Association of Dyslipidemia, Renal dysfunction, and Uricemia with HPV mediated Cervical Cancer

doi:10.21203/rs.3.rs-1821603/v1

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Association of Dyslipidemia, Renal dysfunction, and Uricemia with HPV mediated Cervical Cancer

https://doi.org/10.21203/rs.3.rs-1821603/v1

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Recently obesity, dyslipidemia and uricemia has been implemented in cancer progression and development. Therefore, in the present study lipid profile, renal function and uric acid levels have been evaluated and their association has been assessed in HPV-mediated cervical cancer (CaCx) patients. Women diagnosed with CaCx were tested for HPV infection using conventional PCR. Anthro-demographic and clinicopathological characteristics were recorded and samples from patients (n = 103) and healthy women (n = 108) were analyzed for dyslipidemia (total cholesterol, TC; triglycerides, TG; high-density lipoprotein, HDL; low-density lipoprotein, LDL levels), serum urea, creatinine and uric acid using commercially kits. All statistical analysis was done using SPSS (ver.21.0) and GraphPad. Out of 103 CaCx patients, 86 were HPV + ve and 17 were HPV-ve. BMI was associated with HPV + ve with a higher risk (1.55 folds) while cholesterol was relatively significant in HPV-ve cases with a 1.01 folds crude OR. TG, HDL and LDL were found significantly associated with an increased adjusted OR in HPV + ve cases. Urea levels were found significantly higher in HPV + ve as compared to HPV-ve (1.63 vs 1.12 folds Crude OR). while the adjusted OR became deceased in HPV + ve CaCx patients (1.10) compared to HPV-ve CaCx patients (1.31). Both creatinine and uric acid showed significantly higher adjusted OR (11.07, 1.53) in HPV + ve cases as compared to HPV-ve (10.37, 1.46). Dyslipidemia, renal dysfunction, and uricemia were found clinically significant in CaCx patients. Therefore, TG, HDL, LDL, serum urea, creatinine, and uric acid can be used as prognostic biomarkers for HPV-mediated cervical cancer.

Dyslipidemia

Renal dysfunction

Uricemia

HPV Infection

Cervical Cancer

Cervical cancer (CaCx) is the 9th most severe cancer in the world with 3.4 lakh deaths and > 6.0 lakh new cases worldwide and ranks 4th among women in 2020 [1]. In India, it ranks 2nd with > 1.2 lakh new cases and > 77,000 deaths [1]. The main causing agent of cervical cancer is human papillomavirus (HPV). Approximately, 184 HPV strains have been identified including 15 high-risk HPV (HR-HPV) which are responsible for cervical carcinogenesis [2]. Infection by HR-HPV strains activates certain oncogenes which in turn interfere with protective proteins controlling cell growth [3]. Once these proteins are blocked, cell growth accelerates, leading to tumor development and cancer [4]. Although HR-HPV infection is one of the major risk factors, it is not enough for cervical carcinogenesis. In addition to HR-HPV infection, other risk factors such as age, marriage at an early age, number of abortions, young age at first delivery, parity, oral contraception, multiple sexual partners, low socioeconomic status, and unhealthy living conditions are also responsible for the development of cervical cancer [5–7]. The development of cervical cancer is a multifactorial interaction of genetic, epigenetic and metabolic risk factors, host nutrition, as well as immune response [8].

Recent studies have suggested that obesity, dyslipidemia [9], and Uricemia [10] have significant associations with cancer progression including cancer of the oral cavity [11] breast [12], colorectal, ovary, and prostate [13].

Previous studies have reported that high or low levels of lipids can induce carcinogenesis [14–16] Hypolipidemia/hyperlipidemia has been associated with different types of cancers including gastric cancer [17], prostate [18], and leukemia [19]. Moreover, serum triglycerides have been associated with an increased risk of endometrial cancer [20], while elevated levels of total cholesterol and low-density lipoprotein (LDL) have been reported in colorectal cancer [21]. It has been reported that adipocytes act as energy reservoirs, promoting the rapid growth and metastasis of cancer cells [22]. However, the exact mechanism of lipid (dyslipidemia) mediated cervical carcinogenesis and HPV infection is not well studied. The anti-cancerous therapies have been influenced by lipid profile and lipid peroxidative products like malondialdehyde which cross-links with adenine and cytosine of DNA [23]. This lipid by-product and DNA cross-linking lead to carcinogenicity and mutagenicity in cells [24].

