View of Analysis of Risk Factors of Epithelial Ovarian Cancer; Prevention & Diagnosis

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http://annalsofrscb.ro 780

Analysis of Risk Factors of Epithelial Ovarian Cancer; Prevention &

Diagnosis

Aiman Ashfaq¹, Tayyaba Shan², Nagina Zulfiqar³, Syed Waqas Hassan⁴, Bushra Gul^5*

1,2,4,5*

Department of Biosciences, Faculty of Basic Sciences, University of Wah.

3Department of Statistics, Faculty of Basic Sciences, University of Wah.

2,5*Department of Zoology, Faculty of Biological Sciences, Quaid e Azam University.

Corresponding Author Email: [email protected]

Abstract

To study the clinical heterogeneity of ovarian malignancy growth, what the job ofBRCA2gene in human cell and how it is answerable to ovarian cancer. To study the hereditary qualities and subatomic and organic system include in the advancement of ovarian cancer, distinctive treatment and medical procedures that demonstrated advantageous in rewarding ovarian malignant growth and lessen its danger of reoccurrence. Data is collected from medical record of ovarian cancer patients fromPOF hospital between 1^stNov 2019 to 30^thJan 2020. Medical history of the patient was study in which her biopsy, hormonal, chemotherapy medication ultrasound of pelvic, CA125 blood test, TVUS, Transvaginal ultrasound, family history, imaging test, CT scan, laparoscopy report include. IBM SPSS statistic version 25 software is used to prepared result.

Genetically, ovarian cancer is a heterogeneous and dynamic disease that presents several clinical and research challenges. The most common symptoms among ovarian cancer patients were GT tract symptoms in which pelvic mass, abdominal distension and ascites were most common.

Most of the patient diagnosed at stage 3 and high level of CA125 is noticed in their blood test report. 40% of our patients under study suffer from serous ovarian cancer.60% of our patient treated with chemotherapy and 25% with medication. So, the purpose of our study is to provide relationship between lifestyle risk factors and epithelial cancer diagnosis.

Keywords: Ovarian cancer, risk factors, BRCA2,lifestyle

Introduction

Our body is made up of cells which are the basics building blocks. Cancer is a disease of cell in which body cell divided uncontrolled and die in an unusual way due to which lymph called tumor formation took place (AIHW, Canberra, December 2017).Induction of proliferation of cells and mutations in DNA are the two broad terms for molecular trauma which causes cancer

(Abbas et al., 2021).Normally cell grow and divide but these cells cannot divide normally. There are two types of tumors. Benign tumor (If cell do not migrate to other areas of the body and confine in one area). Malignant tumor (Some cells migrate through blood stream or lymphatic system (lymph fluid) such cell is called cancerous cell(National Comprehensive Cancer Network US.,2017).Cancer is categorized into two types primary and secondary cancer. In Primary cancer, cancer advance within an organ and do not spread to adjacent tissues.Secondary cancer or metastasis, cancer grow and spread to surrounding areas and form tumors at new places. Both ovaries are present in the lower part of the abdomen and both side of the uterus. Ovaries are

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composed of three types of tissue Epithelial, Germinal and Stromal cells. Cells form the outer layer of ovary is called epithelial cell. Germinal cells mature into egg and present inside the ovary. Stromal cells are supporting tissues. These cells produce two important hormone estrogen and progesterone (AIHW, Canberra, December 2017).The most lethal of all female reproductive cancers are ovarian cancer (Slatniket al., 2015). It is also called silent killer; it is not identified even at advanced stages because indicationsare unclear and lack of definitive screening tools.(Jayson et al., 2014). Even in70 % cases the symptoms are not clear even in stage 3 and 4.

After 5-year survival rate for ovarian cancer is 47.4% (ChienIntJGynecolCancer.2018). Ovarian cancer does not begin in ovaries in most cases it starts from the fallopian tube (Mallenet al., 2018). Under the age of 30 ovarian cancer risk are rare.Outcome of the disease is called prognosis (AIHW, Canberra, December 2017).Survival rate of women having ovarian cancer is directly related to the stage of disease at a time of diagnosis (Jayson et al., 2014). There are 90%

chance of 5-year survival if women diagnosed at stage 1. Following were the three types of ovarian cancer. Epithelial cancer Outcome is influence by stage and grade of cancer. If the epithelial cancer is not spread outside of ovary (stage 1) it has good prognosis. Women with advanced cancer may respond very well but there are probabilities that cancer will return, and further treatment is required.Germ cell and stromal cell tumors treatment is successfully done.Borderline tumorshave good prognosis (AIHW, Canberra, December 2017).Epithelial ovarian cancer is divided into 4 types serous, endometrioid, mucinous and clear cell.Epithelial ovarian cancer has 3 sites of origin ovarian, tubal and epithelial site in pelvis. There are 2 categories of epithelial ovarian cancer type 1 tumor and type 2 tumor. Type 1 tumor is less lethal than type 2 tumor. Main causes are continual ovarian cycles, inflammation, endometriosis.

