Genomic Hallmarks Research Articles

Epigenetic and Genomic Hallmarks of PARP-Inhibitor Resistance in Ovarian Cancer Patients.

Patients with advanced-stage epithelial ovarian cancer (EOC) receive treatment with a poly-ADP ribose-polymerase (PARP) inhibitor (PARPi) as maintenance therapy after surgery and chemotherapy. Unfortunately, many patients experience disease progression because of acquired therapy resistance. This study aims to characterize epigenetic and genomic changes in cell-free DNA (cfDNA) associated with PARPi resistance. Blood was taken from 31 EOC patients receiving PARPi therapy before treatment and at disease progression during/after treatment. Resistance was defined as disease progression within 6 months after starting PARPi and was seen in fifteen patients, while sixteen patients responded for 6 to 42 months. Blood cfDNA was evaluated via Modified Fast Aneuploidy Screening Test-Sequencing System (mFast-SeqS to detect aneuploidy, via Methylated DNA Sequencing (MeD-seq) to find differentially methylated regions (DMRs), and via shallow whole-genome and -exome sequencing (shWGS, exome-seq) to define tumor fractions and mutational signatures. Aneuploid cfDNA was undetectable pre-treatment but observed in six patients post-treatment, in five resistant and one responding patient. Post-treatment ichorCNA analyses demonstrated in shWGS and exome-seq higher median tumor fractions in resistant (7% and 9%) than in sensitive patients (7% and 5%). SigMiner analyses detected predominantly mutational signatures linked to mismatch repair and chemotherapy. DeSeq2 analyses of MeD-seq data revealed three methylation signatures and more tumor-specific DMRs in resistant than in responding patients in both pre- and post-treatment samples (274 vs. 30 DMRs, 190 vs. 57 DMRs, Χ2-test p < 0.001). Our genome-wide Next-Generation Sequencing (NGS) analyses in PARPi-resistant patients identified epigenetic differences in blood before treatment, whereas genomic alterations were more frequently observed after progression. The epigenetic differences at baseline are especially interesting for further exploration as putative predictive biomarkers for PARPi resistance.

Abstract 1057: A blood-based multi-omics test for multicancer early detection: Combined retrospective and prospective studies

Abstract Background: Recent studies have demonstrated that blood-based multi-cancer early detection (MCED) approaches may hold promise for identifying asymptomatic cancer patients from general population. However, most studies only exploit a single aspect of cancer hallmarks, which is challenging for the biological reasons as cancer is a heterogenous disease with a wide spectrum of pathological and clinical behaviors. Here we report a multi-omics MCED assay named SeekInCare, a CE-IVD Mark blood test, which incorporates genomic hallmarks: copy number aberrations, fragment size, end motifs and oncogenic viruses via shallow whole genome sequencing from cfDNA, and seven plasma protein tumor markers in 8 ml blood. Methods: SeekInCare was developed using several retrospective cohorts and the method has been described in a publication (DOI: 10.1016/j.jmoldx.2021.06.003) IF: 4.1 Q2. Results: We present the validation in a retrospective cohort consisting of 584 non-cancer individuals and 617 cancer patients covering 27 cancer types. SeekInCare achieved 65.5% sensitivity at 97.9% specificity, resulting in an AUC of 0.936. The sensitivities were 46.9%, 60.0%, 68.9%, 81.8% in stage I, II, III, IV patients. The sensitivities of 10 common cancer types are as the following: breast (46.2%), stomach (46.4%), colorectum (56.5%), gallbladder (60.0%), lung (62.8%), pancreas (64.7%), lymphoma (68.5%), esophagus (70.0%), liver (77.5%), and leukemia (86.7%). These cancer types account for 73.5% of cancer incidence and 81.8% of cancer-related mortality in China. We prospectively evaluated SeekInCare in a real-world cohort consisting of 1203 individuals who received the test as a laboratory developed test (median follow-up time: 753 days) in which it achieved 60.0% sensitivity, 96.1% specificity, 11.5% PPV and 99.7% NPV. Conclusion: The performances of SeekInCare in both retrospective and prospective studies demonstrate that SeekInCare is an effective blood-based MCED test with similar performance as Grail’s Galleri test, which paves the way for clinical utility as a cancer screening test in average-risk populations. Citation Format: Mao Mao, Shiyong Li, Qingqi Ren, Yi Luan, Weijie Liang, Shuaipeng Geng, Dao-Ling Huang, Dandan Zhu, Yinyin Chang, Wei Wu, Yingying Zhang, Linfeng Zhang, Yan Wang, Yumin Feng, Bing Wei, Jie Ma, Chaohui Duan, Guanghui Long. A blood-based multi-omics test for multicancer early detection: Combined retrospective and prospective studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1057.