A previous study reported the association of metabolic-related factors including lipid, urea, creatinine, and uric acid with tumor prognosis and tumorigenesis [25]. Uricemia is the result of abnormal uric acid metabolism which has been associated with pathogenesis of various diseases like gout [26], cardiovascular diseases (CVD) [27], pulmonary diseases [28], and cancer [29]. Although serum uric acid possesses antioxidant properties, increased levels can lead to inflammation and promote tumorigenesis. It has been clinically established that chronic inflammation is associated with cervical carcinogenesis [30]. Therefore, uricemia (hyper/hypo-uricemia) might be involved in the initiation and progression of cervical carcinoma. However, the pathological role of uricemia in HPV-mediated cervical cancer is not well known. The urological complications and renal function (urea and creatinine) also play an important role in prognosis and cancer development [31]. Dyslipidemia, renal dysfunction, and uricemia have not been reported in HPV-mediated cervical cancer. To the best of our knowledge, no study is available to assess the association of dyslipidemia, renal dysfunction, uricemia, and HPV or other HPV-related cancers. Therefore, the present study was undertaken to evaluate the lipid profile, renal function, and uric acid in HPV-infected CaCx patients and healthy women.

Subject Selection

The study subjects comprised of 108 healthy women as controls and 103 cervical cancer (CaCx) patients aged between 30–70 years with the same ethnicity. The patients were enrolled in the outpatient unit of Departments of Radiotherapy as well as Obstetrics and Gynecology, KGMU as per the inclusion/exclusion criteria approved by IEC:

Inclusion criteria: Histo-pathologically positive for all stages of squamous cell carcinoma (SCC) and adenocarcinoma (AC), age 30–70 years with cervical cancer symptoms such as vaginal discharge, pain in the lower abdomen and contact bleeding and cervical biopsy positive.

Exclusion criteria: Age > 70 years, having double malignancy and co-morbidities (diabetes, tuberculosis, HIV), cervical biopsy negative, and those who were not willing to participate in the study. Inclusion criteria of control subjects: Healthy age-matched with no previous history of any cancer and histo-pathologically negative for all stages of SCC and AC.

Anthro-demographic and Clinicopathological Characteristics

CaCx patients and healthy women were interviewed extensively for anthropometric (age and body-mass index), demographic data (residence, literacy, socioeconomic status), obstetric profile (parity, age at full-term pregnancy, menstrual cycle, management of menstrual hygiene, menopause and use of contraceptives) and smoking status in a structured proforma. Clinical diagnosis and staging of patients were performed by expert medical personnels following the guidelines of the International Federation of Gynecology and Obstetrics (FIGO) classification system.

Sample Collection and Processing

Two ml of blood samples were collected from CaCx patients and healthy women in non-EDTA vials for serum separation to be used for biochemical analysis. Serum was separated by centrifugation at 3000 rpm at 4⁰C for 6 minutes and stored at -20⁰C for further use.

Cervix tissue samples were collected by biopsy punch in RNAlater from CaCx patients for HPV testing/genotyping. DNA extraction was done using a commercially available Purelink DNA isolation kit (Invitrogen, USA). DNA quality and quantity were estimated in a Bio-photometer (Eppendorf, Germany) and stored at -20⁰C for further use.

Biochemical Analysis

Serum samples (200μl) were used for biochemical estimation of lipids (total cholesterol, TC; triglycerides, TG; high-density lipoprotein, HDL; low-density lipoprotein, LDL), renal function tests (serum urea and creatinine) and uric acid levels using commercially available CliniQuant FSR Kits (Meril Diagnostics, India) in a Blood Analyzer, (SelectraProS, ELITech Clinical systems, France).

HPV testing and genotyping

All 103 cervical cancer tissue samples were subjected to HPV testing by conventional PCR using PGMY09/11primers (Integrated DNA technologies, IDT, USA) [32]. PCR was performed in a 25 µl reaction mixture containing template (50-100ng), 10pmol of each primer, 200µM dNTPs, and 0.5 U of Taq DNA polymerase (MBI-Fermentas, USA) in a gradient Master Cycler (Eppendorf, Germany) and the amplified products were resolved on 2% agarose gels along with 100bp DNA ladder. The study subjects were categorized into 03 groups viz. Group 1: Healthy women as controls, Group 2: CaCx patients with infection (HPV-positive) and Group 3: CaCx patients without infection (HPV-negative). All were correlated with anthro-demographic, clinicopathological and biochemical parameters.