Endometriosis is a cause of 5% to 15 %of epithelial ovarian cancer.Type 2 tumor is more lethal than type 1 tumor (Slatnik& Duff, 2015). Unfortunately, it is not diagnosed early, and main causes of type 2 tumors are BRCA gene genetic mutation and p53 mutation and tumor suppressing gene.

Structure Of BRCA gene

On long arm of chromosome 13 (13q12.3) BRCA gene is located, and it composed of total 27 exon that encode a protein having 3,418 amino acid. PALB2 done interaction with the N- terminal domain of the BRCA2. 8 BRC repeats located in the central portion of the protein of BRAC gene it play an important role in binding to monomeric RAD51 (RAD51 binding domain:

RAD51-B. BRCA2 binding to single-stranded DNA and poly (ADP-ribose) is promoted by the BRCA2 DNA binding domain (DNA-BD). The TR2 domain interacts with RAD51 nucleo filaments on the C-terminal of BRCA2 (Canneryet al., 1984). RAD51-BD matches to the region that cover AA1003-2082 of BRCA2 exon 11.

Mutations in BRCA2 gene

BRCA2 is tumors suppressor gene involved in the maintenance of genome integrity by means of two main functions: DNA repair by homologous recombination and by Stabilization of replication forks under replication stress BRCA2 interacts directly with RAD51 and promotes its specific recruitment to dbs. sites where recombination is initiated. The improved survival of BRCA1/ BRCA2 germline mutation carriers, especially BRCA2 carriers, compared with non- carriers. However, there is no clear explanation of why BRCA2carriers fare better than BRCA1 carriers. Genetic and functional studies of BRCA2 revealed that mutations located in RAD51-BD impair the ability of BRCA2 to recruit RAD51 (Canneryet al., 1984).Mutations in the RAD51-

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BD (exon 11) of the BRCA2 gene impact progression-free survival (PFS), platinum-free interval (PFI), and overall survival (OS) in ovarian cancer patients. Ovarian cancer patients who were carriers of BRCA2 germline mutation and were treated with DNA damage agent platinum showed prolonged survival. Not all BRCA2 carriers are highly sensitive to DNA damage agents, and the response depends on the location of the mutation in the various functional domains of the protein. Estimates of the lifetime risk for ovarian cancer range from 16% to 60% for BRCA1/2 mutation carriers. Among Ashkenazi Jewish women, in whom one of the three founder BRCA mutations has been found, lifetime ovarian cancer risks were 54% for BRCA1 and 23% for BRCA2 mutations. In support of this hypothesis, many (but not all) studies of the ovaries of ovarian cancer-prone individuals, i.e., women with a family history of ovarian cancer and/or a deleterious BRCA1 or BRCA2 mutation, have reported more changes in their surface epithelium than control ovaries. Additional hypotheses concerning steroid hormones and the retrograde transport of carcinogens through fallopian tubes may also contribute to ovarian cancer risk in certain circumstances and magnitude. However, gonadotropins may also stimulate an ovulation- like loss of the ovarian surface epithelial basement membrane. The loss of basement membrane may dramatically alter the biology of the epithelial cells in tissue organization and cell contact signaling.

Risk Factors

Due to nonspecific symptoms like abdominal bloating, abdominal pain and urinary frequency and changes in bowel habit women’s do not seek medical care and ignore such symptoms.

Ovarian cancer can occur in any women that have no notable risk factors(AmericanCancerSocietyCancerfactsandfigures2018).

Family history women risk of ovarian cancer increases if there is a history of breast and ovarian cancer is present within in family. If there is a mutation in a BRCA 1 and BRCA 2 and MMR gene risk of ovarian cancer increase to 1.6% to 40%,18% and 10 %(Tschernichovsky&

Goodman 2017). If the women are a carrier of these mutation, there are 10% to 40% chances that she will get ovarian cancer by the age of 70. One of the autosomal dominant genetic disorders which is known as Lynch syndrome increases the risk of many types of cancer including colorectal and ovarian cancer. Ovulationalso increases risk of ovarian cancer. More ovulatory cycles more risks of ovarian cancer (Walker et al., 2015).Ovulations promote malignant ovarian tendencies because of pro inflammatory response of distal fallopian tubes (Mallenet al., 2018).

