Molecular features of BRCA1/2 and PALB2 mutation associated pancreatic cancer (PAC).

206 Background: Several clinical reports have indicated increased sensitivity to DNA damaging agents and PARP inhibitors in patients with PAC arising on a background of known BRCA1/2 or PALB2 germline mutation. While the mechanism of tumorigenesis in these cancer remains unclear, it appears likely that BRCA1/2germline mutations can predispose to PAC via 2 mechanisms, only one of which requires loss of the second allele. Determination as to whether biallelic inactivation of these genes is present in the tumor may have important therapeutic implications in predicting sensitivity to PARP inhibitors and other strategies targeting DNA repair. Methods: Following approval by the IRB and human bio specimen utilization committee at MSKCC, full exon sequencing of coding regions of 28 genes including BRCA1, 2 and PALB2 using exon capture by hybridization and next generation sequencing was performed on DNA extracted from 135 PAC samples. In addition, samples were analyzed for the presence of BRCA1 promotor methylation, KRAS hotspot mutations, and genome wide loss of heterozygosity (LOH) as an exploratory assessment of number and length of LOH as a marker of homologous repair deficiency / genomic instability. All patients underwent surgery for PAC at MSKCC after year 2000. Patients were selected on the basis of survival and included if they suffered a cancer-specific death within 1 year of resection or survived at least 30 months. Results: 7 tumors had mutations in BRCA2, 1 in BRCA1 and 1 in PALB2. Of 4 BRCA2 mutated samples evaluated for LOH at the BRCA2 locus, 2 demonstrated LOH while 2 did not. There was no LOH at PALB2 in the sample where a mutation was identified. Activating KRAS mutations were identified in BRCA2 mutated tumors with and without LOH. Methylation of the BRCA1promotor regions was not identified. Conclusions: The frequency of BRCA1/2 mutation carriers was as anticipated in this population. Biallelic loss of BRCA2 or PALB2 are not required for pancreatic tumorigenesis. The benefit of PARP inhibitors in BRCA1 / 2 mutated PAC may be limited to tumors with LOH of these genes. Inactivation of BRCA1 through promoter methylation is not identified in sporadic PAC.

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An integrative molecular framework to predict homologous recombination deficiency.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15664 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15664-e15664

Author(s):

Joshua SK Bell ◽

Aarti Venkat ◽

Jerod Parsons ◽

Catherine Igartua ◽

Benjamin D. Leibowitz ◽

...

Keyword(s):

Homologous Recombination ◽

Snp Array ◽

Parp Inhibitors ◽

Gene Set Enrichment Analysis ◽

Tumor Type ◽

Homologous Recombination Deficiency ◽

Molecular Features ◽

Gene Sets ◽

Genome Wide ◽

A Genome

e15664 Background: Homologous recombination deficiency (HRD) is the primary biomarker for sensitivity to PARP inhibitors, but identifying the genetic and transcriptomic characteristics that fully capture all HRD patients has remained difficult. For example, DNA-based approaches are limited to patients with pathogenic mutations and loss of heterozygosity (LOH) events, and can fail to properly classify patients with variants of unknown significance. To capture more dynamic cellular processes that arise immediately upon induction of HRD through silencing or loss of BRCA 1/2, a more integrated approach that includes both RNA and DNA based models is necessary. Methods: Using DNA sequencing we developed a genome-wide LOH score that combines pathogenic mutation status and LOH at the BRCA1/2 loci, and the proportion of bases sequenced in the Tempus xT panel that undergo LOH. We also developed three independent RNA-based models to predict BRCA deficiency: 1) An elastic net transcriptome model to predict DNA-based HRD scores derived from exome and SNP array data for each tumor type represented in TCGA; 2) A logistic model to detect BRCA1 promoter hypermethylation from the transcriptome in TCGA data; 3) A model that leveraged the mSigDB annotated gene sets to conduct single sample gene set enrichment analysis (ssGSEA) on Tempus-sequenced patients, selecting over a hundred gene sets that were predictive of BRCA-deficiency. These 4 features were combined to develop a stacked, linear-regression model to distinguish BRCA-intact from BRCA-deficient patients. Results: We found that the genome-wide LOH score alone is predictive of BRCA deficiency. However, our integrated model was highly accurate at distinguishing between BRCA-intact and BRCA-deficient patients and outperformed any single RNA- or DNA-based model. Using this model, we identified many patients that are likely to respond to PARP inhibitors that would have been overlooked using RNA or DNA-based inferences alone. Conclusions: Our approach highlights the strength of integrating diverse molecular features to refine diagnosis and enable oncologists to deliver the most effective therapies to patients.