Statistical analysis

Demographic, obstetrics, smoking data are given in percentage, Body Mass Index (BMI), Lipid Profile, Renal Function Test, and Uric acid level are given as mean±SEM. One-way ANOVA or Kruskal Wallis test (depending normality) was used to compare healthy women with CaCx patients with or without HPV infection. Multivariate analysis was performed by fitting logistic regression models to yield odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for variables that were found to have significant association on serum creatinine levels and clinico-pathologic variables, wherever appropriate. All P values were two-sided and differences were considered statistically significant for P<0.05. The statistical analyses were performed by SPSS (Version 21.0).

Cervical Cancer staging and HPV

Most of the CaCx patients (n = 100) had squamous cell carcinoma (SCC), only 03 had adenocarcinoma (ACC). Out of 103 patients, 52.4% belonged to FIGO stage II, 42.7% were stage III, 3.9% stage IV, and 1% stage I. Out of 103 CaCx patients tested for HPV, 86 (83.5%) were found positive while 17 (16.5%) were negative. Out of 86 HPV + ve patients, 60.4% showed the presence of HPV16 and 19.8% showed HPV18.

Anthro-demographic Characteristics

The age distribution of CaCx patients between groups (Healthy, HPV-ve and HPV+ve women) was found to have a significant association (<0.001) (Table 1). HPV+ve CaCx patients belonging to 40-49 years age group were 35%, 50-59 (36%) while 59% and 35% of HPV-ve patients belonged to 50-59- and 60-69-years age group respectively (Table 1).

The residential distribution of CaCx patients within and between the groups (Healthy, HPV-ve and HPV+ve women) did not show any significant association (P=0.357) (Table 1).

Literacy among CaCx patients with or without HPV infection was observed to be 58% and 82% respectively showing significant association (P<0.001) in comparison to healthy women (42%) (Table 1).

The socio-economic distribution of cervical cancer (CaCx) patients and healthy women found a significant association (<0.001) (Table 1). Most of the CaCx HPV-ve patients belonged to the lower class (59%), 35% to the middle class and only 6% belonged to the upper class. CaCx HPV+ve patients (55%) belonged to the middle class, 42% to the lower class, and only 3% to the upper class (Table 1).

The smoking status of CaCx patients was found significantly associated (P=0.025) within and between the groups in comparison to healthy women. HPV+ve CaCx patients (74%) had a smoking history while 35% of HPV-ve CaCx patients were smokers (Table 1).

Clinico-pathological Characteristics

Abnormal obstetrics profiles such as high parity, higher age at first full-term pregnancy, irregular menstrual cycle, menopausal age (>45 years), and adverse menstrual hygiene showed significant association (P<0.001) within and between the groups while use of contraception did not show any association (P=0.111) with cervical cancer development in comparison to healthy women (Table 2).

More than two children were recorded in 86% of CaCx HPV+ve patients and 76% of CaCx HPV-ve patients. Full-term pregnancy age <20 years was seen in 59% of HPV-ve and 53% of HPV+ve CaCx patients. Irregular menstrual cycle was reported in 82% of HPV-ve and 67% of HPV+ve CaCx patients. However, a higher percentage of CaCx patients with menopausal age >45 years and adverse menstrual hygiene was found to be HPV-ve (59 and 94% respectively) (Table 2).

Biochemical Characteristics

Body Mass Index (BMI) was found to be significantly associated (<0.001) in CaCx patients compared to healthy women. The patients with HPV infection showed the highest difference within and between groups (Table 3). Multinomial regression analysis suggested that although BMI increased the risk in HPV-ve CaCx patients by 1.10 folds, it was non-significant while in HPV+ve patients there were significant increase 1.15 folds. When BMI was adjusted with anthr-demographic and clinicopathological characteristics, the risk was found to increase by 1.50 and 1.55 folds respectively in HPV-ve and HPV+ve CaCx patients (Table 4).

Triglycerides (TG), High-density lipoprotein (HDL), Low-density Lipoprotein (LDL), and Cholesterol was found higher in CaCx patients compared to healthy women indicating dyslipidemia in CaCx patients. Dyslipidemia was found to be statistically significant within and between the groups as compared to healthy women (Table 3). Triglycerides (TG), High-density lipoprotein (HDL), and Low-density Lipoprotein (LDL), showed significant differences (<0.001) in HPV+ve CaCx than HPV-ve compared to healthy women while cholesterol level was found to be non-significant (0.776) (Table 3).

