Tumor biology, biomarkers, and liquid biopsy in pediatric renal tumors

Walz, Amy L.; Maschietto, Mariana; Crompton, Brian D.; Evageliou, Nicholas F.; Dix, David; Tytgat, Godelieve A.M.; Gessler, Manfred; Gisselsson, David; Daw, Najat C.; Wegert, Jenny

doi:10.1002/pbc.30130

Cited by 8 publications

(8 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, liquid biopsy analysis of specific tumour markers will be of help in the future. The broad spectrum of Wilms tumour driver genes would still require whole exome or genome sequencing to identify culprits, but this is different for non‐WT cases 36 . The highly specific internal tandem duplications of BCOR in CCSK are amenable to direct PCR testing 37 .…”

Section: Discussionmentioning

confidence: 99%

“…The broad spectrum of Wilms tumour driver genes would still require whole exome or genome sequencing to identify culprits, but this is different for non-WT cases. 36 The highly specific internal tandem duplications of BCOR in CCSK are amenable to direct PCR testing. 37 In addition, the frequent ETV6-NTRK3 translocations, EGFR internal tandem duplications and BRAF alterations in CMN are targetable in liquid biopsy samples.…”

Section: Unilateral Localized Tumoursmentioning

confidence: 99%

See 1 more Smart Citation

How to improve initial diagnostic accuracy of kidney tumours in childhood?—A non‐invasive approach

Welter,

Metternich,

Furtwängler

et al. 2024

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Non‐invasive differentiation of paediatric kidney tumours is particularly important in the SIOP‐RTSG protocols, which recommend pre‐operative chemotherapy without histological confirmation. The identification of clinical and tumour‐related parameters may enhance diagnostic accuracy. Age, metastases, and tumour volume (TV) were retrospectively analysed in 3306 patients enrolled in SIOP/GPOH 9, 93‐01, and 2001 including Wilms tumour (WT), congenital mesoblastic nephroma (CMN), clear cell sarcoma (CCSK), malignant rhabdoid tumour of the kidney (MRTK), and renal cell carcinoma (RCC). WT was diagnosed in 2927 (88.5%) patients followed by CMN 138 (4.2%), CCSK 126 (3.8%), MRTK 58 (1.8%) and RCC 57 (1.7%). CMN, the most common localized tumour (71.6%) in patients younger than 3 months of age, was diagnosed earliest and RCC the latest (median age [months]: 0 and 154, respectively) both associated with significantly smaller TV (median TV [mL]: 67.2 and 45.0, respectively). RCC occurred in >14% of patients older than 120 months or older than 84 months with TV <100 mL. Receiver operating characteristic analyses discriminated WT from CMN, RCC and MRTK regarding age (AUC = 0.976, 0.929 and 0.791) and TV (AUC = 0.768, 0.813 and 0.622). MRTK had the highest risk of metastasis (37.9%) despite young age, whereas the risk of metastasis increased significantly with age in WT. Age and TV at diagnosis can differentiate WT from CMN and RCC. MRTK must be considered for metastatic tumours at young age. Identification of CCSK without histology remains challenging. Combined with MRI‐characteristics, including diffusion‐weighted imaging, and radiomics and liquid biopsies in the future, our approach allows optimization of biopsy recommendations and prevention of misdiagnosis‐based neoadjuvant treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Unilateral Localized Tumoursmentioning

confidence: 99%

How to improve initial diagnostic accuracy of kidney tumours in childhood?—A non‐invasive approach

Welter,

Metternich,

Furtwängler

et al. 2024

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…Due to the small quantity of recovered cfDNA and the characteristics of the mutational profile in pediatric tumors, the application of a target methodology, such as dPCR, can only be of limited use. Nevertheless, the use of CNAs in the peripheral blood can point to the presence of ctDNA [ 49 ]. ctDNA are fragments of around 166 bp DNA released in the blood by the tumor cells and they contain the original tumor molecular alterations.…”

Section: Discussionmentioning

confidence: 99%

Somatic Copy Number Alteration in Circulating Tumor DNA for Monitoring of Pediatric Patients with Cancer

et al. 2023

Self Cite

View full text Add to dashboard Cite

Pediatric tumors share few recurrent mutations and are instead characterized by copy number alterations (CNAs). The cell-free DNA (cfDNA) is a prominent source for the detection of cancer-specific biomarkers in plasma. We profiled CNAs in the tumor tissues for further evaluation of alterations in 1q, MYCN and 17p in the circulating tumor DNA (ctDNA) in the peripheral blood at diagnosis and follow-up using digital PCR. We report that among the different kinds of tumors (neuroblastoma, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, leiomyosarcoma, osteosarcoma and benign teratoma), neuroblastoma presented the greatest amount of cfDNA, in correlation with tumor volume. Considering all tumors, cfDNA levels correlated with tumor stage, metastasis at diagnosis and metastasis developed during therapy. In the tumor tissue, at least one CNA (at CRABP2, TP53, surrogate markers for 1q and 17p, respectively, and MYCN) was observed in 89% of patients. At diagnosis, CNAs levels were concordant between tumor and ctDNA in 56% of the cases, and for the remaining 44%, 91.4% of the CNAs were present only in cfDNA and 8.6% only in the tumor. Within the cfDNA, we observed that 46% and 23% of the patients had MYCN and 1q gain, respectively. The use of specific CNAs as targets for liquid biopsy in pediatric patients with cancer can improve diagnosis and should be considered for monitoring of the disease response.

show abstract

“…Many of these genes are involved in normal kidney development and growth factor signaling. They orchestrate transcriptional programs, chromatin biology, miRNA processing, and genome maintenance [8]. For the most part, there is only a weak correlation between the genetic makeup and the morphology of WTs.…”

Section: Introductionmentioning

confidence: 99%

TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants

Wegert,

Fischer,

Palhazi

et al. 2023

The Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite‐motif‐containing‐28 gene (TRIM28). Case reports and small case series suggest that TRIM28 mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of TRIM28 inactivation and predisposing mutations in a cohort of 126 WTs with >2/3 epithelial cells, spanning 20 years of biobanking in the German SIOP93‐01/GPOH and SIOP2001/GPOH studies. Overall, 44.4% (56/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing TRIM28 sequence variants in each case – either homozygous (~2/3) or heterozygous with epigenetic silencing of the second allele (~1/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc‐binding clusters of the RING, B‐box‐2, and PHD domains or the central coiled‐coil region. TRIM28‐mutant tumors otherwise lacked WT‐typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency. Expression profiling identified TRIM28‐mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested. Importantly, 46% of the TRIM28 mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in TRIM28‐driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

show abstract

Tumor biology, biomarkers, and liquid biopsy in pediatric renal tumors

Cited by 8 publications

References 81 publications

How to improve initial diagnostic accuracy of kidney tumours in childhood?—A non‐invasive approach

How to improve initial diagnostic accuracy of kidney tumours in childhood?—A non‐invasive approach

Somatic Copy Number Alteration in Circulating Tumor DNA for Monitoring of Pediatric Patients with Cancer

TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants

Contact Info

Product

Resources

About