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Germline mutations and somatic inactivation of TRIM28 in Wilms tumour.

ABSTRACT: Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of TRIM28 provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis.

SUBMITTER: Halliday BJ

PROVIDER: S-EPMC6005459 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Germline mutations and somatic inactivation of TRIM28 in Wilms tumour.

Halliday Benjamin J BJ Fukuzawa Ryuji R Markie David M DM Grundy Richard G RG Ludgate Jackie L JL Black Michael A MA Skeen Jane E JE Weeks Robert J RJ Catchpoole Daniel R DR Roberts Aedan G K AGK Reeve Anthony E AE Morison Ian M IM

PLoS genetics 20180618 6

Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurr ...[more]

PMID: 29912901

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Project description:Tumor DNA has been detected in body fluids of cancer patients. Somatic tumor mutations are being used as biomarkers in body fluids to monitor chemotherapy response as a minimally invasive tool. In this study, we evaluated the potential of tracking somatic mutations in free DNA of plasma and urine collected from Wilms tumor (WT) patients for monitoring treatment response. Wilms tumor is a pediatric renal tumor resulting from cell differentiation errors during nephrogenesis. Its mutational repertoire is not completely defined. Thus, for identifying somatic mutations from tumor tissue DNA, we screened matched tumor/leukocyte DNAs using either a panel containing 16 WT-associated genes or whole-exome sequencing (WES). The identified somatic tumor mutations were tracked in urine and plasma DNA collected before, during and after treatment. At least one somatic mutation was identified in five out of six WT tissue samples analyzed. Somatic mutations were detected in body fluids before treatment in all five patients (three patients in urine, three in plasma, and one in both body fluids). In all patients, a decrease of the variant allele fraction of somatic mutations was observed in body fluids during neoadjuvant chemotherapy. Interestingly, the persistence of somatic mutations in body fluids was in accordance with clinical parameters. For one patient who progressed to death, it persisted in high levels in serial body fluid samples during treatment. For three patients without disease progression, somatic mutations were not consistently detected in samples throughout monitoring. For one patient with bilateral disease, a somatic mutation was detected at low levels with no support of clinical manifestation. Our results demonstrated the potential of tracking somatic mutations in urine and plasma DNA as a minimally invasive tool for monitoring WT patients. Additional investigation is needed to check the clinical value of insistent somatic mutations in body fluids.

Project description:ObjectivesIn breast cancer (BC) patients, the frequency of germline BRCA mutations (gBRCA) may vary according to the ethnic background, age, and family history of cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the second most common somatic mutated gene in BC; however, the association of mutations in both genes with cancer has not been thoroughly investigated. Thus, our aims were to investigate gBRCA mutation frequency in a cohort of postmenopausal Brazilian BC patients and the association of gBRCA1/BRCA2 and PIK3CA somatic mutations.MethodsForty-nine postmenopausal (>55 years) and forty-one young (≤35 years) BC patients were included in this study. The postmenopausal group included patients who reported a positive family history of cancer. For these patients, gBRCA1/BRCA2 were sequenced using next-generation sequencing (NGS) or Sanger sequencing. Data for gBRCA in young patients were already available from a previous study. DNA from formalin-fixed, paraffin-embedded (FFPE) tumors was obtained from 27 postmenopausal and 41 young patients for analyzing exons 9 and 20 of PIK3CA. The association between gBRCA1/BRCA2 and somatic mutations in PIK3CA was investigated.ResultsThe overall frequency of gBRCA1/BRCA2 among the 49 postmenopausal patients was 10.2%. The frequencies of somatic mutations in PIK3CA in the postmenopausal and young patients were 37% and 17%, respectively (ns). The most common PIK3CA mutation was found to be E454A. Nonsense and frameshift mutations, which may counteract the oncogenic potential of PIK3CA were also detected. Regardless of age, 25% of BRCA1/BRCA2 mutation carriers and non-carriers , each, had PIK3CA somatic mutations.ConclusionsData obtained indicate that BRCA1/BRCA2 gene testing may be considered for postmenopausal patients with BC who have a family history of cancer. Although some of them are not considered pathogenic, somatic variants of PIK3CA are frequently observed in BC patients, especially in postmenopausal patients.

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Germline mutations and somatic inactivation of TRIM28 in Wilms tumour.

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Germline mutations and somatic inactivation of TRIM28 in Wilms tumour.

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