Multinomial regression analysis predicted the risk of TG, HDL, and LDL in CaCx HPV-ve CaCx patients and showed a significant association while cholesterol was found non-significant with a crude odds ratio of 1.02, 1.03, 1.02 and 1.01 respectively. In case of HPV+ve patients, TG and LDL showed an increased crude odds ratio up to 1.03 folds, while HDL and cholesterol were found to be similar in HPV-ve CaCx patients compared to healthy women (Table 4). When dyslipidemia was adjusted with anthro-demographic and clinico-pathological parameters, the adjusted odds ratio (OR) of TG, HDL, LDL, and TC increased upto 1.04, 1.03, 1.02, and 0.99 folds in HPV-ve patients, and in case of HPV+ve CaCx patients, the adjusted odds ratio of TG and HDL increased upto 1.05 folds, LDL and cholesterol showed upto 1.03 and 0.99 odds ratio respectively (Table 4).

Urea level was found to be highest in HPV-ve CaCx patients and creatinine level was highest in HPV+ve patients which indicated a significant association between renal dysfunction and CaCx (<0.001) (Table 3). Urea levels impacted the cancer progression with or without HPV infection independently (<0.001) with increasing risk upto 1.12 folds in HPV-ve CaCx while 1.63 folds in HPV+ CaCx patients. Likewise, creatinine levels also increased the risk significantly by 2.66 folds in HPV+ve CaCx and 2.29 folds in HPV-ve CaCx (Table 4). However, after adjustment renal dysfunction increased the relative risk up to 1.10 to 1.31 in HPV+ve to HPV-ve while for creatinine the odds ratio increased up to 10.37 to 11.07 folds in HPV-ve and HPV+ve CaCx patients respectively (Table 4).

The uric acid level was found higher among CaCx patients compared to healthy women which indicated hyperuricemia. Hyperuricemia was associated significantly (<0.001) within and between the groups in comparison to healthy women (Table 3). Hyperuricemia also increased the risk of cancer progression without or with HPV infection up to 1.23 -1.30 folds crude odds ratio and showed a significant association both in HPV-ve CaCx (0.005) and HPV+ve CaCx (<0.001) (Table 4). However, the adjusted odds ratio of uricemia was significantly increased up to 1.46 to 1.53 folds in HPV-ve CaCx (0.022) and HPV+ve CaCx (<0.004) when compared to healthy women.

Epidemiological and clinical data suggested that cervical cancer development is a multifactorial and complex process in which human papillomavirus (HPV) infection takes a central role [3] along with other risk factors such as advanced age, illiteracy, low socioeconomic status (SES), smoking, parity, age at first full-term pregnancy, irregular menstrual cycle, menopause age, menstrual hygiene, sexual behavior and family history [35–37]. The association of HPV infection illustrated that in females this might be due to sexual transmission of the virus as well as the possibility of autoinfection by urogenital contact among women as a result of poor sanitation and hygiene. In the present study, the prevalence of HPV infection is approximately 83% in cervical cancer cases. HPV testing is expensive; thus, screening is not common in the general population specially in developing countries. Therefore, there is an emergent need to make the HPV tests cheaper and accessible to the entire population.

In the present study, as shown by FIGO staging, a higher percentage of patients (52.4 and 42.7) showed stage II and III cervical cancer with a significant association, unlike other stages. Out of 103 CaCx patients, 100 (97.1%) show squamous cell carcinoma (SSC) while 03 (2.9%) were moderately differentiated. The result was consistent with the findings of Jiang et al, (2022) and Afroj et al, (2017) [38]. The present work investigated age, demographic profile, anthropometric profile, and clinic-pathological characteristics of cervical cancer patients with or without HPV infection and healthy women. Age is a crucial factor in malignancy, most studies showed that malignancy presented more in the elderly population when compared to young ones. The mean age of cervical cancer cases was higher (40–59 years), and a significant difference (< 0.001) in age distribution was found in 40-49- and 50-59-years aged patients with HPV + ve, while 60–69 years in HPV-ve patients in comparison to healthy women (Table 1). The cervical cancer cases belonged to a higher age group (> 40 years) and showed a significant association in the study population which is consistent with Afroj et al. (2017) [38] that reported the median age as 45 years but unlike Gupta et al, (2016) [5] who reported > 40 years. Since cervical cancer progression takes 10–15 years to manifest, cases with HPV infection are subjected to several other risk factors and the disease manifests beyond 40 years of age [4] while HPV-ve CaCx patients showed a delayed onset of the disease by > 20 years. However, it was reported that girls who are 15–19 years old are more susceptible to HPV infection [37].

