Dataset Information

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer.

ABSTRACT: Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC.

SUBMITTER: Hartman TR

PROVIDER: S-EPMC7419503 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer.

Hartman Tiffiney R TR Demidova Elena V EV Lesh Randy W RW Hoang Lily L Richardson Marcy M Forman Andrea A Kessler Lisa L Speare Virginia V Golemis Erica A EA Hall Michael J MJ Daly Mary B MB Arora Sanjeevani S

Scientific reports 20200811 1

Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by A ...[more]

PMID: 32782288

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Project description:BackgroundGenome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs in human DDR genes.MethodsWe identified 169 DDR genes by referring to various databases and identified PVs in the DDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the results using the GraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000 ancient humans developed a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data, we performed a molecular archeological analysis to compare the DDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using the CodeML in PAML for phylogenetic analysis.ResultsOur phylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Our archeological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We also observed similar pattern of quantitative PV distribution between modern and ancient humans. We further detected a set of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals.ConclusionsOur study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

Project description:BackgroundLittle is known about the prevalence of a history of cancer and its impact on clinical outcome in mitral regurgitation (MR) patients undergoing transcatheter mitral valve repair (TMVR).ObjectivesThe purpose of this study is to investigate the prevalence of cancer, baseline inflammatory parameters, and clinical outcome in MR patients undergoing TMVR.MethodsConsecutive patients undergoing a MitraClip procedure were enrolled, and the patients were stratified into two groups: cancer and non-cancer. Baseline complete blood counts (CBC) with differential hemograms were collected prior to the procedure to calculate the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR). All-cause death within a one-year was examined.ResultsIn total, 82 out of 446 patients (18.4%) had a history of cancer. Cancer patients had a significantly higher baseline PLR [181.4 (121.1-263.9) vs. 155.4 (109.4-210.4); P = 0.012] and NLR [5.4 (3.5-8.3) vs. 4.0 (2.9-6.1); P = 0.002] than non-cancer patients. A Kaplan-Meier analysis revealed that cancer patients had a significantly worse prognosis than non-cancer (estimated 1-year mortality, 20.2 vs. 9.2%; log-rank P = 0.009), and multivariable analyses of three models showed that cancer history was an independent factor for 1-year mortality. Patients who died during follow-up had a significantly higher baseline PLR [214.2 (124.2-296.7) vs. 156.3 (110.2-212.1); P = 0.007] and NLR [6.4 (4.2-12.5) vs. 4.0 (2.9-6.2); P < 0.001] than survivors.ConclusionsIn MitraClip patients, a history of cancer was associated with higher inflammatory parameters and worse prognosis compared to non-cancer patients. Central Illustration. Clinical outcomes and baseline PLR and NLR values accord-ing to one-year mortality. (Left) Patients who died within the follow-up period had a significantly higher baseline PLR (214.2 [124.2-296.7] vs 156.3 [110.2-212.1]; P = 0.007) and NLR (6.4 [4.2-12.5] vs 4.0 [2.9-6.2]; P < 0.001) than patients who survived. PLR, platelet-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio (Right) A Kaplan-Meier analysis revealed that cancer patients had a significantly worse prognosis than non-cancer patients (estimated one-year mortality, 20.2 vs 9.2%; log-rank P = 0.009).

Dataset Information

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer.

Publications

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer.

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