Genomic hallmarks and therapeutic targets of ribosome biogenesis in cancer.

Hyperactive ribosome biogenesis (RiboSis) fuels unrestricted cell proliferation, whereas genomic hallmarks and therapeutic targets of RiboSis in cancers remain elusive, and efficient approaches to quantify RiboSis activity are still limited. Here, we have established an in silico approach to conveniently score RiboSis activity based on individual transcriptome data. By employing this novel approach and RNA-seq data of 14 645 samples from TCGA/GTEx dataset and 917 294 single-cell expression profiles across 13 cancer types, we observed the elevated activity of RiboSis in malignant cells of various human cancers, and high risk of severe outcomes in patients with high RiboSis activity. Our mining of pan-cancer multi-omics data characterized numerous molecular alterations of RiboSis, and unveiled the predominant somatic alteration in RiboSis genes was copy number variation. A total of 128 RiboSis genes, including EXOSC4, BOP1, RPLP0P6 and UTP23, were identified as potential therapeutic targets. Interestingly, we observed that the activity of RiboSis was associated with TP53 mutations, and hyperactive RiboSis was associated with poor outcomes in lung cancer patients without TP53 mutations, highlighting the importance of considering TP53 mutations during therapy by impairing RiboSis. Moreover, we predicted 23 compounds, including methotrexate and CX-5461, associated with the expression signature of RiboSis genes. The current study generates a comprehensive blueprint of molecular alterations in RiboSis genes across cancers, which provides a valuable resource for RiboSis-based anti-tumor therapy.

Non-Genomic Hallmarks of Aging-The Review.

Aging is a natural, gradual, and inevitable process associated with a series of changes at the molecular, cellular, and tissue levels that can lead to an increased risk of many diseases, including cancer. The most significant changes at the genomic level (DNA damage, telomere shortening, epigenetic changes) and non-genomic changes are referred to as hallmarks of aging. The hallmarks of aging and cancer are intertwined. Many studies have focused on genomic hallmarks, but non-genomic hallmarks are also important and may additionally cause genomic damage and increase the expression of genomic hallmarks. Understanding the non-genomic hallmarks of aging and cancer, and how they are intertwined, may lead to the development of approaches that could influence these hallmarks and thus function not only to slow aging but also to prevent cancer. In this review, we focus on non-genomic changes. We discuss cell senescence, disruption of proteostasis, deregualation of nutrient sensing, dysregulation of immune system function, intercellular communication, mitochondrial dysfunction, stem cell exhaustion and dysbiosis.

Prospective study to assess treatment response and predict patient prognosis by a blood-based multi-omics assay in lymphoma patients.

116 Background: Lymphoma represents a diverse group of cancer that arises from clonal proliferation of lymphocytes. Clinical existing imaging and biomarkers do not reliably predict treatment response across diverse lymphoma subtypes and treatment regimens. Only rare data show circulating tumor DNA (ctDNA) testing may perform as a good predictive biomarker for assessment of therapeutic response. We conducted a prospective study to assess treatment response and predict patient prognosis via our multi-omics assay (SeekInClarity) in lymphoma patients. Methods: SeekInClarity assay utilized common 7 protein tumor markers (PTMs) and cancer genomic hallmarks: copy number aberration (CNA) and fragment size (FS), which were analyzed by shallow whole genome sequencing, to calculate the molecular tumor burden (MTB) score. 8ml peripheral blood samples were collected from patients before and after every 2 cycles of treatment respectively, meanwhile, samples from a part of patients after 1 cycle of treatment were also collected. Results: Before treatment, 95 out of 133 patients (71.4%) were succeeded in detecting cancer signals with higher MTB scores (defined as baseline+). The proportion of patients with baseline+ was higher in patients with higher tumor stages. After 2 cycles of treatment, 39 out of 112 patients had a higher MTB score (defined as MRD+). The proportion of patients with progression in MRD+ group was significantly higher than that in MRD- group (p&lt;0.001). Meanwhile, MRD+ patients had a worse PFS than MRD- patients (p &lt;0.0001, HR: 26.4, 95% CI:8.7~80.3), regardless of tumor stages, lymphoma subtypes and treatment regimens. Among baseline+ patients, after 2 cycles of treatment the patients with MTB score decrease had a better PFS than that with MTB score increase (P&lt;0.001, HR: 7.5 95% CI:0.7~76.7). Among the baseline- group, patients who remained negative after treatment had extremely well PFS (100% PFS). As for the patients after 1 cycle of treatment, MTB value has a good concordance with that after 2 cycles of treatment which demonstrated a lead time in monitoring treatment response. 54 patients with longitudinal monitoring samples, 9(16.7%) patients were always MRD- during the treatment, who had the best PFS (100% PFS), regardless of baseline status. 11 out of 54 patients with always MRD+ had the worst PFS (p &lt; 0.05). Conclusions: This study demonstrates the clinical utility of multidimensional blood-based SeekInClarity assay in pan-cancer/pan-indication treatment response assessment and patient prognosis. After treatment, the dynamic change of MTB score and MRD status were independently associated with patient’s PFS, which indicated both could be used as biomarkers to predict the effectiveness of treatment. Compared with clinical image evaluation after 2 cycles of treatment, SeekInClarity test after 1 cycle of treatment is sufficient to assess treatment response.

