Germline Mutation Landscape and Associated Clinical Characteristics in Chinese Patients With Renal Cell Carcinoma

Kong, Wen; Yang, Tongtong; Wen, Xiaodong; Mu, Zhongyi; Zhao, Cheng; Han, Shufen; Tian, Jing; Zhang, Xinhao; Zhou, Tao; Zhang, Yanrui; Feng, Li; Cao, Shanbo; Wang, Huina; Zhang, Jin

doi:10.3389/fonc.2021.737547

Cited by 13 publications

(11 citation statements)

References 42 publications

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Section: Discussioncontrasting

confidence: 99%

“…Consistent with prior reports, 10,24 we detected germline alterations at the highest frequency in CHEK2 and FH . Unlike other reports of Asian patients that demonstrate a comparable frequency in germline alterations in patients with RCC, 25,26 our rate of germline alterations in EAS (7%) and SAS (0%) was low. TCGA analyses have indicated a lower rate of somatic VHL and PBRM1 in AFR patients compared with EUR patients, with a continuous trend based on the size of GA fraction of these ancestries 9,27 .…”

Section: Discussioncontrasting

confidence: 99%

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Genomic ancestry in kidney cancer: Correlations with clinical and molecular features

Kotecha,

Knezevic,

Arora

et al. 2023

Cancer

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IntroductionGenetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities.MethodsA retrospective review of patients with renal cell carcinoma (RCC) was performed and correlated GA with clinicopathologic, somatic, and germline molecular data. All patients underwent next‐generation sequencing of normal and tumor DNA using Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets, and contribution of African (AFR), East Asian (EAS), European (EUR), Native American, and South Asian (SAS) ancestry was inferred through supervised ADMIXTURE. Molecular data was compared across GA groups by Fisher exact test and Kruskal–Wallis test.ResultsIn 953 patients with RCC, the GA distribution was: EUR (78%), AFR (4.9%), EAS (2.5%), SAS (2%), Native American (0.2%), and Admixed (12.2%). GA distribution varied by tumor histology and international metastatic RCC database consortium disease risk status (intermediate‐poor: EUR 58%, AFR 88%, EAS 74%, and SAS 73%). Pathogenic/likely pathogenic germline variants in cancer‐predisposition genes varied (16% EUR, 23% AFR, 8% EAS, and 0% SAS), and most occurred in CHEK2 in EUR (3.1%) and FH in AFR (15.4%). In patients with clear cell RCC, somatic alteration incidence varied with significant enrichment in BAP1 alterations (EUR 17%, AFR 50%, SAS 29%; p = .01). Comparing AFR and EUR groups within The Cancer Genome Atlas, significant differences were identified in angiogenesis and inflammatory pathways.ConclusionDifferences in clinical and molecular data by GA highlight population‐specific variations in patients with RCC. Exploration of both genetic and nongenetic variables remains critical to optimize efforts to overcome health‐related disparities.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features

Kotecha,

Knezevic,

Arora

et al. 2023

Cancer

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“…However not all the CSGs harbouring a PGV were known to be associated with predisposition to RCC (only 4.5% of all cases had a PGVs in a CSG (VHL, FLCN, MET, TSC1/2, FH, SDHA/B/C/D, BAP1 and CHEK2) recognised as being associated with RCC predisposition) [18]. Other studies have reported a similar overall frequency of PGVs in RCC CSGs [17,42]; and higher frequencies (~9%) have been reported in case series in which ascertainment has been biased towards early onset and/or advanced stage RCC [43,44]. An extensive genomic analysis focusing on MPRT has not yet been performed within published series of unselected RCC but estimates of the diagnostic yield in MPRT have varied between 7% and 29%, [44,45].…”

Section: Discussionmentioning

confidence: 96%

Characteristics, aetiology and implications for management of multiple primary renal tumours: a systematic review

Zhang,

Andreou,

Bhatt

et al. 2024

Eur J Hum Genet

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In a subset of patients with renal tumours, multiple primary lesions may occur. Predisposition to multiple primary renal tumours (MPRT) is a well-recognised feature of some inherited renal cancer syndromes. The diagnosis of MPRT should therefore provoke a thorough assessment for clinical and genetic evidence of disorders associated with predisposition to renal tumourigenesis. To better define the clinical and genetic characteristics of MPRT, a systematic literature review was performed for publications up to 3 April 2024. A total of 7689 patients from 467 articles were identified with MPRT. Compared to all patients with renal cell carcinoma (RCC), patients with MPRT were more likely to be male (71.8% versus 63%) and have an earlier age at diagnosis (<46 years, 32.4% versus 19%). In 61.1% of cases MPRT were synchronous. The proportion of cases with similar histology and the proportion of cases with multiple papillary renal cell carcinoma (RCC) (16.1%) were higher than expected. In total, 14.9% of patients with MPRT had a family history of cancer or were diagnosed with a hereditary RCC associated syndrome with von Hippel-Lindau (VHL) disease being the most common one (69.7%), followed by Birt-Hogg-Dubé (BHD) syndrome (14.2%). Individuals with a known or likely genetic cause were, on average, younger (43.9 years versus 57.1 years). In rare cases intrarenal metastatic RCC can phenocopy MPRT. We review potential genetic causes of MPRT and their implications for management, suggest an approach to genetic testing for individuals presenting with MPRT and considerations in cases in which routine germline genetic testing does not provide a diagnosis.

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“…Among the 18 VHL patients with LDs who were identified using NGS, 11.1% (2 of 18) had other germline mutations. In a recent study, 42.9% (3 of 7) of patients with VHL disease were identified to simultaneously harbour other germline mutations 31. In addition, some case reports have shown that patients with VHL germline mutations could harbour some other germline mutations such as DM1 mutations, CPT2 mutations, Xp11.2 translocations/TFE3 gene fusion and TMEM 127 mutations 32–35.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions

Zhang

Yang

et al. 2022

J Med Genet

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BackgroundApproximately 20%–40% of patients with von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary disease, exhibit large deletions (LDs). Few studies have focused on this population. Hence, we aimed to elucidate the genotype–phenotype correlations and clinical outcomes in VHL patients with LDs.MethodsIn this retrospective study, we included 119 patients with VHL disease from 50 unrelated families in whom LDs were detected using traditional and next-generation sequencing methods. Other germline mutations were confirmed by Sanger sequencing. Genotype–phenotype correlations and survival were analysed in different groups using Kaplan-Meier and Cox regression. We also evaluated therapeutic response to tyrosine kinase inhibitor (TKI) therapy.ResultsThe overall penetrance of patients aged <60 was 95.2%. Two VHL patients with LDs also carried CHEK2 and FLCN germline mutations. An earlier age of onset of retinal haemangioblastoma was observed in the next generation. Patients with exon 2 deletion of VHL had an earlier onset age of renal cell carcinoma and pancreatic lesions. The risk of renal cell carcinoma was lower in VHL patients with LDs and a BRK1 deletion. The group with earlier age of onset received poorer prognosis. Four of eight (50%) patients showed partial response to TKI therapy.ConclusionThe number of generations and the status of exon 2 could affect age of onset of VHL-related manifestations. Onset age was an independent risk factor for overall survival. TKI therapy was effective in VHL patients with LDs. Our findings would further support clinical surveillance and decision-making processes.

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Germline Mutation Landscape and Associated Clinical Characteristics in Chinese Patients With Renal Cell Carcinoma

Cited by 13 publications

References 42 publications

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features

Characteristics, aetiology and implications for management of multiple primary renal tumours: a systematic review

Genotype–phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions

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