Residence, literacy, and socioeconomic status (SES) are major demographic risk factors that affect the health and hygiene of a community. Socio-economic status refers to social and economic factors including literacy, income or wealth which influence the attitude of an individual or group within the community. It was observed that about 76% of HPV-ve and 72% of HPV + ve patients came from rural areas and showed a significant association (Table 1) which was opposed to Gupta et al, (2016) [5]. Low-income, less educated and working-class population are less likely to have cancer screening than their counterparts. The results showed that 42% of HPV + ve patients were from lower SES and 55% were from middle SES. The result did not show any correlation of SES with HPV infection (Table 1). A similar study was conducted in 22 European countries which showed that socio-economic inequalities influence the occurrence of cervical cancer [39]. These results highlight the potential benefits of population-based screening programs, although their implementation should be preceded by careful consideration of the principles of early disease detection [35].

In the present study, it was found that the percentage of illiterate women was higher among HPV-ve than HPV + ve patients with a significant association (Table 1). Kashyap et al (2019) [40] and Parikh et al (2003) [39] found that illiteracy was also a co-factor associated with cervical cancer. This observation is along the line that women from less educated, socially backward, and low economic backgrounds were less aware of cervical cancer. It is quite apparent that with less education amongst women, there is a lack of awareness about sexual habits, personal hygiene, and their implications.

Cigarette smoking is an environmental risk factor that links many cancers including cervical cancer and is independent of sexual behavior and socioeconomic status [5, 38, 41–42]. Smoking has been linked to the secretion of tumor-specific metabolites in cervical mucus. This mucus maintains cervical oncogenic infection (Otani et al, 2019) and also increases the production of reactive oxygen species (ROS) in cells, resulting in oxidative lesions in DNA [42]. Exposure to cigarette smoke carcinogens induces gene mutation and other genetic effects in targeted tissues, which are hallmarks of cancer [43]. Further, our study observed that the percentage of smokers amongst HPV + ve patients was higher (74%) in comparison to HPV-ve patients (35%) (Table 1). Our results showed that smokers are more prone to HPV infection than non-smokers. Thus, smoking can promote HPV infection which increased the risk of disease. However, this result is favored by an earlier study where it was shown that termination of smoking facilitated the decline of cervical cancer (McIntyre-Seltman et al, 2005). The effects of smoking have been well studied and showed a strong association with cervical cancer [35, 42, 44].

Early age of marriage (< 20 years) indicates exposure to sexual activities leading to HPV infection and early pregnancy, a well-known etiological factor for cervical cancer [35]. Among the clinic-pathological characteristics, only parity showed a correlation with HPV infection in the present study (Table 2). A significant decline in cervical cancer is likely due to changes in marriage and family planning, supported by underlying improvements in education and socioeconomic status [45]. National programs on screening for cervical cancer reduced the incidence and mortality rate in developed countries such as Denmark and Finland. The present study also suggested that multiparity is significantly associated with a higher risk of cervical cancer in the study population (Table 2). Age at full-term pregnancy and high parity can put women at a higher risk of HPV infection and thereby cervical cancer [35, 42, 46].

Women who used oral contraceptive pills (OCPs) for more than 5 years did not show any significant correlation to cervical cancer with HPV-ve or HPV + ve in comparison to healthy women (Table 2). Long-term use of oral contraceptives could be a cofactor that increases the risk of cervical carcinoma up to four-fold in HPV + ve cases [46]. However, not much information is available worldwide about HPV status thus further work is required to enroll long-term users of oral contraceptives in cervical screening programs [35, 46].

