The main symptom of the disease is itching of the vulva, which very often becomes very persistent and unbearable. Other symptoms are: 1) Genital pain; 2) Vulvar swelling; 3) Increased secretions with possible presence of blood; 4) Superficial inguinal lymph node swelling; 5) Difficulty urinating and / or defecating; 6) Weakness - fatigue (75). In case of early-stage diagnosis, a radical local resection can be performed without lymph node dissection. Unfortunately, vulvar cancer in most cases is diagnosed usually at advanced stage. The surgical techniques applied in these cases depend on the respective stage of the disease. A radical “butterfly” type vasectomy is usually performed with lymph node dissection (removal of the perineum, anus, and rectum may be required) or radical resection. In addition, the patient may need to undergo a cycle of radiation and/or chemotherapy (71). Bodelon

This review of the literature indicates that in recent years there has been a lot of research on the genetic contribution to the development of gynecological cancer. Several signaling pathways and oncogenes have been implicated in the development, growth, and metastasis of gynecological cancer. Conflicts of Interest The Authors declare that they have no competing interests in relation to this work. Authors’ Contributions S.D, G.N, C.A, K.NE and S.P; Contributed to conception and design. K.NE, N.T, F.Z, AK and P.A.; were responsible for overall supervision. SA, S.AA, D.M and K.A; Drafted the manuscript, which was revised by K.NE. All Authors read and approved the final manuscript.