Distinct genomic landscape in colorectal mucinous carcinoma via comprehensive genomic profiling.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 222-222
Author(s):  
Liang Huang ◽  
Shuangling Luo ◽  
FangQin Xue ◽  
Yi Xiao ◽  
Ziqiang Wang ◽  
...  
Keyword(s):  
Early Stage ◽  
Regional Lymph Node ◽  
Genomic Analysis ◽  
Mucinous Carcinoma ◽  
Braf V600e ◽  
Response To Treatment ◽  
Molecular Profile ◽  
Molecular Features ◽  
Genomic Landscape ◽  
Recombination Pathway

222 Background: Mucinous carcinoma (MC), accounting for 10-15% of colorectal cancer (CRC), has long been associated with an inferior response to treatment. MC as an unfavorable prognostic factor in early stage CRC remains questionable. In this study, we used a large CRC cohort to define the genomic landscape of MC and identify prognostic and clinically actionable information. Methods: The 1226 CRC patient cohort included 997 adenocarcinomas (AC), 129 MC, and 110 adenocarcinomas with mucous composition (AMC). All of the pathological sections were verified by an experienced pathologist. FFPE tumor samples and matched peripheral blood were sequenced using a 450-cancer-related gene panel. Results: MC was significantly associated with right colon (p<0.001) and regional lymph node metastasis (p=0.004) compared to AC. We found a higher mutation rate of BRAF V600E (10.9% vs. 3.3%), PIK3CA (28.7% vs. 19.2%), SMAD4 (34.1% vs. 19.1%), BRCA1/2 (16.3% vs. 6.8%) and homology recombination pathway (40.3% vs. 22.7%), and a lower rate of TP53 (53.5% vs. 79.5%), APC (46.5% vs. 75.1%,), and HER2 amplification (0% vs. 2.1%,) in MC than in AC. MC had a significantly higher proportion of microsatellite instability-high (MSI-H) tumors (22.5% vs. 6.8%, p<0.001). Furthermore, in tumors with MSI stable, POLE mutation was more frequent in MC than in AC (7.0% vs. 2.6%, p=0.094) and resulted in dramatic elevated tumor mutational burden (TMB, range 79.5-591.5 muts/Mb), indicating up to 30% of MC patients may benefit from immunotherapy. MSI-H was associated with better prognosis (5-y DFS, MSI-H 86.7% vs. MSS 56.7%) in stage II/III CRC patients with MC. Importantly, AMC mimicked the genomic features of MC rather than AC. Conclusions: For the first time, comprehensive genomic analysis revealed that MC had distinct molecular features, indicating promising clinically application for both immunotherapy and targeted therapy. Early stage MC had a diverse prognosis due to MSI status and should be interpreted differently. The similarity of molecular profile between AMC and MC suggested the possible usage of MC, but not AC, clinical strategy for AMC.

scholarly journals Distinct Genomic Landscape of Colorectal Mucinous Carcinoma Determined via Comprehensive Genomic Profiling: Steps to a New Treatment Strategy

2021 ◽  
Vol 11 ◽  
Author(s):  
Liang Huang ◽  
Shuanglin Luo ◽  
Xingwei Zhang ◽  
Yonghua Cai ◽  
Fangqin Xue ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Mucinous Carcinoma ◽  
Molecular Signature ◽  
Response To Treatment ◽  
Mutation Rates ◽  
Genomic Features ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
New Treatment ◽  
Generation Sequencing