There are many factors that decrease risks of ovarian cancer are pregnancy, breastfeeding, early menopause, early onset of menses and birth control use.Endometriosis is associated with epithelial ovarian cancer. Endometriosis that links to epithelial ovarian cancer develop in younger women and have better prognosis. There is no evidence that women chance of getting ovarian cancer decrease if we remove endometriosis lesions (SchenkenEndometriosis:pathogenesis). There are very few studies that shows what is the relationship between dietary fibers and ovarian cancer. Huang et al said ovarian cancer chances decreases if we increased intake of dietary fiber(Huanget al., 2018). If women increase soy in her diet risk of epithelial ovarian cancer decrease.There will be high risk of developing ovarian cancer if there is a low level of Vitamin D in diet.There are certain ethnic group that have genetic risk of developing ovarian cancer is very high like Dutch, French Canadian, Jewish and Icelandic descent (Guoet al., 2018).

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Prevention

To prevent ovarian cancer then educating women and health care providers about sign and symptoms, risk factors play a very important role. According to one of the study women in general population were unable to identify sign and symptoms of ovarian cancer and certain factors were associated wrongly with ovarian cancer. Only 40% women were slightly familiar with ovarian cancer sign and symptoms (Goldsteinet al, 2015).

Teaching about ovarian cancer sign and symptoms and risk factors to general populations and to women’s that may have a chance to develop cancer in near future increases health awareness this will also decrease the late diagnosis cases. Interruption of ovulation:40 %-50% ovarian cancer risk decreases due to oral contraceptive. Longer the use of oral contraceptive more the chances of getting ovarian cancer decreases. The women risk of getting ovarian cancer decreases by interruption ofovulation. Disruption of ovulation occur in many ways like removal of fallopian tube or ovaries, pregnancy, breastfeeding. If women become pregnant under the age of 25 risk of getting ovarian cancer also decreases.In one of the study it is mentioned that ovarian cancer chances decreases with use of aspirin (NCCN; ovarian cancer).While other studies reveal that there is no effect of aspirin and use of aspirin decreases the chances of ovarian cancer.

Endometriosis produce inflammation that produce carcinogenesis, by using anti-inflammatory medication produce positive effect by decrease further tumor formation (Mallenet al., 2018).

Screening & Diagnosis

Ovarian cancer screening become very difficult because of nonspecific symptoms. Initially tumor marker CA125 (cancer antigen 125) used as a screening tool for ovarian cancer. But now CA125 marker is no more used as a screening tool because of lack of specificity and sensitivity.

There is no effective screening tool for ovarian cancer, but combination of different tools is very effective. There are certain proteins produced by cancerous cell which is called tumor markers.

The most common protein produced by cancerous cell is CA125.In patient suffering from cancer level of CA125 is very high but there are many reasons behind high level of CA125 like ovulation, menstruation, kidney disease and fibroid. It can be used: At diagnosis; If women are through menopause than CA125 test is more accurate for diagnosing ovarian cancer than in women’s who have not. Initial ovarian cancer patient has normal ovarian CA125 level due to this combination of CA125 blood test and ultrasound is used. During treatment, If the cancerous cell produces CA125, the blood test is done to know how well the treatment is working. If the level of CA125 is decreasing means the treatment is working well but if the level is rising, then treatment is not working well (NCCN Guidelines, 2017). A transvaginal sonography is not specific for ovarian cancer if it is solely used but if it is combined with CA125 marker human epididymis protein 4 it became effective for ovarian cancer. Core needle biopsy play an important role in diagnosing ovarian cancer. In this treatment aspirated tissue is examined closer to discover malignancies.

Methodology

Data was collected from the patient who referred to medical oncology department of POF hospitalWahcantt, Pakistan. Information was collected between 1^st Nov2019 to 30^th Jan 2020.

Eligibility criteria required for all the documentation related to ovarian cancer and ability of close relative and patient herself to provide information. In this analysis the patients that were suffering from any type of ovarian cancer whether initial or last stage and patients undergoing chemotherapy as well as the patient that were recovered from the ovarian cancer were included.

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Information was collected from the patient and their close relative during the interview.Medical history of the patient was studied in which her biopsy, hormonal, chemotherapy medication ultrasound of pelvic, CA125 blood test, Transvaginal ultrasound, family history, imaging test, CT scan, laparoscopy report included.

