Genomic instability in patients with autosomal-dominant polycystic kidney disease

Li, Ming; Qin, Songbing; Wang, Lili; Zhou, Juying

doi:10.1177/0300060513475956

Cited by 16 publications

(18 citation statements)

References 25 publications

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“…Another group found that mutated polycystins lead to chromosome segregation and cytokinetic defects and polyploidy [125, 126]. One provocative study found that peripheral blood lymphocytes of patients with ADPKD show higher intrinsic rates of DNA damage, and an increased susceptibility to DNA damage [127]. Both polycystin 1 and polycystin 2 are functionally expressed in B-lymphoblastoid cells [128, 129], while polycystin 1 is also expressed in peripheral blood lymphocytes [130].…”

Section: Adpkd and The Hallmarks Of Cancermentioning

confidence: 99%

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

et al. 2015

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Autosomal dominant polycystic kidney disease (ADPKD) is a progressive inherited disorder in which renal tissue is gradually replaced with fluid-filled cysts, giving rise to chronic kidney disease (CKD) and progressive loss of renal function. ADPKD is also associated with liver ductal cysts, hypertension, chronic pain and extrarenal problems such as cerebral aneurysms. Intriguingly, improved understanding of the signalling and pathological derangements characteristic of ADPKD has revealed marked similarities to those of solid tumours, even though the gross presentation of tumours and the greater morbidity and mortality associated with tumour invasion and metastasis would initially suggest an entirely different disease processes. The commonalities between ADPKD and cancer are provocative, particularly in the context of recent preclinical and clinical studies of ADPKD that have shown promise with drugs that were originally developed for cancer. The potential therapeutic benefit of such repurposing has led us to review in detail the pathological features of ADPKD through the lens of the defined, classic hallmarks of cancer. In addition, we have evaluated features typical of ADPKD, and determined whether evidence supports the presence of such features in cancer cells. This analysis, which places pathological processes in the context of defined signalling pathways and approved signalling inhibitors, highlights potential avenues for further research and therapeutic exploitation in both diseases.

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Section: Adpkd and The Hallmarks Of Cancermentioning

confidence: 99%

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

et al. 2015

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“…It also reflects that general genomic instability presumably precedes cyst development. 16,17 BUB1 haploinsufficiency is a known driver of chromosomal instability resulting in LOH and tumorigenesis, 23,26 and a 2q13 microdeletion has previously been described. 26,27 Although we show that it is unlikely that this specific gene is generally involved in LOH in PLD, other drivers of genetic instability may be present in the disease.…”

Section: Discussionmentioning

confidence: 99%

“…Complete loss of cyst gene expression from diseased epithelium follows loss-of-heterozygosity (LOH), [10][11][12][13][14][15] which may be related to cyst genetic instability. 16,17 The proportion of somatic variants varies with the gene that is affected in the germline. Recent studies found that second, somatic variants or LOH occurred in 56/71 liver cysts (79%) from patients with PRKCSH variants, 11 in 4/5 (80%) PKD2 variant carriers, 18 but only 1/14 cysts (7%) from a patient with a SEC63 variant.…”

Section: Introductionmentioning

confidence: 99%

Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes

et al. 2016

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Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.

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“…64 Moreover, a recent study indicated potential genomic instability in peripheral blood lymphocyte DNA isolated from ADPKD patients. 65 Chronic inflammation and oxidative stress occur in ADPKD, and both processes have been linked to molecular mechanisms associated with DNA damage and chromosomal instability leading to cancer initiation. 66 There is also strong evidence suggesting that gene dosage alone, whether associated with increased or decreased expression of Pkd1 or Pkd2, is sufficient for cyst development.…”

Section: Second Hit and Potential Third Hit?mentioning

confidence: 99%

Autosomal dominant polycystic kidney disease: genetics, epidemiology, and treatment

Reed-Gitomer¹

2014

AGG

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Abstract:Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal genetic disorder, accounting for 2%-8% of end-stage renal disease worldwide. While development of renal cysts is the major characteristic of ADPKD, several disease-related complications contribute significantly to morbidity and mortality. Since introduction of renal replacement therapies, cardiovascular disease is the leading cause of death among ADPKD patients. Loss of renal function requiring renal replacement therapy occurs in 50% of patients by the age of 60 years. The results of recent large epidemiological studies in ADPKD have shown little progress in delaying onset of renal failure despite an improvement in patient mortality. Significant progress has been made over the past decade in elucidating the genetics of the disorder. Genetic testing is now available in most countries, and development of more reliable methods for prenatal diagnosis of ADPKD has increased the sensitivity of testing. While there are no approved drugs for treatment of ADPKD within the USA, the first agent targeting renal disease progression in this disorder was recently approved for clinical use in Japan. Furthermore, several additional drugs for treatment of ADPKD are currently under clinical investigation. Overall, this presents an optimistic future for new therapeutic interventions in this disease. This paper reviews the current knowledge related to the epidemiology, genetics, and treatment of ADPKD.

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Genomic instability in patients with autosomal-dominant polycystic kidney disease

Cited by 16 publications

References 25 publications

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes

Autosomal dominant polycystic kidney disease: genetics, epidemiology, and treatment

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