Utilize protein markers and genomic features for minimal residual disease detection in hepatocellular carcinoma.

e15054 Background: Several studies have shown the clinical value of using circulating tumor DNA (ctDNA) for minimal residual disease (MRD) detection, which is more sensitive than traditional imaging methods. However, most MRD detection technologies focus on identifying mutations and require cancer tissue samples. These methods often have limitations, such as high cost, inaccessible cancer tissue, or inability to overcome tumor heterogeneity. SeekInCure is a cost-effective multi-dimensional MRD test that does not require cancer tissue analysis. The purpose of this prospective study was to evaluate the potential broad clinical utility of SeekInCure for detecting MRD in patients with hepatocellular carcinoma (HCC). Methods: 34 HCC patients undergoing radical surgery were prospectively enrolled in this study from Peking University Shenzhen Hospital. Peripheral blood samples of 8 mL were collected before and after surgery and analyzed using the SeekInCure assay, which integrates the protein tumor marker (AFP) and cancer genomic hallmarks: copy number aberrations and fragment size from ctDNA. Patients with positive results for AFP and/or ctDNA in the preoperative/postoperative samples were defined as MRD-positive (MRD+), while negative results were defined as MRD-negative (MRD-). Results: Of the 34 patients, 73.5% (25/34) were in early stages (stages I/II: 61.8%/11.8%), and 61.8% (21/34) received adjuvant therapies. The median follow-up was 279.5 days, ranging from 90 to 1,253 days. 82% (28/34) of the patients had MRD+ results in the preoperative samples, which showed remarkable sensitivity in a cohort with more than 70% of early-stage patients. Our previous findings were confirmed, with preoperative MRD+ patients having worse survival than MRD- patients1. After radical surgery, 26.5% (9/34) were MRD+. MRD+ patients had worse survival than MRD- patients, with a median overall survival (OS) time of 298 days for MRD+ patients, while the OS time for MRD- patients was not reached (P &lt; 0.01). 6 patients with MRD- in both pre- and post-operative samples had a very favorable outcome (100% OS). Conversely, 9 patients with both positive results had the worst outcome. We also found that MRD- patients receiving adjuvant therapies did not have a survival benefit compared to those without adjuvant therapies, but MRD+ patients receiving adjuvant therapies had better OS than those without adjuvant therapies (P = 0.026). Conclusions: This study confirms the excellent performance of our SeekInCure assay, which does not require cancer tissue analysis, in detecting MRD and the prognostic value of MRD in HCC patients. Adjuvant has no influence on survival, especially in MRD- patients, which indicates that amost one-third of HCC patients do not need additional adjuvant therapy.

Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer

BackgroundTherapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative G0 state, which is difficult to capture and whose mutational drivers remain largely unknown.ResultsWe develop methodology to robustly identify this state from transcriptomic signals and characterise its prevalence and genomic constraints in solid primary tumours. We show that G0 arrest preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We employ machine learning to uncover novel genomic dependencies of this process and validate the role of the centrosomal gene CEP89 as a modulator of proliferation and G0 arrest capacity. Lastly, we demonstrate that G0 arrest underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single-cell data.ConclusionsWe propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state.

