Showing papers by "Suet Yi Leung published in 2022"
TL;DR: In this article , a whole genome sequence of 152 colonic crypts from normal and neoplastic epithelial tissues from 10 Lynch Syndrome (LS) patients was used to demonstrate the genomic stability of epithelial cells with heterozygous germline MMR gene mutations.
Abstract: Abstract Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.
11 citations
TL;DR: In this article , a whole genome sequence of 152 colonic crypts from normal and neoplastic epithelial tissues from 10 Lynch Syndrome (LS) patients was used to demonstrate the genomic stability of epithelial cells with heterozygous germline MMR gene mutations.
Abstract: Abstract Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.
8 citations
TL;DR: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.
Abstract: Objective Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. Design We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. Results 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. Conclusions The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.
3 citations
TL;DR: In this article , a statistical approach was developed to identify patients with GCV-associated mutational signature (GCV sig ) from targeted sequenced data of tumour samples, and cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs.
Abstract: Abstract Background Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. Methods This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCV sig ) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. Results Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCV sig . A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCV sig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCV sig in cell lines and organoids. Conclusions In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.
3 citations
01 Sep 2022
TL;DR: In this article , the authors demonstrate that chemoresistance can be derived from an aberrant lipid metabolism driven by alterations in RNA editing and identified an actionable target to circumvent chemoreaction in gastric cancer patients.
Abstract:
Background
The emergence of chemoresistance to 5-fluorouracil and cisplatin (5FU+CDDP) combination treatment curtailed long-term clinical benefits in gastric cancer (GC) patients. However, the targetable drivers governing 5FU+CDDP resistance remain elusive due to the paucity of physiologically and therapeutically relevant models.Methods
5FU+CDDP resistant GC patient-derived organoid lines representative of the intestinal subtype were established. Comparative analyses using whole-exome sequencing (WES-seq) coupled with RNA-sequencing (RNA-seq) were performed. Clinical relevance, functional significance and mechanistic consequences were examined in GC organoid cultures and GC organoid xenografts.Results
JAK/STAT signaling and its downstream adenosine deaminases acting on RNA 1 (ADAR1) are shown to be concomitantly upregulated in the resistant lines. Functional characterization demonstrated that ADAR1 confers chemoresistance and self-renewal in an RNA-dependent manner. WES-seq coupled with RNA-seq identified enrichment of hyperedited lipid metabolism genes in resistant compared to parental lines. ADAR1-mediated A-to-I editing on 3’UTR of stearoyl-CoA desaturase (SCD1) increased binding of the KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting stability of SCD1 expression. Consequently, SCD1 endows chemoresistance by facilitating lipid droplet formation to alleviate ER stress; and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogated 5FU+CDDP chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score corresponds to a worse prognosis and predicts response to 5FU- and/or platinum-based chemotherapy.Conclusions
We demonstrate that chemoresistance can be derived from an aberrant lipid metabolism driven by alterations in RNA editing and identified an actionable target to circumvent chemoresistance in GC.TL;DR: In this paper , a Bayesian model was proposed to capture the methylation signatures of different subtypes from paired normal and tumor methylation array data, and applied to synthetic and empirical data showed high clustering accuracy, and was able to identify the possible epigenetic cause of a cancer subtype.
Abstract: Abstract Aberrant DNA methylation is the most common molecular lesion that is crucial for the occurrence and development of cancer, but has thus far been underappreciated as a clinical tool for cancer classification, diagnosis or as a guide for therapeutic decisions. Partly, this has been due to a lack of proven algorithms that can use methylation data to stratify patients into clinically relevant risk groups and subtypes that are of prognostic importance. Here, we proposed a novel Bayesian model to capture the methylation signatures of different subtypes from paired normal and tumor methylation array data. Application of our model to synthetic and empirical data showed high clustering accuracy, and was able to identify the possible epigenetic cause of a cancer subtype.
TL;DR: It is shown that gastric glands are clonal structures and accrue approximately 27 single base substitutions per year, and mutations that exhibit driver mutations, a recurrent trisomy or elevated mutation loads only overlap minimally, suggesting a highly variable and patient-specific mutation and selection landscape in the normal gastric epithelium.
Abstract:
Gastric cancer is the third leading cause of cancer-related mortality globally and is often associated with infectious agents such as the bacterium Helicobacter pylori. However, the background mutational landscape in normal gastric epithelium and the first genomic steps towards the formation of gastric cancer remain poorly understood. Here, we use whole-genome sequencing of microdissected gastric glands (n=271) from 30 patients, 18 of whom had gastric cancer. We show that gastric glands are clonal structures and accrue approximately 27 single base substitutions per year. While the mutational signatures in most normal glands reflect age-related mutagenesis, gastric glands sampled close to a tumor showed exposure to a mutagenic process enriched in tumors (COSMIC reference mutational signature SBS17). Phylogenetic analysis shows that acquisition of SBS17 substitutions is closely linked to overt malignant transformation. We also observe widespread trisomies of specific chromosomes, which are recurrently and independently acquired in many gastric glands of the same patient. Mutations in genes encoding epigenetic modifiers and chromatin remodelers showed evidence of positive selection and were highly enriched in some patients. This was confirmed by targeted sequencing of cancer genes in a further 1008 gastric glands. Strikingly, glands that exhibit driver mutations, a recurrent trisomy or elevated mutation loads only overlap minimally, suggesting a highly variable and patient-specific mutation and selection landscape in the normal gastric epithelium. Taken together, these results give novel insights into the preclinical evolution of gastric malignancies.
Citation Format: Tim H. Coorens, Grace Collord, Hyungchul Jung, Yichen Wang, Sonia Zumalave, Daniel Leongamornlert, Luiza Moore, Krishnaa Mahbubani, Kourosh Saeb-Parsy, Suet Yi Leung, Michael R. Stratton. Recurrent trisomies, variable selection and precancerous evolution in the normal gastric epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 226.