Susceptibility of Developing Renal and Lung Cancer in Polycystic Kidney Disease Patients: An Evidence in Reaching Consensus

Objective . Te association between Polycystic Kidney Disease (PKD) and susceptibility to developing oncogenicity states remains controversial


Introduction
Polycystic Kidney Disease (PKD) is a common genetic disorder, occurring in approximately 1 in every 1000 live births [1]. It is characterized by the formation of multiple cysts in both kidneys, which further progress in size, leading to renal enlargement, insufciency, and failure with extrarenal manifestations. PKD eventually results in dialysis and even renal transplantation as the ultimate treatment, and 50% of PKD patients progress to end-stage renal disease (ESRD). Furthermore, PKD patients have been reported to have a 1.6 to 3.2-fold relative mortality rate compared to the general population [2]. Te disease may also adversely impact the liver, pancreas, and colon leading to cardiac valvular defects and intracranial arterial aneurysms. PKD occurs in two forms, i.e., autosomal dominant (ADPKD) and autosomal recessive (ARPKD), in which ADPKD is caused by mutations in either of the two genes (PKD1) and (PKD2) encoding plasma membrane-spanning proteins polycystin 1 and polycystin 2, respectively [3], regulating tubular and vascular development in the kidneys and other organs.
In contrast, PKHD1 has been identifed as the major gene for ARPKD [4]. PKD proteins are confned to the cilial body, and renal cilia loss or abnormalities are associated with cyst development [5]. Although every cell in a heterozygous individual with autosomal dominant PKD carries a copy of the mutated PKD gene and a normal allele, renal cysts form only in a tiny fraction of the tubules, primarily the collecting ducts. It is believed that cyst formation occurs after an epithelial cell sustains a second genetic "hit" that compromises the function of the normal allele [6]. In contrast, the PKHD1 gene is highly expressed in fetal and adult kidneys and at lower levels in the liver [7].
Genomic instability is a term used to describe the acquisition of alterations in the genome, including chromosomal destabilization, gene amplifcation, and DNAdamaging agents associated with mutations. It has been proposed that genomic instability could be a driving force behind multistep carcinogenesis [8]. Te DNA of patients with genomic instability is often more susceptible to mutagens than the general population [9]. As recent clinical and animal studies have reported PKD subjects with genomic instability [10][11][12][13], these patients may have a higher risk of developing the malignant disease. Terefore, we conducted a nationwide cohort study using the Taiwan National Health Insurance Research Database (NHIRD) to identify whether PKD patients are prone to developing the malignant disease.

Data Source.
In this nationwide cohort study, we employed the Longitudinal Health Insurance Database (LHID) obtained from the NHIRD from 2000 to 2010 ( Figure 1). Taiwan's National Health Insurance program was launched in 1995 and contains healthcare data of 23 million population comprising nearly 99% of Taiwan's population. Te LHID consisted of 1 million benefciaries randomly sampled from the original NHI benefciaries, which consisted of deidentifed secondary data ranging from demographic data to detailed orders from ambulatory and inpatient care. Tese data are released mainly for research purposes, comprising the entire registry, and claim data from this health insurance system. NHIRD has been comprehended as the basis for study in several research articles [14][15][16], and the accuracy of diagnoses based on this database has been validated previously for numerous diseases [17][18][19][20] Te exclusion criteria included patients under 18 years of age, ESRD, and a history or diagnosis of any cancer within the frst year of the follow-up period. For analysis, we collected information such as comorbidities, including the Charlson comorbidity index score, diabetes mellitus, hypertension, chronic kidney disease, coronary artery disease, dyslipidemia, and chronic liver disease. Data regarding the residential area's monthly income and urbanization levels were obtained as a substitute for socioeconomic status. Times of ambulatory visits in the past year were also collected as a marker of healthcare utilization.

Outcomes.
Te Catastrophic Illness Registry was employed to identify patients who were diagnosed with cancer. Terefore, the endpoint of the current study was the incidence of any form of cancer. Pathohistological confrmation is required for a diagnosis of cancer to be reported in the Catastrophic Illness Registry. All patients were followed until the manifestation of cancer, a dropout from the NHI program, death, or the end of 2010.

