Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing

Truong, Hong; Sheikh, Rania; Kotecha, Ritesh; Kemel, Yelena; Reisz, Peter; Mehta, Nikita; Khurram, Aliya; Vijai, Joseph; Mandelker, Diana; Latham, Alicia; Ceyhan‐Birsoy, Ozge; Ladanyi, Marc; Shah, Neil; Walsh, Michael F.; Voss, Martin H.; Lee, Chung-Han; Russo, Paul; Coleman, Jonathan; Hakimi, A. Ari; Feldman, Darren R.; Stadler, Zsofia K.; Motzer, Robert J.; Offit, Kenneth; Patil, Sujata; Carlo, Maria I.

doi:10.1016/j.euo.2021.09.005

Cited by 19 publications

(19 citation statements)

References 21 publications

(21 reference statements)

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“…17 In the Copenhagen General Population Study, 18 the c.1100del variant was associated with breast and stomach cancers and enriched in kidney cancers and sarcomas, but this was not significant after correcting for multiple comparisons. CHEK2 PVs have been associated with colorectal, kidney, prostate, and thyroid cancers, 11,[19][20][21][22][23][24] but these findings are limited by small sample sizes and high genetic homogeneity.…”

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confidence: 99%

Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care—Checking CHEK2

et al. 2022

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ImportanceGermline CHEK2 pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited.ObjectiveTo compare cancer phenotypes of frequent CHEK2 PVs individually and collectively by variant type.Design, Setting, and ParticipantsThis retrospective cohort study was carried out in a single diagnostic testing laboratory from 2012 to 2019. Overall, 3783 participants with CHEK2 PVs identified via MGPT were included. Medical histories of cancer in participants with frequent PVs, negative MGPT (wild type), loss-of-function (LOF), and missense were compared.Main Outcomes and MeasuresParticipants were stratified by CHEK2 PV type. Descriptive statistics were summarized including median (IQR) for continuous variables and proportions for categorical characteristics. Differences in age and proportions were assessed with Wilcoxon rank sum and Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals were calculated, and P values were corrected for multiple comparisons where appropriate.ResultsOf the 3783 participants with CHEK2 PVs, 3473 (92%) were female and most reported White race. Breast cancer was less frequent in participants with p.I157T (OR, 0.66; 95% CI, 0.56-0.78; P<.001), p.S428F (OR, 0.59; 95% CI. 0.46-0.76; P<.001), and p.T476M (OR, 0.74; 95% CI, 0.56-0.98; P = .04) PVs compared with other PVs and an association with nonbreast cancers was not found. Following the exclusion of p.I157T, p.S428F, and p.T476M, participants with monoallelic CHEK2 PV had a younger age at first cancer diagnosis (P < .001) and were more likely to have breast (OR, 1.83; 95% CI, 1.66-2.02; P < .001), thyroid (OR, 1.63; 95% CI, 1.26-2.08; P < .001), and kidney cancer (OR, 2.57; 95% CI, 1.75-3.68; P < .001) than the wild-type cohort. Participants with a CHEK2 PV were less likely to have a diagnosis of colorectal cancer (OR, 0.62; 95% CI, 0.51-0.76; P < .001) compared with those in the wild-type cohort. There were no significant differences between frequent CHEK2 PVs and c.1100del and no differences between CHEK2 missense and LOF PVs.Conclusions and RelevanceCHEK2 PVs, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type. CHEK2 PVs were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other CHEK2 PVs, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with CHEK2 PVs.

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confidence: 99%

Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care—Checking CHEK2

et al. 2022

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“…Furthermore, patients with VHL disease with CHEK2 germline mutation seem to have more severe symptoms, especially for RCC. Some studies have also demonstrated that CHEK2 germline mutations could be detected in early-onset RCC or associated with renal cancer 30 36. Coincidentally, a recent case report showed that an earlier age of onset of pancreatic neuroendocrine tumour was observed in a patient with both VHL and SDHA germline mutations 37.…”

Section: Discussionmentioning

confidence: 99%

“…The availability of NGS technology has made the identification of VHL mutations easier 30. Simultaneously, it has facilitated the sequencing of numerous genomes and identification of de novo mutations.…”

