The impact of rare germline variants on human somatic mutation processes

Vali-Pour, M.; Lehner, Ben; Supek, Fran

doi:10.1038/s41467-022-31483-1

Cited by 21 publications

(21 citation statements)

References 145 publications

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“…We created a subset of 1543 relevant genes: cancer genes from the MutPanning list 35 and Cancer Gene Census list 68 , and furthermore we included genes associated with chromatin and DNA damage 69 . As control, we used a subset of 1000 random genes selected as in 69 . We applied the analysis for two different features: copy number alterations (CNA) and deleterious point mutations.…”

Section: Association Analysis Of Gene Mutations With Rmd Global Signa...mentioning

confidence: 99%

Cell cycle alterations associate with a redistribution of mutation rates across chromosomal domains in human cancers

Salvadores

Supek

2022

Preprint

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Somatic mutations in human have a heterogeneous genomic distribution, with increased numbers of mutations in late-replication time (RT), heterochromatic domains of chromosomes. While this regional mutation rate density (RMD) landscape is known to vary between tissues and due to deficiencies in DNA repair, we asked whether it varies between individual tumors and what would be the mechanisms underlying such variation. Here, we identified 13 RMD signatures that describe mutation redistribution across megabase-scale domains in ~4200 tumors. Of those, 10 RMD signatures corresponded to groupings or subdivisions of cancerous tissues and cell types. We further identified 3 global RMD signatures of somatic mutation landscapes that transcended cancer types. One is a known general loss of RMD variation, previously associated with DNA mismatch repair failures, and was here additionally linked with homologous recombination (HR) repair deficiencies. Next, we identified a global RMD signature affecting facultative heterochromatin domains. This RMD signature strongly reflects regional variation in DNA replication time and in heterochromatin across state tumor samples, and is associated with altered cell cycle control. Finally we identified a global RMD signature associated with TP53 loss-of-function, mainly affecting the very late RT regions. The local mutation rates in 26%-75% of cancer genes are notably changed in the tumors affected by these three global RMD signatures of mutation redistribution. Our study highlights how the plasticity of chromatin states and the RT program in cancers bears upon the regional somatic mutation rate landscape, and the downstream consequences on mutation supply to disease genes.

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Section: Association Analysis Of Gene Mutations With Rmd Global Signa...mentioning

confidence: 99%

Cell cycle alterations associate with a redistribution of mutation rates across chromosomal domains in human cancers

Salvadores

Supek

2022

Preprint

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“…ERCC5 is known to be involved in the NER pathway as an endonuclease, but it has been shown that this gene is also involved in the BER ( 117 ) and HR ( 108 ) pathways. EXO1 is involved in the HR and MMR pathways as an exonuclease ( 118 , 119 ). FANCC plays a role in the FA pathway as a member of the core complex ( 120 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic analyses of DNA repair pathway associated genes implicate new candidate cancer predisposing genes in ancestrally defined ovarian cancer cases

et al. 2023

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Not all familial ovarian cancer (OC) cases are explained by pathogenic germline variants in known risk genes. A candidate gene approach involving DNA repair pathway genes was applied to identify rare recurring pathogenic variants in familial OC cases not associated with known OC risk genes from a population exhibiting genetic drift. Whole exome sequencing (WES) data of 15 OC cases from 13 families tested negative for pathogenic variants in known OC risk genes were investigated for candidate variants in 468 DNA repair pathway genes. Filtering and prioritization criteria were applied to WES data to select top candidates for further analyses. Candidates were genotyped in ancestry defined study groups of 214 familial and 998 sporadic OC or breast cancer (BC) cases and 1025 population-matched controls and screened for additional carriers in 605 population-matched OC cases. The candidate genes were also analyzed in WES data from 937 familial or sporadic OC cases of diverse ancestries. Top candidate variants in ERCC5, EXO1, FANCC, NEIL1 and NTHL1 were identified in 5/13 (39%) OC families. Collectively, candidate variants were identified in 7/435 (1.6%) sporadic OC cases and 1/566 (0.2%) sporadic BC cases versus 1/1025 (0.1%) controls. Additional carriers were identified in 6/605 (0.9%) OC cases. Tumour DNA from ERCC5, NEIL1 and NTHL1 variant carriers exhibited loss of the wild-type allele. Carriers of various candidate variants in these genes were identified in 31/937 (3.3%) OC cases of diverse ancestries versus 0-0.004% in cancer-free controls. The strategy of applying a candidate gene approach in a population exhibiting genetic drift identified new candidate OC predisposition variants in DNA repair pathway genes.

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“…Except for two cases with an exceptionally high number of de novo sequence variants in which we were unable to define a genuinely disease predisposing one, the rate of all other patients was within the normal range. To which extent such apparently innocuous inherited and de novo variants, might still influence the likelihood of disease manifestation and its further development by impacting the mutational processes in the respective somatic cells, remains to be investigated ( 11 , 38 , 39 ). Although this information might at present be primarily of scientific interest, it may certainly also become of practical and clinical relevance in the future.…”

Section: Discussionmentioning

confidence: 99%

Resolving inherited and de novo germline predisposing sequence variants by means of whole exome trio analyses in childhood hematological malignancies

Brozou

Yasin²,

Brandes³

et al. 2023

Front. Pediatr.

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Molecular screening tools have significantly eased the assessment of potential germline susceptibility factors that may underlie the development of pediatric malignancies. Most of the hitherto published studies utilize the comparative analyses of the respective patients' germline and tumor tissues for this purpose. Since this approach is not able to discriminate between de novo and inherited sequence variants, we performed whole exome trio analyses in a consecutive series of 131 children with various forms of hematologic malignancies and their parents. In total, we identified 458 de novo variants with a range from zero to 28 (median value = 3) per patient, although most of them (58%) had only up to three per exome. Overall, we identified bona fide cancer predisposing alterations in five of the investigated 131 (3.8%) patients. Three of them had de novo pathogenic lesions in the SOS1, PTPN11 and TP53 genes and two of them parentally inherited ones in the STK11 and PMS2 genes that are specific for a Peutz-Jeghers and a constitutional mismatch repair deficiency (CMMRD) syndrome, respectively. Notwithstanding that we did not identify a disease-specific alteration in the two cases with the highest number of de novo variants, one of them developed two almost synchronous malignancies: a myelodysplastic syndrome and successively within two months a cerebral astrocytoma. Moreover, we also found that the rate of de novo sequence variants in the offspring increased especially with the age of the father, but less so with that of the mother. We therefore conclude that trio analyses deliver an immediate overview about the inheritance pattern of the entire spectrum of sequence variants, which not only helps to securely identify the de novo or inherited nature of genuinely disease-related lesions, but also of all other less obvious variants that in one or the other way may eventually advance our understanding of the disease process.

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The impact of rare germline variants on human somatic mutation processes

Cited by 21 publications

References 145 publications

Cell cycle alterations associate with a redistribution of mutation rates across chromosomal domains in human cancers

Cell cycle alterations associate with a redistribution of mutation rates across chromosomal domains in human cancers

Genetic analyses of DNA repair pathway associated genes implicate new candidate cancer predisposing genes in ancestrally defined ovarian cancer cases

Resolving inherited and de novo germline predisposing sequence variants by means of whole exome trio analyses in childhood hematological malignancies

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