Statistical Analysis.
Te risk of cancer among the patients with PKD was determined with the Standardized Incidence Ratio (SIR), which is defned as the ratio of observed to the expected cancer numbers. Te expected number of cancer patients was estimated by adding up the national incidence rate of cancers according to age (in 5-year intervals), sex, and calendar year by the corresponding stratum-specifc person-time accumulated in the cohort. Te population of each age and sex strata for Taiwan was based on the population census 2001. Similarly, stratum-specifc incidence rates were derived from the cancer registry data 2001. Te 95% Confdence Intervals (CI) for the SIRs were estimated assuming the observed number of cancers followed a Poisson probability distribution. We used univariate and multivariate backward conditional Cox proportional hazards models to analyze the association between PKD and cancer and identify cancer development predictors among patients with PKD. Risk factors with a p value <0.1 were entered into the multivariate analysis. Microsoft SQL Server 2008 R2 (Microsoft Corp., Redmond, Washington, USA) was used for data linkage, processing, and sampling. All statistical analyses were conducted using STATA statistical software (version 12.0; StataCorp., Texas, USA). A p value <0.05 was considered statistically signifcant.

Characteristics of the Study Population.
For 10 years (2000-2010), the entire cohort was observed for 8,014 people and identifed 1820 PKD patients meeting the inclusion criteria (Table 1). Te mean age of patients at the time of diagnosis of PKD was 59.5 ± 17.5 years. Of these, the   Table 2).
In the subgroup analysis (Table 3), we found a signifcantly higher risk of kidney cancer in the patients aged <65 years (SIR 7.39, 95% CI 1.99∼18.93) than those elderly patients, especially in the females (SIR 9.81, 95%1.10∼35.41, p < 0.05). When stratifed by duration of diagnosis of PKD, the SIRs were the highest after 1∼3 years of diagnosis of PKD.