Body mass index (BMI) is an extensive risk factor for the assessment of morbidity and mortality of the disease. It has been associated with diabetes, dyslipidemia, renal dysfunction, cardiovascular diseases, hypertension, gallbladder stone, breathlessness, and certain cancers including breast and cervical [47, 48, 49]. Raised BMI contributes to the various pathophysiological roles in chronic inflammation, hormone dysregulation, and metabolic disturbances which leads to the weakening of the immune system and increased susceptibility to viral and bacterial infections [49–50]. In case of cervical cancer, women with raised BMI are more prone to HPV infection or incapable of clearing an acquired infection. However, the role of BMI and HPV infection are poorly defined and open to debate. Previous cross-sectional studies reported that the prevalence of HPV infection increased with obesity [48–49]. Unlike, Liu et al (2015), the incidence, clearance, and persistence of HPV were similar in normal women to overweight and obese women. In the present study, BMI showed a significant difference (p = 0.027) in HPV-ve and HPV + ve patients (Table 3). However, maximum likelihood estimation showed no association in HPV-ve CaCx patients but HPV + ve CaCx ones were significantly associated with a 1.15-folds risk. When BMI was adjusted with anthro-demographic characteristics like age, literacy, socioeconomic status, and clinic-pathological characteristics such as multiparity, age at full-term pregnancy, irregular menstrual cycle, menstrual hygiene, and age at menopause, it showed a significant association with HPV-ve patients with 1.49 folds risk while HPV + ve with an increased risk upto 1.55 folds (Table 4). This indicates that raised BMI may be a contributing factor for HPV infection and its persistence.

Lipids are important constituents of cell membranes that have been utilized by tumour cells for the fulfilment of bioenergy and biomass production [51]. Although various epidemiological reports were controversial regarding the association of dyslipidemia with cervical cancer, the present study showed significant differences (p = < 0.001) in triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels. Hence, dyslipidemia may be a causative factor for CaCx with HPV infection. Our findings resembled that of Mary et al, (2021) [52] and Jiang et al, (2022) [53]. However, there are controversial studies regarding the association of lipid profile in CaCx patients [54–56]. Dyslipidemia has also been reported in breast cancer patients in support of the present study [9, 14–15]. Therefore, cervical cancer is coupled to a disordered lipid profile characterized by higher TG, HDL, and LDL levels and lower cholesterol levels.

Renal dysfunction is a frequent complication in various cancers of prostate, bladder, uterus, and cervix. It can be acute/chronic and preventable/reversible with prompt diagnosis and treatment [57. In the advanced stage of cancer, the connective tissues at the distal ureter develop tumor parametrium in cervical cancer [52]. In the present study, elevated levels of urea and creatinine were found to be significantly different (p = < 0.001) in HPV + ve CaCx patients (Table 3). This is the first report to our knowledge indicating elevated levels of creatinine during HPV infection and that urea is associated with CaCx independently. Similarly, creatinine levels were reported to be higher in the liver, colon, uterine, and CaCx. [34, 52, 58].

Previous studies suggested that metabolic by-products and related factors play an important role in cancer development, incidence, diagnosis, and prognoses like dyslipidemia and hyperuricemia [25]. Impairment of uric acid leads to hyperuricemia and it is involved in the physiopathogenesis of gout, cardiovascular diseases, respiratory diseases, and cancer [26–27].

In the present study, increased levels of uric acid showed significant difference (p = < 0.001) in HPV + ve and HPV-ve patients compared to healthy women (Table 3). In multinomial regression analysis, uric acid showed a 1.23 odds ratio for HPV-ve and the adjusted odds ratio was 1.46 folds while for HPV + ve patients it increased from 1.30 to 1.53 folds crude to adjusted odds ratio in comparison to healthy women. Two groups have independently reported that hyperuricemia is a major metabolic indicator for the poor prognosis of CaCx [29, 52]. Although uric acid possesses antioxidant properties but its increased level leads to chronic and systematic inflammatory responses in the human body and thus promotes tumorigenesis.

The limitations of this study warrant consideration. The population size was small and only included patients from northern India. Thus, the study population is not representative of the entire Indian population. It is also possible that there might be unmeasured confounding variables. The strength of the study was that treatment-naïve dyslipidemia, renal dysfunction, and uricemia subjects were considered for the study.