Results

Mean ages of the women in our data is 60 and median was 59. Mean weight and height of the ovarian cancer patients in our data is 72.5 and 5.49. Mostly women belong to middle (40%) and low class (40%). 85% of women do not have any history of ovarian cancer.65 % of women have no family history of malignancy only 35 % of women have family history of any malignancy.80% of women do not have any personal history of any malignancy and only 20%

person have personal malignancy history (Fig 2).10% of women said they have cyst in their uterus and 10 % said they have heavy vagina bleeding and 80 % said that there is no history of any gynecological problem (Figure 3).45% of patients were using oral contraceptives 50%(Fig 1). 15% of patients were using mineral water,while 45% said they use tap water and 40 % were using underground water.

Figure 1. History Of Oral Contraceptives

Figure 2: History of malignancy of patient

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Figure 3: History of Gynecological problem

5% of the women have still birth and 15% have miscarriage (Table 1).50% said their first menstrual cycle begin at 15-16 years and 25% said their menstrual cycle begins at 11-12 years.

40% women have their menopause at 48-50 year and 20% have their menopause at 57-60 (see table 3). 65% of the women have chemotherapy, 25% use medication and 10% use not any kind of treatment for ovarian cancer (see table 2). 35% of the women removed their uterus and 65%

had not. 35 % of the women had their 1 child at 1923 years and 30% had their 1 child at 27-29.

60% of the women have stage 3 ovarian cancer, 25 % have stage 2 cancer,10% have stage 1 and 5% have stage 4 ovarian cancer.80% of the women have not noticed any kind of pain and 20% of the women have noticed a little bit pain. 55% of the women carry out lactation for 1 years,15%

for 1.5 year and 10% for 2 years.

Table 1: History of stillbirth or miscarriages

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Table 2: Treatment used for ovarian cancer

Table 3: Age at Menopause

Table 4: Percentage of Pelvic mass in ovarian cancer patients

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65% of the ovarian cancer women have large pelvic mass,20% have medium and only 15% have small pelvic mass (see table 4).85% of the women have bulky mass and 15% of the women had not. 85% of the women suffering from Ascites and 15% of the women were not.65 % of the women suffering from large amount of pleural effusion and 15% have small amount of pleural effusion.70% of the women have large amount of abdominal pap smear and 15% of the women have small amount of abdominal pap smear. 85% of the women have high amount CA125 level and 15% have low amount of CA125 level (see table 5). 55% of the women suffer from abnormal LFT’S and 45% of the women do not suffer from abnormal LFT’s.

Table 5: Levels of CA125 in blood

Table 6: Stage of ovarian cancer

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Table 7: Percentage of affecties with Ascites

60% of the women have stage 3, 25% have stage 2, 10 % have stage 2 and only 5 % have stage 4 of ovarian cancer (see table 7).60% of the women have grade 2 cancer, 30% have grades 3 and 10% have grade 1 ovarian cancer (table 8).40% have serous, 25% have mucinous,15 % have endometrioid and 10% have clear cell ovarian cancer (table 9).

Table 8: Grade of ovarian cancer

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Table 9: Type of ovarian cancer

Figure 4

Women with the age 48-50, 10% of them have stage 1, 20 % of them stage 2 and 40 % have stage 3 ovarian cancer.Women with the age 54-56, 10% of them have stage 2 and 30 % of them have stage 3 ovarian cancer. Women with the age 57-60 ,10% of them have stage 2 cancer and 30 % of them have stage 3 cancer.

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Figure 5

Ovarian cancer patients with the age 51-55, 10% of them have serous and 10 % of them have mucinous cancer. Patient with the age 56-60 ,30 % of them have serous cancer 20% of them have mucinous cancer and 10 % of them have endometroid cancer.

Figure 6

Women with the weight 80 have 30 % high level of CA125 in the blood as compared to the women having the weight of 60 with 10% of CA125 in the blood similarly women with weight

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70 have high level of CA125 as compared women having the weight of 60 but less than the women with the weight of 80.

Figure 7

60 % of the women with the stage 3 receiving chemotherapy and 40 % of them receiving medication .40 % of the women with stage 2 cancer they are receiving chemotherapy and 10 % of them receiving medication.

Figure 8

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67% of the patient with serous cancer said they suffer from Ascites while 10% of them said they do not suffer from Ascites .30 % of the of the patient with endometrioid cancer said they suffer from Ascites .10% of the patient with borderline cancer said they suffer from Ascites while 105 said they do not.