Discussion
So far, the clear evidence on pathological crosstalk between PKD and malignancy is inconclusive and debatable. Tis concern has also been raised by Cachat and Renella and advocated to investigating this association in populations younger than 20 years [21]. Tis might be attributed to the low prevalence of PKD and the lack of a powerful tool for screening. Studies have implied that PKD may be associated with renal cell carcinoma [22]. In a population-based cohort study, signifcantly higher risks of liver, colon, and kidney cancer have been documented [23]. A recent case report on 5 patients revealed the risk of hepatocellular carcinoma, testicular germ cell tumor, renal rhabdoid tumor, and perivascular epithelioid cell tumor [24]. However, our main fndings showed that PKD patients are more likely to develop kidney cancer than the general population. In contrast, female PKD patients may have a higher risk of developing lung cancer than their normal counterparts. In PKD, ECM fbrotic remodeling accompanies cyst expansion and participates in progressive declining renal function [25]. Te degree of fbrosis has been identifed as the most critical manifestation associated with the progression to ESRD. Using Else Kröner-Fresenius Registry and histopathological registry for PKD, Jilg et al. showed that PKD patients may have a higher risk of renal cell carcinoma [26]. In another study, among 79 dialysis patients who required nephrectomy, patients with uremia caused by PKD had a 2∼3 times higher risk of renal cell carcinoma than those with uremia caused by other etiologies [27]. However, the conclusion of these studies is limited by the small patient number in the dialysis population. End-stage renal disease (ESRD) is a wellestablished risk factor for renal cell carcinoma, especially when associated with acquired cystic kidney disease [28,29]. In contrast to previous studies, we used a nationwide screening method to identify a large PKD population, excluding ESRD patients, to rule out the infuence of dialysis and acquired cystic kidney disease. Our study provides relatively nonbiased data supporting PKD patients with a high risk of developing kidney malignancy.
Common pathological features of PKD include abnormal cell proliferation, disturbance of cell polarity along with dediferentiation, extracellular matrix remodeling, and the development of interstitial fbrosis [30]. Some of these pathological changes share a similar mechanism of neoplasm formation, especially cell dediferentiation and abnormal proliferation. Te PKD corpus gene PKD1 is nonkidney-specifc and has been recognized to exhibit a tumor regulation efect. PKD1 prevents tumor epithelialmesenchymal change [31] and has been reported to regulate the malignant potential of human osteosarcoma negatively [32]. Notably, the downregulation of PKD1 in gastric carcinoma promotes invasive phenotype change and could result in a poor prognosis [33].
A notable fnding in our study is a higher risk of developing lung cancer in female PKD patients (Figure 2). Tough it is still unclear whether etiologic factors contributing to lung cancer difer in women and men; however, a stable incidence of age-adjusted lung cancer in females while a continued decrease in males has been observed [34,35]. In female PKD patients, the pulmonary epithelial cell may be prone to genomic instability and developing lung neoplasm. Tough epidemiological studies reported a 2-fold greater risk of developing kidney cancer in their lifetime in males than females [36], a study on a European cohort showed that the male-to-female ratio was almost equal in patients more than 70 years compared to a 2 : 1 ratio at ages 41-60 years [37], indicating a possible role of female hormones. Specifcally, the physiological and hormonal alterations, such as increased estrogen levels, renal hyperfltration, and weight gain, could also be attributed to the association of parity with kidney cancer.
Further, multivariate analysis showed a signifcant risk factor for cancer in the PKD population in males with an HR of 1.85. Tis result aligns with a previous study on 5654 renal cancer patients treated at ten international academic centers, in which females demonstrated a 19% reduced death risk compared to males (HR � 0.81) [38]. Experimental and clinical studies have shown that targeting estrogen/ERs signaling pathways might protect against certain renal disorders. Furthermore, in seminal research after inducing ischemia-reperfusion injury, females showed less severe renal functional impairment and reduced histologic damage [39]. Tis gender inconsistency may be ascribed to the protective impact of female hormones.
Besides, recent observational studies have strongly indicated that the risk of renal cell carcinoma (RCC) in chronic kidney disease (CKD) patients, particularly end-stage kidney  European Journal of Cancer Care disease (ESKD), is approximately 3-7 times higher than in the general population. Te precise mechanism of renal insufciency transforming healthy kidney cells into tumor cells remains unknown. Reportedly, CKD may lead to RCC through underlying cystic disease or oxidative stress mechanisms. Conversely, RCC can contribute to the development of CKD due to factors such as the tumor itself, surgical reduction of renal mass (partial or radical nephrectomy), and perioperative acute kidney injury. Terefore, the relationship between CKD and RCC is complex,  bidirectional, and multifactorial. Te hypothesis suggests that various factors, such as chronic infammation related to uremia, oxidative stress, retention of uremic toxins and solutes, compromised immune function, the dialysis procedure, exposure to medications and toxins, as well as the presence of comorbid conditions, collectively contributing to an elevated risk of several cancers, including RCC [40][41][42]. Apart from several strengths, our study also has some limitations. Firstly, the Taiwan NHIRD does not ofer detailed personal history and lifestyle information, such as smoking habits, body mass index, and functional capacity, which may impact PKD characteristics. Terefore, in addition to generating signifcant and noteworthy associations, our study might encounter detection or Berkson bias leading to spurious confounding factors caused by conditional factors such as an increased probability of receiving kidney ultrasound/computed tomography exam or hospitalization rate in PKD patients compared to the general population [43]. Secondly, all the data used in this study have been recorded with ICD-9-CM codes, making it infeasible to classify disease status further or determine disease lesions. Tirdly, the NHIRD does not include laboratory data, which could have been valuable for our analysis. Fourthly, we did not investigate the incidence of cerebral vascular accidents in ADPKD patients. Lastly, we did not analyze the impact of medications, such as renin-angiotensin-aldosterone system blockades and statins, on PKD patients.

Conclusions
Our investigation revealed that overall PKD patients are prone to develop kidney cancer, while female PKD patients may have a higher risk of lung and mediastinal cancer. Patients aged <65 may be at a higher risk of kidney cancer than elderly patients, particularly females. However, further extensive research is needed to reach a consensus and validate the hypothesis through elucidating underlying mechanisms.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.