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Clinically important molecular features of Peruvian colorectal tumours: high prevalence of DNA mismatch repair deficiency and low incidence of KRAS mutations

Pathology ◽

10.1097/pat.0b013e3283437613 ◽

2011 ◽

Vol 43 (3) ◽

pp. 228-233 ◽

Cited By ~ 9

Author(s):

C.M. Egoavil ◽

P. Montenegro ◽

J.L. Soto ◽

L. Casanova ◽

J. Sanchez-Lihon ◽

...

Keyword(s):

Mismatch Repair ◽

Mismatch Repair Deficiency ◽

Kras Mutations ◽

Dna Mismatch ◽

Molecular Features ◽

Repair Deficiency ◽

High Prevalence ◽

Low Incidence ◽

Colorectal Tumours ◽

Dna Mismatch Repair Deficiency

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Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽

10.3390/biom11050750 ◽

2021 ◽

Vol 11 (5) ◽

pp. 750

Author(s):

Kiyohiro Ando ◽

Akira Nakagawara

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Progression ◽

Parp Inhibitors ◽

Cell Cycle Checkpoint ◽

Mitotic Catastrophe ◽

Malignant Neoplasms ◽

Checkpoint Kinases ◽

Molecular Features ◽

Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

npj Precision Oncology ◽

10.1038/s41698-021-00187-y ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Robert L. Hollis ◽

Barbara Stanley ◽

John P. Thomson ◽

Michael Churchman ◽

Ian Croy ◽

...

Keyword(s):

High Risk ◽

Ovarian Carcinoma ◽

Expression Patterns ◽

Parp Inhibitors ◽

Receptor Expression ◽

Cancer Type ◽

Sequencing Data ◽

Molecular Features ◽

Endometrioid Ovarian Carcinoma ◽

Molecular Landscape

AbstractEndometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR−/ER + , PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.

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Racial Differences in Esophageal Squamous Cell Carcinoma: Incidence and Molecular Features

BioMed Research International ◽

10.1155/2017/1204082 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Shirui Chen ◽

Kai Zhou ◽

Liguang Yang ◽

Guohui Ding ◽

Hong Li

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Cancer ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Racial Differences ◽

Squamous Cell ◽

Geographic Location ◽

Molecular Features ◽

Genome Wide ◽

White Patients

The incidence and histological type of esophageal cancer are highly variable depending on geographic location and race/ethnicity. Here we want to determine if racial difference exists in the molecular features of esophageal cancer. We firstly confirmed that the incidence rate of esophagus adenocarcinoma (EA) was higher in Whites than in Asians and Blacks, while the incidence of esophageal squamous cell carcinoma (ESCC) was highest in Asians. Then we compared the genome-wide somatic mutations, methylation, and gene expression to identify differential genes by race. The mutation frequencies of some genes in the same pathway showed opposite difference between Asian and White patients, but their functional effects to the pathway may be consistent. The global patterns of methylation and expression were similar, which reflected the common characteristics of ESCC tumors from different populations. A small number of genes had significant differences between Asians and Whites. More interesting, the racial differences of COL11A1 were consistent across multiple molecular levels, with higher mutation frequency, higher methylation, and lower expression in White patients. This indicated that COL11A1 might play important roles in ESCC, especially in White population. Additional studies are needed to further explore their functions in esophageal cancer.

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Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian cancer (HGOC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5537 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5537-5537

Author(s):

Tanya Kwan ◽

Amit M. Oza ◽

Domenica Lorusso ◽

Carol Aghajanian ◽

Ana Oaknin ◽

...

Keyword(s):

Clinical Characteristics ◽

Maintenance Treatment ◽

Parp Inhibitor ◽

Progression Free Survival ◽

Molecular Characteristics ◽

Brca Mutations ◽

Molecular Features ◽

Brca1 Promoter Methylation ◽

Genome Wide ◽

To Receive

5537 Background: ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor (PARPi) rucaparib as maintenance treatment in HGOC patients (pts) who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. Methods: Pts were randomized 2:1 to receive rucaparib 600 mg BID or placebo. At the data cutoff of Dec 31, 2019, 33/375 (9%) and 1/189 (0.5%) pts were still ongoing and receiving rucaparib or placebo, respectively. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were compared between pts who derived exceptional benefit (PFS ≥2 yrs), and those with disease progression on first scan (≈12 wks; the short-term [ST] subgroup) within each treatment arm. Results: Of 564 pts, 83 (15%) showed exceptional benefit: 79/375 (21%) in the rucaparib arm and 4/189 (2%) in the placebo arm. Within the rucaparib arm, exceptional benefit pts had more favorable clinical prognostic factors at baseline compared with the ST subgroup (Table). While BRCA mutations were enriched in the rucaparib exceptional benefit subgroup, 34/79 (43%) of these pts were BRCA wild type. Among other biomarkers, RAD51C/D mutations were associated with exceptional benefit; low genome-wide loss of heterozygosity was enriched within the ST subgroup; and high BRCA1 methylation was present at similar fractions. Trends were similar in the placebo arm (Table). Conclusions: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, pts with favorable clinical characteristics and known mechanisms of PARPi sensitivity. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of HGOC pts. Clinical trial information: NCT01968213. [Table: see text]

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Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

10.1101/203224 ◽

2017 ◽

Author(s):

Stephen J. Pettitt ◽

Dragomir B. Krastev ◽

Inger Brandsma ◽

Amy Drean ◽

Feifei Song ◽

...