The present study dealt with the clinical association of dyslipidemia, renal dysfunction, and uricemia in cervical cancer patients with or without HPV infection and healthy women. BMI, TG, HDL, LDL, creatinine, and uric acid are elevated in CaCx patients with HPV infection along with anthro-demographic and clinicopathological characteristics as cofactors. Age (40–49 years) and multiparity are major co-factors responsible for HPV-mediated cervical cancer. Furthermore, dyslipidemia may be a major complication of hypertension and heart-related disease in the advanced stage of cervical cancer. Similarly, renal dysfunction and uricemia may cause kidney failure in the future or patients may have a poor treatment outcome. However, women with advanced age can prevent or delay the disease by managing their clinic-pathological characteristics. TG, HDL, LDL, serum urea, creatinine, and uric acid can be used as prognostic biomarkers for HPV-mediated cervical cancer.

Statement of Ethics

Before the study, sample collection procedures were informed to all subjects and their guardians after duly written consent in compliance with the Helsinki Declaration. The study was approved by the institutional ethics committee (256/Ethics/R.Cell-18 Dated 24/09/2018).

Conflict of interest: All the authors have no conflict of interest.

Acknowledgments
The authors extend their gratitude to Indian Council of Medical Research (ICMR), New Delhi, University Grant Commission (UGC), New Delhi, India and Centre of Excellence, Higher Education, Government of Uttar Pradesh, Lucknow, India for financial support. ASK is thankful to Indian Council of Medical Research (ICMR), New Delhi, India for providing senior research fellowship.

Author contributions: Atar Singh Kushwah: Conceptualized, conducted and analysed, wrote the manuscript draft. Rajnikant Mishra: Provided scientific advice, critically reviewed the manuscript. Shambhavi Mishra: Analysed data and provided technical support, critically reviewed manuscript. Kirti Srivastava: Provided sample material, conceptualized, conducted and

supervised this study, provided scientific advice to the study, reviewed and edited the manuscript. Monisha Banerjee: Conceptualized, conducted and analysed this study, wrote and edited the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Funding: None

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Table 1: Anthro-demographic characteristics and smoking status of healthy women and cervical cancer (CaCx) patients (HPV-ve and HPV+ve).

Demographic Profile		Healthy Women N=108 (%)	CaCx HPV-ve N=17 (%)	CaCx HPV+ve N=86 (%)	P-value
Age (in years)	30-39	30 (27.8)	01 (06)	15 (17)	<0.001
	40-49	25 (23.1)	00 (00)	30 (35)
	50-59	33 (30.6)	06 (35)	31 (36)
	60-69	20 (18.5)	10 (59)	10 (12)
Residence	Rural	71 (65.7)	13 (76)	62 (72)	0.357
Residence	Urban	37 (34.3)	04 (24)	24 (28)	0.357
Literacy	Illiterate	45 (41.7)	14 (82)	50 (58)	<0.001
Literacy	Literate	63 (60)	03 (18)	36 (42)	<0.001
Socio-economic status (SES)	Upper	18 (16.7)	01 (06)	03 (03)	<0.001
	Middle	59 (54.6)	06 (35)	47 (55)
	Lower	31 (28.7)	10 (59)	36 (42)
Smoking	Non-Smokers	51 (47.3)	11 (65)	48 (26)	0.025
Smoking	Smokers	57 (52.7)	06 (35)	38 (74)	0.025

Table 2: Clinicopathological characteristics and smoking status of healthy women and cervical cancer (CaCx) patients (HPV-ve and HPV+ve).

Obstetrics profile		Healthy Women N=108 (%)	CaCx HPV-ve N=17 (%)	CaCx HPV+ve N=86 (%)	P-value
Parity	None	13(12.05)	00(00)	03(04)	<0.001
	<2	55(50.9)	04(24)	09(10)
	>2	40(37.05)	13(76)	74(86)
Age at first full-term pregnancy	>20	80(74.1)	07(41)	40(47)	<0.001
Age at first full-term pregnancy	<20	28(25.9)	10(59)	46 (53)	<0.001
Menstrual Cycle	Regular	105(97.2)	03(18)	28(33)	<0.001
Menstrual Cycle	Irregular	03(2.8)	14(82)	58(67)	<0.001
Menopausal Age	None	28(25.9)	00(00)	08(09)	<0.001
	<45	40(37.05)	07(41)	44(51)
	>45	40(37.05)	10(59)	34(40)
Menstrual Hygiene	Napkins	52(48.1)	01(06)	24(28)	<0.001
Menstrual Hygiene	Cloths	56(51.9)	16(94)	62(72)	<0.001
Use of Contraception	None	107(99.07)	16(94)	81(94)	0.111
Use of Contraception	OCPs	01(0.93)	01(06)	05(06)	0.111

Table 3: Body mass Index (BMI), lipid profile, renal function, and uric acid levels in healthy women and cervical cancer (CaCx) patients (HPV-ve and HPV+ve).

