High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

Diets, Illja J.; Waanders, Esmé; Ligtenberg, Marjolijn J. L.; Bladel, Diede A.G. van; Kamping, Eveline J.; Hoogerbrugge, Peter M.; Hopman, Saskia; Olderode-Berends, Maran J. W.; Gerkes, Erica H.; Koolen, David A.; Marcelis, Carlo; Santen, Gijs W.E.; Belzen, Martine J. van; Mordaunt, Dylan; McGregor, Lesley; Thompson, Elizabeth; Kattamis, Antonis; Pastorczak, Agata; Młynarski, Wojciech; Ilenčíková, Denisa; Silfhout, Anneke Vulto van; Gardeitchik, Thatjana; Bont, Eveline S. de; Loeffen, Jan; Wagner, Anja; Mensenkamp, Arjen R.; Kuiper, Roland P.; Hoogerbrugge, Nicoline; Jongmans, Marjolijn C.J.

doi:10.1158/1078-0432.ccr-17-1725

Cited by 56 publications

(69 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have recently shown that clinical exome sequencing is an effective strategy for the diagnosis of known and novel genetic tumor predisposition syndromes. 20 Here, we report how application of exome sequencing in two centers independently resulted in the identification of pathogenic TRIM28 frameshift mutations in two families with very similar clinical presentations of Wilms tumor. A subsequent screening of a validation cohort revealed seven additional individuals with germline mutations, and one individual with a somatic mutation in TRIM28.…”

Section: Discussionmentioning

confidence: 95%

“…Data analysis focused on shared variants between the siblings and revealed a heterozygous c.246_247del variant in the TRIM28 gene, predicted to cause a frameshift and premature stop codon after 6 amino acids p.(Cys83Phefs*6) (NM_005762.2). No other variants of interest were identified …”

Section: Resultsmentioning

confidence: 99%

“…No other variants of interest were identified. 20 In the second family (FAM#2), two brothers were diagnosed with unilateral and bilateral Wilms tumor (FAM#2: individual 3 and 4, Fig. 1b, Supporting Information Fig.…”

Section: Clinical Reports Of Two Index Familiesmentioning

confidence: 99%

See 2 more Smart Citations

TRIM28 haploinsufficiency predisposes to Wilms tumor

Diets

Hoyer

Ekici

et al. 2019

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss‐of‐function effect of the mutations identified. The tumors showed an epithelial‐type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss‐of‐heterozygosity (LOH) of the TRIM28‐locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial‐type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

TRIM28 haploinsufficiency predisposes to Wilms tumor

Diets

Hoyer

Ekici

et al. 2019

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…The genes with the highest number of reported germline variants included TP53 , NF1 and BRCA2 40. The other study selected 40 childhood cancer patients with a suspected genetic predisposition to cancer, detecting pathogenic or likely pathogenic germline variants in 20% (8/40) of patients with childhood cancer 41. Of the 146 genes considered for initial investigation, germline variants were reported in five genes ( DICER1 , CHEK2 , APC , BRCA2 and TP53 ) 41.…”

Section: Discussionmentioning

confidence: 99%

“…The other study selected 40 childhood cancer patients with a suspected genetic predisposition to cancer, detecting pathogenic or likely pathogenic germline variants in 20% (8/40) of patients with childhood cancer 41. Of the 146 genes considered for initial investigation, germline variants were reported in five genes ( DICER1 , CHEK2 , APC , BRCA2 and TP53 ) 41. Both studies detected heterozygous germline variants in 1.3% (12/914) or 7.5% (3/40) of patients, respectively, in genes primarily associated with predisposition to adult cancer ( BRCA2 , MSH2 , MSH6 , PMS2 and CHEK2 ) 40 41…”

Section: Discussionmentioning

confidence: 99%

Investigation of clinically relevant germline variants detected by next-generation sequencing in patients with childhood cancer: a review of the literature

et al. 2018

View full text Add to dashboard Cite

Genetic predisposition is an important underlying cause of childhood cancer, although the proportion of patients with childhood cancer carrying predisposing pathogenic germline variants is uncertain. This review considers the pathogenic or likely pathogenic germline variants reported by six studies that used next-generation sequencing to investigate genetic predisposition in selected cohorts of patients with childhood cancer and used incompletely overlapping gene sets for analysis and interpretation. These six studies reported that 8.5%–35.5% of patients with childhood cancer carried clinically relevant germline variants. Analysis of 52 autosomal dominant cancer predisposition genes assumed common to all six studies showed that 5.5%–25.8% of patients with childhood cancer carried pathogenic or likely pathogenic germline variants in at least one of these genes. When only non-central nervous system solid tumours (excluding adrenocortical carcinomas) were considered, 8.5%–10.3% of the patients carried pathogenic or likely pathogenic germline variants in at least one of 52 autosomal dominant cancer predisposition genes. There was a lack of concordance between the genotype and phenotype in 33.3%–57.1% of the patients reported with pathogenic or likely pathogenic germline variants, most of which represented variants in autosomal dominant cancer predisposition genes associated with adult onset cancers. In summary, germline genetic testing in patients with childhood cancer requires clear definition of phenotypes and genes considered for interpretation, with potential to inform and broaden childhood cancer predisposition syndromes.

show abstract

DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

Apellaniz-Ruiz

McCluggage

Foulkes

2020

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of “new” morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1‐associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.

show abstract

High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

Cited by 56 publications

References 42 publications

TRIM28 haploinsufficiency predisposes to Wilms tumor

TRIM28 haploinsufficiency predisposes to Wilms tumor

Investigation of clinically relevant germline variants detected by next-generation sequencing in patients with childhood cancer: a review of the literature

DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

Contact Info

Product

Resources

About