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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“…The Nordic Twin study has placed the genetic heritability of RCC as high as 38% 2 , however, only a fraction of the heritability is explained by currently identified rare and common RCC risk loci. Moving beyond known RCC risk genes (eTable 1) 3,4 , several pan-RCC studies have reported rare germline PVs in DNA damage repair (DDR) genes such as CHEK2, ATM, or BRCA1/2 [5][6][7][8][9][10] , suggesting that inherited defects in DDR may contribute to RCC risk. However, most studies lacked ancestry-matched cancer-free controls to formally test these hypotheses.…”

Section: Introductionmentioning

confidence: 99%

Integrative Analysis of Germline Rare Variants in Clear and Non-Clear Cell Renal Cell Carcinoma

Han

Camp

Chu

et al. 2023

Preprint

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IMPORTANCE RCC encompasses a set of histologically distinct cancers with a high estimated genetic heritability, of which only a portion is currently explained. Previous rare germline variant studies in RCC have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification that may significantly impact the interpretation and discovery of certain candidate risk genes. OBJECTIVE To evaluate the enrichment of germline PVs in established cancer-predisposing genes (CPGs) in clear cell and non-clear cell RCC patients compared to cancer-free controls using approaches that account for population stratification and to identify unconventional types of germline RCC risk variants that confer an increased risk of developing RCC. DESIGN, SETTING, AND PARTICIPANTS In 1,436 unselected RCC patients with sufficient data quality, we systematically identified rare germline PVs, cryptic splice variants, and copy number variants (CNVs). From this unselected cohort, 1,356 patients were ancestry-matched with 16,512 cancer-free controls, and gene-level enrichment of rare germline PVs were assessed in 143 CPGs, followed by an investigation of somatic events in matching tumor samples. MAIN OUTCOMES AND MEASURES Gene-level burden of rare germline PVs, identification of secondary somatic events accompanying the germline PVs, and characterization of less-explored types of rare germline PVs in RCC patients. RESULTS In clear cell RCC (n = 976 patients), patients exhibited significantly higher prevalence of PVs in VHL compared to controls (OR: 39.1, 95% CI: 7.01-218.07, p-value:4.95e-05, q-value:0.00584). In non-clear cell RCC (n = 380 patients), patients carried enriched burden of PVs in FH (OR: 77.9, 95% CI: 18.68-324.97, p-value:1.55e-08, q-value: 1.83e-06) and MET (OR: 1.98e11, 95% CI: 0-inf, p-value: 2.07e-05, q-value: 3.50e-07). In a CHEK2-focused analysis with European cases and controls, clear cell RCC patients (n=906 European patients) harbored nominal enrichment of the previously reported low-penetrance CHEK2 variants, p.Ile157Thr (OR:1.84, 95% CI: 1.00-3.36, p-value:0.049) and p.Ser428Phe (OR:5.20, 95% CI: 1.00-26.40, p-value:0.045) while non-clear cell RCC patients (n=295 European patients) exhibited nominal enrichment of CHEK2 LOF germline PVs (OR: 3.51, 95% CI: 1.10-11.10, p-value: 0.033). RCC patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset compared to patients without any germline PVs in CPGs (Mean: 46.0 vs 60.2 years old, Tukey adjusted p-value < 0.0001), and more than half had secondary somatic events affecting the same gene (n=10/15, 66.7%, 95% CI: 38.7-87.0%). Conversely, patients with rare germline PVs in CHEK2 exhibited a similar age of disease onset to patients without any identified germline PVs in CPGs (Mean: 60.1 vs 60.2 years old, Tukey adjusted p-value: 0.99), and only 30.4% of the patients carried secondary somatic events in CHEK2 (n=7/23, 95% CI: 14.1-53.0%). Finally, rare pathogenic germline cryptic splice variants underexplored in RCC were identified in SDHA and TSC1, and rare pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA, and VHL. CONCLUSIONS AND RELEVANCE This systematic analysis supports the existing link between several RCC risk genes and elevated RCC risk manifesting in earlier age of RCC onset. Our analysis calls for caution when assessing the role of germline PVs in CHEK2 due to the burden of founder variants with varying population frequency in different ancestry groups. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants, such as cryptic splice variants and CNVs.

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Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing

Cited by 19 publications

References 21 publications

Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care—Checking CHEK2

Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care—Checking CHEK2

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

Integrative Analysis of Germline Rare Variants in Clear and Non-Clear Cell Renal Cell Carcinoma

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