Parameters	Healthy Women (Mean±SE)	CaCx HPV-ve (Mean±SE)	CaCx HPV+ve (Mean±SE)	P-value	Reference Range*
Body Mass Index (Kg/M²)
BMI	22.5±0.3	23.7±1.1	24.4±0.5	0.027	18-25
Lipid Profile (mg/dl)
TG	61.7±2.5	134.9±22.1	199.7±14.2	<0.001	35-170
HDL	70.7±3.2	108.4±8.6	116.9±4.7	<0.001	30-85
LDL	80.5±3.6	126.7±13.0	143.8±6.9	<0.001	100-159
TC	150.5±2.8	177.0±23.6	183.2±9.3	0.776	140-250
Renal Function Test (mg/dl)
Urea	18.2±1.0	49.8±5.3	41.6±2.1	<0.001	5-18
Creatinine	0.8±0.05	1.9±0.5	2.5±0.2	<0.001	0.5-1.1
Uricemia (mg/dl)
Uric Acid	5.1±0.2	7.4±0.4	8.3±0.5	<0.001	2.5-6.8

Significance =<0.05; BMI=Body-Mass Index; TG=Triglyceride; HDL=High Density Lipoprotein; LDL=Low Density Lipoprotein. *National Cholesterol Education Programme (NCEP) guidelines, 2001 [33]. Dyslipidemia (≥170mg/dl for hypertriglyceridemia; <30mg/dl for Low HDL; and ≥160 High LDL; ≥250mmol/l for hypercholesterolemia), Renal dysfunction (≥18md/dl for Urea; 1.1mg/dl for Creatinine), Uricemia (≥6.8mmol/l for uric acid) [34].

Table 4: Multinomial logistic regression analysis of biochemical parameters in healthy women vs HPV-ve CaCx patients and healthy women vs HPV+ve CaCx patients.

Parameters

Healthy Women vs HPV-ve CaCx

Healthy Women vs HPV+ve CaCx

P-value

Crude Odds Ratio (95% CI)

P-value

Adjusted Odds Ratio (95% CI)

P-value

Crude Odds Ratio (95% CI)

P-value

Adjusted Odds Ratio (95% CI)

Body Mass Index (Kg/M²)

BMI

0.165

1.10(0.96-1.26)

0.013

1.49(1.09-2.05)

0.001

1.15(1.06-1.25)

0.003

1.55(1.17-2.05)

Lipid Profile (mg/dl)

<0.001

1.02(1.01-1.03)

0.003

1.04(1.01-1.07)

<0.001

1.03(1.02-1.04)

0.001

1.05(1.02-1.07)

HDL

<0.001

1.03(1.01-1.04)

0.052

1.03(1.00-1.06)

<0.001

1.03(1.02-1.04)

0.001

1.05(1.02-1.07)

LDL

<0.001

1.02(1.02-1..04)

0.020

1.02(1.01-1.04)

<0.001

1.03(1.02-1.04)

0.004

1.03(1.01-1.04)

0.106

1.01(0.99-1.01)

0.192

0.99(0.98-1.01)

<0.001

1.01(1.00-1.01)

0.784

0.99(0.99-1.01)

Renal Function Test (mg/dl)

Urea

<0.001

1.12(1.09-1.16)

<0.001

1.31(1.16-1.58)

<0.001

1.63(1.17-2.28)

<0.001

1.10(1.07-1.13)

Creatinine

<0.001

2.29(1.48-3.52)

0.021

10.37(1.42-75.91)

<0.001

2.66(1.84-3.85)

0.018

11.07(1.51-80.85)

Uricemia (mg/dl)

Uric Acid

0.005

1.23(1.06-1.43)

0.022

1.46(1.06-2.02)

<0.001

1.30(1.18-1.44)

0.004

1.53(1.15-2.05)

Significance and Bold: <0.05 at 95% Confidence interval; BMI=Body-Mass Index; TG=Triglyceride; HDL=High Density Lipoprotein; LDL=Low Density Lipoprotein

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Association of Dyslipidemia, Renal dysfunction, and Uricemia with HPV mediated Cervical Cancer

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Cervical Cancer staging and HPV

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