Keyword(s):

Catalytic Domain ◽

Synthetic Lethality ◽

Parp Inhibitor ◽

Point Mutations ◽

Underlying Mechanism ◽

Parp Inhibitors ◽

High Density ◽

Single Amino Acid ◽

Genome Wide ◽

Amino Acid Mutations

AbstractPARP inhibitors (PARPi) target homologous recombination defective tumour cells via synthetic lethality. Genome-wide and high-density CRISPR-Cas9 “tag, mutate and enrich” mutagenesis screens identified single amino acid mutations in PARP1 that cause profound PARPi-resistance. These included PARP1 mutations outside of the DNA interacting regions of the protein, such as mutations in solvent exposed regions of the catalytic domain and clusters of mutations around points of contact between ZnF, WGR and HD domains. These mutations altered PARP1 trapping, as did a mutation found in a clinical case of PARPi resistance. These genetic studies reinforce the importance of trapped PARP1 as a key cytotoxic DNA lesion and suggest that interactions between non-DNA binding domains of PARP1 influence cytotoxicity. Finally, different mechanisms of PARPi resistance (BRCA1 reversion, PARP1, 53BP1, REV7 mutation) had differing effects on chemotherapy sensitivity, suggesting that the underlying mechanism of PARPi resistance likely influences the success of subsequent therapies.

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Genomic hallmarks of cellular dormancy in cancer and therapeutic implications

10.21203/rs.3.rs-1104031/v1 ◽

2021 ◽

Author(s):

Maria Secrier ◽

Anna Wiecek ◽

Stephen Cutty ◽

Daniel Kornai ◽

Mario Parreno-Centeno ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Therapy Resistance ◽

Therapeutic Resistance ◽

Epigenetic Mechanisms ◽

Therapeutic Implications ◽

Damage Repair ◽

Repair Deficiency ◽

Cell Data ◽

Cell Cycle Kinase

Abstract Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative, quiescent or ‘dormant’ state, which is difficult to capture and whose mutational drivers remain largely unknown. We developed methodology to uniquely identify this state from transcriptomic signals and characterised its prevalence and genomic constraints in solid primary tumours. We show dormancy 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 uncover novel genomic dependencies of this process, including the amplification of the centrosomal gene CEP89 as a driver of dormancy impairment. Lastly, we demonstrate that dormancy underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single cell data, and propose a signature of dormancy-linked therapeutic resistance to further study and clinically track this state.

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Genome-Wide DNA Methylation Profiles of Phlegm-Dampness Constitution

Cellular Physiology and Biochemistry ◽

10.1159/000487976 ◽

2018 ◽

Vol 45 (5) ◽

pp. 1999-2008 ◽

Cited By ~ 3

Author(s):

Haiqiang Yao ◽

Shanlan Mo ◽

Ji Wang ◽

Yingshuai Li ◽

Chong-Zhi Wang ◽

...

Keyword(s):

Dna Methylation ◽

Metabolic Disorders ◽

Mononuclear Cells ◽

Metabolic Diseases ◽

Body Type ◽

Peripheral Blood Mononuclear ◽

Molecular Features ◽

Genome Wide ◽

A Genome ◽

Differentially Methylated Genes

Background/Aims: Metabolic diseases are leading health concerns in today’s global society. In traditional Chinese medicine (TCM), one body type studied is the phlegm-dampness constitution (PC), which predisposes individuals to complex metabolic disorders. Genomic studies have revealed the potential metabolic disorders and the molecular features of PC. The role of epigenetics in the regulation of PC, however, is unknown. Methods: We analyzed a genome-wide DNA methylation in 12 volunteers using Illumina Infinium Human Methylation450 BeadChip on peripheral blood mononuclear cells (PBMCs). Eight volunteers had PC and 4 had balanced constitutions. Results: Methylation data indicated a genome-scale hyper-methylation pattern in PC. We located 288 differentially methylated probes (DMPs). A total of 256 genes were mapped, and some of these were metabolic-related. SQSTM1, DLGAP2 and DAB1 indicated diabetes mellitus; HOXC4 and SMPD3, obesity; and GRWD1 and ATP10A, insulin resistance. According to Ingenuity Pathway Analysis (IPA), differentially methylated genes were abundant in multiple metabolic pathways. Conclusion: Our results suggest the potential risk for metabolic disorders in individuals with PC. We also explain the clinical characteristics of PC with DNA methylation features.

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