Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases

Yngvadóttir, Bryndís; Andreou, Avgi; Bassaganyas, Laia; Larionov, Alexey; Cornish, Alex J.; Chubb, Daniel; Saunders, Charlie N; Smith, Philip; Zhang, Huairen; Cole, Yasemin; Consortium, Genomics England Research; Larkin, James; Browning, Lisa; Turajlic, Samra; Litchfield, Kevin; Houlston, Richard S.; Maher, Eamonn R.

doi:10.1093/hmg/ddac089

Cited by 15 publications

(25 citation statements)

References 54 publications

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“…In the present study, the association remains significant even when correcting for multiple comparisons, likely due to the larger sample size. This association is further supported by studies of patients with kidney cancers in which CHEK2 PVs were overrepresented and found in 2%-3.5% of patients . More data on the prognosis of CHEK2 -associated kidney cancers including modeling and cost-effectiveness studies are needed to inform screening.…”

Section: Discussionsupporting

confidence: 90%

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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Section: Discussionsupporting

confidence: 90%

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

et al. 2022

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“…In contrast to prior studies 9,11,12 , LOF variants in CHEK2 were not significantly enriched in ccRCC after excluding low-penetrance variants (OR: 1.01, CI: 0.41-2.52; p-value of 0.980, qvalue: 0.997) or nccRCC (OR: 2.82, CI: 1.13-7.05; p-value of 0.0536, q-value: 0.79). No other DDR genes were enriched with PVs in ccRCC or nccRCC patients compared to the cancer-free controls (eTables 7 and 8).…”

Section: Patientsmentioning

confidence: 62%

“…Attempts to demonstrate association by comparing frequencies of PVs in RCC cases against public databases such as ExAC 66 or gnomAD 56 are fraught with major technical limitations, including that the samples are likely not sequenced using the same sequencing platform, variants were not called using the same variant discovery pipeline and were not processed identically, and cases and controls were not ancestry-matched to ensure a robust statistical comparison. Recently, two studies leveraged case-control approaches to report an association of rare germline PVs in CHEK2 with an elevated risk of RCC 11,12 . However, both studies treated different subtypes of RCC together as a single phenotype and included CHEK2 variants with distinct population properties.…”

Section: Discussionmentioning

confidence: 99%

“…These factors may explain why in our study, the CHEK2 variant was detected in only 0.35% of RCC cases, where most patients were from the U.S. and patients were unselected for family history. Meanwhile, this variant was identified in more than 1% of RCC cases in a UK-based RCC association study 11 and significant enrichment of CHEK2 germline PVs was reported in studies with patients selected for positive family history 9 or positive CHEK2 germline variant carrier status in panel sequencing 12 . The variation in population frequency of CHEK2 variants combined with prior studies lacking robust genetic ancestry inference and case-control matching may partially explain the disagreeing risk assessment within and across cancer types for this gene 78 .…”

Section: Discussionmentioning

confidence: 99%

“…Two recent studies performed case-control gene-level burden analyses, in RCC alone 11 and across cancer types, finding a higher burden of germline PVs in CHEK2 in RCC patients compared to matched controls 12 . However, these studies pooled all RCC subtypes together as one phenotype for association testing, although clear cell RCC (ccRCC) and non-clear cell RCCs (nccRCC, e.g., papillary, chromophobe) have distinct molecular and clinical features 13,14 .…”

Section: Introductionmentioning

confidence: 99%

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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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Cancer Survivorship Care in the United States at Facilities Accredited by the Commission on Cancer

Stal,

Miller,

Mullett

et al. 2024

JAMA Netw Open

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ImportanceSince 2021, American College of Surgeons Commission on Cancer (CoC) accreditation standards require providing a survivorship program for patients with adult-onset cancer treated with curative intent. Since more than 70% of all patients with cancer in the US are treated at CoC-accredited facilities, this presents an opportunity for a landscape analysis of survivorship care availability.ObjectiveTo determine the prevalence, types, and outcomes of cancer survivorship services at CoC-accredited facilities.Design, Setting, and ParticipantsThis survey study used an anonymous, online, cross-sectional survey conducted from May 4 to 25, 2023. Participants were CoC-accredited facilities in the US representing diverse CoC program categories, institutional characteristics, geographic regions, and practice types. Department of Veterans Affairs cancer programs were excluded due to data usage restrictions. Data were analyzed from July to October 2023.ExposureCoC Survivorship Standard 4.8 was released in October 2019 and programs were expected to adhere to the Standard beginning January 1, 2021.Main Outcomes and MeasuresQuestions included self-reported survivorship program characteristics, availability of services aligned to CoC Survivorship Standard 4.8, and perceived program impacts. Response frequencies and proportions were determined in aggregate and by CoC program category.ResultsThere were 1400 eligible programs, and 384 programs participated (27.4% response rate). All regions and eligible program categories were represented, and most had analytic caseloads of 500 to 4999 patients in 2021. Most survivorship program personnel included nurses (334 programs [87.0%]) and social workers (278 programs [72.4%]), while physical (180 programs [46.9%]) and occupational (87 programs [22.7%]) therapists were less common. Services most endorsed as available for all survivors were screening for new cancers (330 programs [87.5%]), nutritional counseling (325 programs [85.3%]), and referrals to specialists (320 programs [84.7%]), while treatment summaries (242 programs [64.7%]), and survivorship care plans (173 programs [43.0%]), sexual health (217 programs [57.3%]), and fertility (214 programs [56.9%]) were less common. Survivorship services were usually delivered by cancer treatment teams (243 programs [63.3%]) rather than specialized survivorship clinics (120 programs [31.3%]). For resources needed, additional advanced practice clinicians with dedicated survivorship effort (205 programs [53.4%]) and electronic health record enhancements (185 programs [48.2%]) were most endorsed. Lack of referrals and low patient awareness were endorsed as the primary barriers. A total of 335 programs (87.2%) agreed that Survivorship Standard 4.8 helped advance their programs.Conclusions and RelevanceThese findings of this survey study of CoC-accredited programs establish a benchmark for survivorship care delivery in the US, identify gaps in specific services and opportunities for intervention, contribute to longitudinal reevaluation for tracking progress nationally, and suggest the value of survivorship care standards.

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Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases

Cited by 15 publications

References 54 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

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

Cancer Survivorship Care in the United States at Facilities Accredited by the Commission on Cancer

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