Abstract 4277: Measuring proliferation rates of distinct tumour clones using single-cell DNA sequencing

Abstract Background: Tumour proliferation rate is a key phenotypic feature of cancer, with higher rates linked to poorer clinical outcomes. Thus far, proliferation rates have been measured using pathological or experimental techniques on bulk tumour samples. However, while tumours are heterogeneous compositions of distinct clones with varying levels of fitness, measuring the proliferation of individual clones has not been possible to date. We hypothesise that enabling the identification of the most proliferative clones would reveal genomic hallmarks of aggressive clones, or the prediction of their potential phenotype, e.g., metastatic potential. Methods: We have developed SPRINTER (Single-cell Proliferation Rate Inference in Neoplasms Through Evolutionary Routes), a novel computational method to measure proliferation rates in individual tumour clones using single-cell whole-genome DNA sequencing. To assess the accuracy and power of SPRINTER, we have also developed an experimental approach to DNA sequence &amp;gt;18,000 single cells, accurately separated in different DNA-replication phases. We have sequenced and applied SPRINTER to &amp;gt;10,000 non-small cell lung cancer cells from longitudinal and metastatic tumour samples within the TRACERx study and PEACE autopsy programme. We have further analysed published data from &amp;gt;10,000 breast cancer cells. Results: We demonstrate that SPRINTER can accurately identify subpopulations of cells with different proliferation rates using relatively small numbers of cells, in contrast to previous preliminary approaches. While our estimates are concordant with previous bulk experimental studies (5-40%), we importantly have identified clonal heterogeneity in proliferation rates. Using bulk analysis, we have identified patterns of dissemination of tumour clones in non-small cell lung cancer. Integrating this with single-cell data, our results indicate that more widely disseminating tumour clones have higher proliferation rates, suggesting a link between proliferation and dissemination potential. We additionally find that clones are more proliferative in the metastatic versus the primary setting. Furthermore, we have identified high proliferation clones that may have a selective advantage in a breast tumour, and have inferred that they likely arose recently in cancer evolution. Conclusions: We have developed a novel method that enables accurate identification of proliferation rates of individual tumour clones using single-cell DNA sequencing data, allowing the investigation of genomic hallmarks in highly proliferative clones that might lead to higher fitness. Citation Format: Olivia Lucas, Sophie Ward, Rija Zaidi, Mark Hill, Emilia Lim, Haoran Zhai, Abigail Bunkum, Sonya Hessey, Michelle Dietzen, Andrew Rowan, Cristina Naceur-Lombardelli, Nnenna Kanu, Mariam Jamal-Hanjani, Charles Swanton, Simone Zaccaria. Measuring proliferation rates of distinct tumour clones using single-cell DNA sequencing. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4277.

Reference genomes of channel catfish and blue catfish reveal multiple pericentric chromosome inversions

BackgroundChannel catfish and blue catfish are the most important aquacultured species in the USA. The species do not readily intermate naturally but F1 hybrids can be produced through artificial spawning. F1 hybrids produced by mating channel catfish female with blue catfish male exhibit heterosis and provide an ideal system to study reproductive isolation and hybrid vigor. The purpose of the study was to generate high-quality chromosome level reference genome sequences and to determine their genomic similarities and differences.ResultsWe present high-quality reference genome sequences for both channel catfish and blue catfish, containing only 67 and 139 total gaps, respectively. We also report three pericentric chromosome inversions between the two genomes, as evidenced by long reads across the inversion junctions from distinct individuals, genetic linkage mapping, and PCR amplicons across the inversion junctions. Recombination rates within the inversional segments, detected as double crossovers, are extremely low among backcross progenies (progenies of channel catfish female × F1 hybrid male), suggesting that the pericentric inversions interrupt postzygotic recombination or survival of recombinants. Identification of channel catfish- and blue catfish-specific genes, along with expansions of immunoglobulin genes and centromeric Xba elements, provides insights into genomic hallmarks of these species.ConclusionsWe generated high-quality reference genome sequences for both blue catfish and channel catfish and identified major chromosomal inversions on chromosomes 6, 11, and 24. These perimetric inversions were validated by additional sequencing analysis, genetic linkage mapping, and PCR analysis across the inversion junctions. The reference genome sequences, as well as the contrasted chromosomal architecture should provide guidance for the interspecific breeding programs.

Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways

Radiation-induced sarcoma (RIS) is a rare but serious late complication arising from radiotherapy. Despite unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic alterations in them. We analyzed whole-genome sequencing in 11 RIS genomes matched with normal genomes to identify somatic alterations potentially associated with RIS development. Furthermore, the abundance of mutations, mutation signatures, and structural variants in RIS were compared with those in radiation-naïve spontaneous sarcomas. The mutation abundance in RIS genomes, including one hypermutated genome, was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations. The genomic footprints of nonhomologous end joining are prevalent at indels of RIS genomes compared with those in spontaneous sarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis was identified along with predisposing germline variants in the DNA-damage–repair pathways in RIS genomes. The characterization of RIS genomes on a whole-genome sequencing scale highlighted that the nonhomologous end joining pathway was associated with tumorigenesis, and it might pave the way for the development of advanced diagnostic and therapeutic strategies for RIS.

7MO Measuring proliferation rates of distinct tumour clones using single-cell DNA sequencing

Tumour proliferation rate is a key phenotypic feature of cancer, with higher rates linked to poorer clinical outcomes. Thus far, proliferation rates have been measured using pathological or experimental techniques on bulk tumour samples. However, tumours are heterogeneous compositions of distinct clones with varying levels of fitness. We hypothesise that identifying the most proliferative clones would enable the identification of genomic hallmarks of aggressive clones, or the prediction of their potential phenotype, e.g., metastatic potential.

329. IMPROVED TUMOUR PURITY AND PLOIDY ESTIMATION FROM LASER CAPTURE MICRODISSECTED ESOPHAGEAL ADENOCARCINOMA SAMPLES

Abstract Large scale sequencing efforts by The Cancer Genome Atlas (TCGA), among others, have generated detailed genomic data for esophageal adenocarcinoma. However, samples with low cancer purity (i.e. high amounts of normal DNA) will limit accurate inference of copy number aberrations, a genomic hallmark of esophageal adenocarcinoma. This consequently restricts more advanced analysis such as quantifying intratumor heterogeneity or inferring tumor evolution. We have systematically collected biopsies from pre-treatment and post-induction esophageal adenocarcinoma tumors. Laser capture microdissection (LCM) was utilized to enrich for tumor cells for whole genome sequencing. Matching blood was utilized as germline control. Cancer purity and ploidy was estimated using a developed method tailored to the high genomic instability observed in EAC samples. This method uses both sequencing depth and minor allele frequencies to infer ploidy and purity. The esophageal adenocarcinoma dataset from TCGA were used as comparison. We achieved significantly higher tumor cellularity in surgical resection specimens (n = 8) compared to TCGA (71%+/−11 vs. 58%+/−18). Interestingly, tumor cellularity from biopsy specimens (n = 25) remained similar to TCGA despite LCM (65%+/−13), which is likely due to TCGA only using surgical resections that were pre-selected to have at least 60% cellularity, while we applied no histopathological cellular constraints on our samples. Estimated ploidy was similar between biopsy of primary tumors and surgical resection specimens compared to TCGA (2.67+/−0.58, 2.72+/−0.70, 2.64+/−0.75). There was a trend towards higher ploidy (3.07+/− 0.13) in metastatic biopsies (n = 3) but additional specimens are required. Laser capture microdissection of post-induction esophageal adenocarcinoma surgical resection specimens has resulted in significantly higher tumor purity in whole genome sequencing data. This will allow for improved inferences of phylogenetic trees between pre- and post- induction samples and quantification of subclonal copy number aberrations or intratumor heterogeneity.

Chromosome Translocations, Gene Fusions, and Their Molecular Consequences in Pleomorphic Salivary Gland Adenomas.

Salivary gland tumors are a heterogeneous group of tumors originating from the major and minor salivary glands. The pleomorphic adenoma (PA), which is the most common subtype, is a benign lesion showing a remarkable morphologic diversity and that, upon recurrence or malignant transformation, can cause significant clinical problems. Cytogenetic studies of >500 PAs have revealed a complex and recurrent pattern of chromosome rearrangements. In this review, we discuss the specificity and frequency of these rearrangements and their molecular/clinical consequences. The genomic hallmark of PA is translocations with breakpoints in 8q12 and 12q13-15 resulting in gene fusions involving the transcription factor genes PLAG1 and HMGA2. Until recently, the association between these two oncogenic drivers was obscure. Studies of the Silver–Russel syndrome, a growth retardation condition infrequently caused by mutations in IGF2/HMGA2/PLAG1, have provided new clues to the understanding of the molecular pathogenesis of PA. These studies have demonstrated that HMGA2 is an upstream regulator of PLAG1 and that HMGA2 regulates the expression of IGF2 via PLAG1. This provides a novel explanation for the 8q12/12q13-15 aberrations in PA and identifies IGF2 as a major oncogenic driver and therapeutic target in PA. These studies have important diagnostic and therapeutic implications for patients with PA.

