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Project description:Background: In ~50% of Lynch syndrome (LS)-suspected patients (also called Lynch-like syndrome, LLS), the causal mechanism for cancer predisposition remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive genetic and epigenetic analysis. Methods: One hundred and fifteen LLS patients harboring MMR deficient tumors and no pathogenic germline MMR gene mutations were included in this study. Mutational analysis of 26 colorectal cancer associated genes was performed by using a customized multigene panel and massively parallel sequencing. Pathogenicity of MMR variants was assessed by mRNA analysis and multifactorial likelihood calculations. Genome-wide methylome analysis was perfomed by using the Infinium HumanMethylation450K BeadChip. Results: The multigene panel analysis revealed the presence of two MMR gene truncating mutations not found in previous analysis. Of a total of 15 MMR variants of unknown significance identified, five - present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes (MSH3, MUTYH, POLD1, APC, EPCAM, BUB1, FAN1, EXO1 or PSM1) were found in 12 probands. Methylome analysis detected one constitutional MLH1 epimutation in an individual diagnosed with CRC at age 42, but no additional differentially methylated regions were identified in LLS compared to LS patients or healthy individuals. Conclusions: In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allows the identification of deleterious MMR mutations as well as new LLS candidate genes. Moreover, constitutional epimutations in non-LS-associated genes are not responsible for the MMR-deficient phenotype observed in LLS patients.
2019-03-09 | GSE128067 | GEO
Project description:Background: In ~50% of Lynch syndrome (LS)-suspected patients (also called Lynch-like syndrome, LLS), the causal mechanism for cancer predisposition remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive genetic and epigenetic analysis. Methods: One hundred and fifteen LLS patients harboring MMR deficient tumors and no pathogenic germline MMR gene mutations were included in this study. Mutational analysis of 26 colorectal cancer associated genes was performed by using a customized multigene panel and massively parallel sequencing. Pathogenicity of MMR variants was assessed by mRNA analysis and multifactorial likelihood calculations. Genome-wide methylome analysis was perfomed by using the Infinium HumanMethylation450K BeadChip. Results: The multigene panel analysis revealed the presence of two MMR gene truncating mutations not found in previous analysis. Of a total of 15 MMR variants of unknown significance identified, five - present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes (MSH3, MUTYH, POLD1, APC, EPCAM, BUB1, FAN1, EXO1 or PSM1) were found in 12 probands. Methylome analysis detected one constitutional MLH1 epimutation in an individual diagnosed with CRC at age 42, but no additional differentially methylated regions were identified in LLS compared to LS patients or healthy individuals. Conclusions: In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allows the identification of deleterious MMR mutations as well as new LLS candidate genes. Moreover, constitutional epimutations in non-LS-associated genes are not responsible for the MMR-deficient phenotype observed in LLS patients.
2019-03-09 | GSE128064 | GEO
Project description:The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutional MLH1 epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS.
| S-EPMC7408773 | biostudies-literature
Project description:Comprehensive constitutional genetic and epigenetic characterization of Lynch-like individuals
| PRJNA526232 | ENA
Project description:Comprehensive constitutional genetic and epigenetic characterization of Lynch-like individuals [Blood]
| PRJNA526230 | ENA
Project description:Comprehensive constitutional genetic and epigenetic characterization of Lynch-like individuals [FFPE]
| PRJNA526234 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-11-28 | GSE107353 | GEO
Project description:There are more than 4,000 phenotypes for which the molecular basis is at least partly known. Though defects in primary DNA structure constitute a major cause of these disorders, epigenetic disruption is emerging as an important alternative mechanism in the etiology of a broad range of congenital and developmental conditions. These include epigenetic defects caused by either localized (in cis) genetic alterations or more distant (in trans) genetic events but can also include environmental effects. Emerging evidence suggests interplay between genetic and environmental factors in the epigenetic etiology of several constitutional "epi/genetic" conditions. This review summarizes our broadening understanding of how epigenetics contributes to pediatric disease by exploring different classes of epigenomic disorders. It further challenges the simplistic dogma of "DNA encodes RNA encodes protein" to best understand the spectrum of factors that can influence genetic traits in a pediatric population.
| S-EPMC5288004 | biostudies-literature
Project description:Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary lobe. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n=23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with TERT promoter mutation. The second group (n=16) contained most GCTs and a subset of SCOs, which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances is significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p= 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: One subtype is defined by granular cell histology, has low mutation rates and favorable outcome. The other two subtypes have SCO or PITUI histology but are separated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK alterations that represent potential therapeutic targets.
2021-10-19 | GSE185041 | GEO
Project description:Lynch-like syndrome (LLS) is an increasingly common clinical challenge with an underlying molecular basis mostly unknown. To shed light onto it, we focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES) of 15 patients, and additionally analyzing their corresponding tumor mutational burden (TMB) and mutational signatures. We identified four cases (27%) with double somatic putative variants in mismatch repair (MMR) core genes, as well as three additional cases (20%) with double MSH3 somatic alterations in tumors with unexplained MSH2/MSH6 loss of expression, and two cases (13%) with POLD1 potential biallelic alterations. Average TMB was significantly higher for LLS cases with double somatic alterations. Lastly, nine predicted deleterious variants in genes involved in the DNA repair functions and/or previously associated with CRC were found in nine probands, four of which also showed MMR biallelic somatic inactivation. In conclusion, we contribute new insights into LLS CRC, postulating MSH3 and POLD1 double somatic alterations as an underlying cause of a microsatellite instability (MSI) phenotype, proposing intrinsic biological differences between LLS with and without somatic alterations, and suggesting new predisposing candidate genes in this scenario.
| S-EPMC7999079 | biostudies-literature