Discussion

Ovarian malignant is the most widely recognized disease of gynecology in Pakistani women in contrast to few other nations of Asia. There has been an expansion in the examination enthusiasm for screening of ovarian malignant growth with greater part of research being centered around utilization of biomarkers and pelvic ultrasound with multimodal evaluations for early identification of ovarian disease (Menonet al., 2009). In the course of the most recent decade, research has been intensified on indication-based location of ovarian malignant growth with the potential preferred position of early recognition and auspicious treatment (Bankheadet al., 2005). Like Japanese,Indian and Israeli women’s the means age of ovarian cancer is 60 years in Pakistan women. However, Genetics as well as environment factors may involve but reason remain unknown still. National cancer institute in Pakistan is the organization in which the treatment of ovarian cancer done.55 % women do not take Oral contraceptive. It is interesting to note that there are very few cases of late childbirth and early menopause and null parity.

Symptoms of ovarian cancer were vague and not clear. In the development of ovarian cancer family history is the important factor of ovarian cancer. Most of the respondent were either uncertain or not knowing the significance of family ancestry of ovarian disease. Only a minority are defined as hereditary ovarian cancers. 7 % of our patient have positive family history of ovarian cancer. Generally relative of these patients have first degree relationship with the patient and the greater part of them had either bosom or ovarian malignancy. This raises the probability of hereditary components playing a progressively significant job in ovarian malignancy.

Consanguineous relationships are normal in Pakistan. Thirty five percent of all patients in our arrangement had consanguineous relationships. More research is expected to contemplate the impact of association in Pakistani patients with epithelial ovarian disease, especially in those with positive family ancestry. Clinical introduction and lab highlights of our patients are very attribute of the ailment. The information on manifestations and hazard components of ovarian malignancy among women in everyone is low, however, that women with ovarian cancer do suffer from symptoms (Lockwoodet al., 2009). It is hard to recognize the manifestations of ovarian malignant growth from those of different conditions, for example, irritable bowel syndrome or other gastrointestinal infection. In this study 20% of women suffer from abdominal pain,85 % from abdominal distension and,80 % from nausea and dyspepsia, bulky uterus notices in 85% women’s and 35% suffer from vaginal bleeding and 85% also suffer from Ascites. The present perception may propose that while analyzing the ovarian malignancy, equivalent importance should be given to stomach, gastrointestinal, and protected side effects.

Ladies with ovarian malignant growth experience side effects all the more every now and again, harshly, and relentlessly than ladies without the malady. On chromosome 17q21 and 13q1213 BRCA 1 and BRCA 2 gene were present. BRCA1 and BRCA2 play an important part in the reaction to cellular stress, the localization to sites of damaged DNA, and the activation of DNA repair processes. Both genes through the conservative mechanism of homologous recombination repair DSB (Abbas et al., 2021). Large numbers of mutation could occur in both of these tumor suppressor gene which can cause protein inactivation. The concept of “BRCAness” illustrate the traits that some cancers may be occur due to BRCA1/2mutation (Turner et al., 2004). Through a

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number of epigenetic mechanisms such as promoter hyper methylation and loss of heterozygosity the inactivation of BRCA1 occur which may become the cause of ovarian cancer (Bozzettiet al., 2004). Ovarian cancer patients with the mutation of BRCA1 carriers diagnosed at younger age (52-year average age) compared to women with BRCA2 mutation carriers diagnosed at age of 62.

Level of CA125 in the blood is very important indication in clinical practice and in the preclinical asymptomatic phase of the disease its level increases. Level of CA125 is used to predict the level of malignancy of ovary. Sensitivity of CA125 in predicting ovarian cancer is 81

% to 91%.(Canneryet al., 1984). In this study 85 % of the women with ovarian cancer have high CA125 blood level while only 15 % have low CA125 level (Zurawskiet al., 1988).It is suggested that lady with sign and symptoms of ovarian malignancy should have a cautious pelvic assessment. The National Institute for Health and Clinical Excellence (NICE, UK) Referral rules for suspected disease in 2005 suggested that any lady with a considerable stomach or pelvic mass on assessment that isn't clearly uterine fibroids or not of gastrointestinal or urological beginning ought to have a ultrasound examine.In the event that the sweep is reminiscent of malignant growth, or if ultrasound isn't accessible, a pressing referral ought to be made. It is critical to take note of that NICE, UK has refreshed the direction for acknowledgment and starting administration of ovarian malignant growth in 2011, which presently proposes that those patients identified by assessment to have ascites, or abdominal or pelvic mass should be referred urgently (NIH Clinicalguideline122).

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