Templated Insertions Are Associated Specifically with BRCA2 Deficiency and Overall Survival in Advanced Ovarian Cancer.

Small, templated insertions indicative of theta-mediated end-joining likely can be used in conjunction with other HRD mutational signatures as a prognostic tool for patient response to therapies targeting HR deficiency.

Integrated analysis reveals the molecular features of fibrosis in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer. High fibrosis, marked by increased collagen fibers, is widespread in TNBC and correlated with tumor progression. However, the molecular features of fibrosis and why it results in a poor prognosis remain poorly understood. Based on multiomics datasets of TNBC, we evaluated the pathological fibrosis grade of 344 samples for further analysis. Genomic, transcriptomic, and immune changes were analyzed among different subgroups of fibrosis. High fibrosis was an independent adverse prognosis predictor and had interactions with low stromal tumor-infiltrating lymphocytes. Genomic analysis identified copy number gains of 6p22.2–6p22.1 (TRIM27) and 20q13.33 (CDH4) as genomic hallmarks of tumors with high fibrosis. Transcriptome analysis revealed the transforming growth factor-beta pathway and hypoxia pathway were key pro-oncogenic pathways in tumors with high fibrosis. Moreover, we systematically evaluate the relationship between fibrosis and different kinds of immune and stromal cells. Tumors with high fibrosis were characterized by an immunosuppressive tumor microenvironment with limited immune cell infiltration and increased fibroblasts. This study proposes new insight into the genomic and transcriptomic alterations potentially driving fibrosis. Moreover, fibrosis is related to an immunosuppressive tumor microenvironment that contributes to the poor prognosis.

Integrating Circulating Tumor DNA Features and Plasma Protein Markers to Detected Early Lymphoid Neoplasm

IntroductionThe disease burden of lymphoid neoplasm has been rising in China over the last decade. But most patients manifest with advanced stage disease at initial diagnosis, and the prognosis is poor with a 5-year survival rate of 38.3%. Here we reported a novel multivariate cancer risk score (CRS) model which is used to detect early lymphoid neoplasm from the peripheral blood. It incorporates three cancer hallmarks, copy number aberrations (CNA) and fragment size (FS) via shallow whole genome sequencing (sWGS) from cell-free DNA (cfDNA), and a panel of seven tumor protein markers in a single blood draw (10ml).Methods44 newly diagnosed and untreated stage I-IV lymphoid neoplasm patients and 247 healthy individuals with no cancer diagnosis were enrolled in this study. 10ml peripheral blood was collected from each participant after enrollment. cfDNA was extracted and subjected to sWGS whereas plasma was subjected to measure the levels of 7 PTMs. The cancer risk score (CRS) of a subject was calculated via an established CRS model [1].ResultsFirstly, genomic and epigenetic features were explored from cfDNA sWGS results. CNA is a ubiquitous genomic hallmark in a wide spectrum of cancers. In this study, 26 of the 44 (59.1%) lymphoid neoplasm patients had CNA in at least one genomic segment (>5Mb). FS feature of cfDNA bears the correspondence of the epigenetic landscapes of cells that give rise to those cfDNA fragments. When CNA was combined with FS, 29 (65.9%) patients were able to be detected by the CNA+FS classifier. On the other hand, 13 (29.5%) patients were tested positive by PTMs alone, indicating non-DNA molecular surrogates can also serve as cancer biomarkers with acceptable performance. When CNA, FS and PTM were incorporated into a multidimensional and multivariate CRS model, it achieved the best performance allowing 31 (70.0%) lymphoid neoplasm cases to be identified with a positive predictive value (PPV) of 86.1% at 98.0% specificity. The sensitivity of CRS model increases with the advances of disease with a sensitivity of 50.0% in early stage (stage I -Ⅱ) and 90.0% in late stage (stage Ⅲ-Ⅳ).ConclusionIn summary, this study provides an efficient and non-invasive method to detect lymphoid neoplasm. Instead of relying only on one dimension of cancer markers, the multidimensional approach which incorporating CNA, fragment size and protein markers is plausible in early detection of lymphoid neoplasm with sufficient accuracy and robustness. DisclosuresZhu: Clinical Laboratories, Shenyou Bio: Current Employment. Li: SeekIn Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Geng: Clinical Laboratories, Shenyou Bio: Current Employment. Chang: Clinical Laboratories, Shenyou Bio: Current Employment. Chen: SeekIn Inc: Current Employment, Current holder of individual stocks in a privately-held company. Mao: SeekIn Inc: Current Employment, Current holder of individual stocks in a privately-held company.

Down-regulation of MYH10 driven by chromosome 17p13.1 deletion promotes hepatocellular carcinoma metastasis through activation of the EGFR pathway.

Somatic copy number alterations (CNAs) are a genomic hallmark of cancers. Among them, the chromosome 17p13.1 deletions are recurrent in hepatocellular carcinoma (HCC). Here, utilizing an integrative omics analysis, we screened out a novel tumour suppressor gene within 17p13.1, myosin heavy chain 10 (MYH10). We observed frequent deletions (~38%) and significant down‐regulation of MYH10 in primary HCC tissues. Deletion or decreased expression of MYH10 was a potential indicator of poor outcomes in HCC patients. Knockdown of MYH10 significantly promotes HCC cell migration and invasion in vitro, and overexpression of MYH10 exhibits opposite effects. Further, inhibition of MYH10 markedly potentiates HCC metastasis in vivo. We preliminarily elucidated the mechanism by which loss of MYH10 promotes HCC metastasis by facilitating EGFR pathway activation. In conclusion, our study suggests that MYH10, a candidate target gene for 17p13 deletion, acts as a tumour suppressor and may serve as a potential prognostic indicator for HCC patients.

Whole-Genome Sequencing Reveals Comprehensive Genomic Profiles of Radiation-Induced Sarcomas

<h3>Purpose/Objective(s)</h3> Radiation-induced sarcoma (RIS) is a rare secondary malignancy resulting from ionizing radiation-related treatment after a long latency period. Despite the unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic alterations in them. <h3>Materials/Methods</h3> We performed whole-genome sequencing (WGS) of 11 cases of RIS matched with normal genomes to identify somatic alterations potentially associated with RIS development. <h3>Results</h3> The mutation abundance of RIS genomes including one hypermutated genome was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations (SVs). The effects of non-homologous end joining on short insertions-deletions and SVs were substantial in RIS genomes, compared with in spontaneous osteosarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis and predisposing germline variants in DNA damage-repair pathways were identified. <h3>Conclusion</h3> Taken together, WGS-scale characterization of RIS genomes may pave the way for advanced diagnostic and therapeutic strategies for RIS.

Intraductal Papillary Mucinous Carcinoma Versus Conventional Pancreatic Ductal Adenocarcinoma: A Comprehensive Review of Clinical-Pathological Features, Outcomes, and Molecular Insights.

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the “intestinal pathway”, to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.

Phenotypic and genomic hallmarks of a novel, potentially pathogenic rapidly growing Mycobacterium species related to the Mycobacterium fortuitum complex

Previously, we have identified a putative novel rapidly growing Mycobacterium species, referred to as TNTM28, recovered from the sputum of an apparently immunocompetent young man with an underlying pulmonary disease. Here we provide a thorough characterization of TNTM28 genome sequence, which consists of one chromosome of 5,526,191 bp with a 67.3% G + C content, and a total of 5193 predicted coding sequences. Phylogenomic analyses revealed a deep-rooting relationship to the Mycobacterium fortuitum complex, thus suggesting a new taxonomic entity. TNTM28 was predicted to be a human pathogen with a probability of 0.804, reflecting the identification of several virulence factors, including export systems (Sec, Tat, and ESX), a nearly complete set of Mce proteins, toxin-antitoxins systems, and an extended range of other genes involved in intramacrophage replication and persistence (hspX, ahpC, sodA, sodC, katG, mgtC, ClpR, virS, etc.), some of which had likely been acquired through horizontal gene transfer. Such an arsenal of potential virulence factors, along with an almost intact ESX-1 locus, might have significantly contributed to TNTM28 pathogenicity, as witnessed by its ability to replicate efficiently in macrophages. Overall, the identification of this new species as a potential human pathogen will help to broaden our understanding of mycobacterial pathogenesis.