Colorectal mucinous carcinoma (MC) is associated with inferior prognosis and response to treatment compared to adenocarcinoma (AC). The molecular landscapes of MC and adenocarcinoma with mucous composition (AMC) are not well-defined. We aimed to describe the genomic landscape of MC and AMC in a large colorectal cancer cohort. Tumor samples from patients with MC, AMC, or AC were analyzed using next-generation sequencing. MC had a molecular signature distinct from that of AC; genomic features were similar between AMC and MC but not between AMC and AC. HER2 amplification and TP53 and APC mutation rates were lower, whereas SMAD4, PIK3CA, ACVR2A, KMT2D, LRP1, TGFBR2, GRIN2A, BRAF V600E, PTEN, and BRCA2 mutation rates were higher in MC than in AC. The mutation frequencies in MAPK, PI3K, and TGF-β pathways were higher, whereas those of cell cycle proteins and Wnt were lower in MC and AMC than in AC. The proportion of hypermutated tumors was significantly higher in MC and AMC than in AC. As MC has a distinct molecular signature from AC, immunotherapy can be potentially applied in treating MC. Similar molecular profiles of AMC and MC suggest that treatment strategies for MC, but not AC, can be used for AMC treatment.

Comprehensive genomic landscape in Chinese patients with urothelial carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17009-e17009
Author(s):  
Haige Chen ◽  
Ruiyun Zhang ◽  
Shiqing Chen ◽  
Yuezong Bai
Keyword(s):  
Urothelial Carcinoma ◽  
Large Scale ◽  
Clinical Laboratory ◽  
Genomic Analysis ◽  
Chinese Patients ◽  
Variants Of Unknown Significance ◽  
Molecular Features ◽  
Genomic Landscape ◽  
Ffpe Tumor ◽  
Somatic Alterations

e17009 Background: Recent therapeutic advances, such as immunotherapy and FGFR-targeted therapy, have greatly improved the prognosis of patients with urothelial carcinoma (UC). Revealing comprehensive genomic features could evolve our understanding of UC, however the genomic landscape in Chinese UC has not been fully elucidated. In the present study, we investigated the molecular features of Chinese UC patients. Methods: Genomic profiling was performed through next generation sequencing (NGS) from Chinese patients with UC between January, 2017 and November, 2019 in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab. DNA was extracted from formalin fixed paraffin-embedded (FFPE) tumor specimens or fresh tumor tissue. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay or Ventana PD-L1 SP263 assay. Data analyses were performed using SPSS and R 3.6.1. Results: A total of 298 Chinese UC patients who have undergone NGS were included in this study, including 210 (70.5%) male and 88 (29.5%) female patients. The median age was 66 (range, 19-91) years old. The most common somatic alterations were detected in TP53 (57.0%), KMT2D (42.6%), TERT (28.2%), KDM6A (26.5%) and PIK3CA (18.8%). Of the 243 patients who were evaluated for PD-L1 expression, 78 (32.1%) had a PD-L1 Tumor Proportion Score (TPS) of 1% or greater, and 18 (7.4%) had a PD-L1 TPS of 50% or greater. The median TMB value was 9.7 muts/Mb (range: 0-175.0). 138 (46.3%) patients harbored alterations in DNA damage repair (DDR) genes, including pathogenic or likely pathogenic mutations (MUT) and variants of unknown significance (VOUS). The most common somatic alterations in DDR genes were detected in ATM (9.4%), BRCA2 (9.4%), BRIP1 (5.0%), ATR (4.7%) and BRCA1 (4.7%). Significant differences of TMB were observed among DDR-MUT group, DDR-VOUS group and DDR-WT group (mTMB = 16.1, 14.0 and 7.3 muts/Mb, respectively, P < 0.001). Seven (2.4%) patients were identified as MSI-H, including five patients in DDR-MUT group (12.8%) and two patients in DDR-VOUS group (2.0%). Conclusions: This is the first large-scale comprehensive genomic analysis for Chinese patients with UC. These results provide a better understanding of molecular features in Chinese UC patients which may lead to an improvement in the personalized treatment for these patients.

Circulating Tumor DNA as a Biomarker for Outcomes Prediction in Colorectal Cancer Patients

2020 ◽  
Vol 21 ◽  
Author(s):  
Angelica Petrillo ◽  
Massimiliano Salati ◽  
Dario Trapani ◽  
Michele Ghidini
Keyword(s):  
Colorectal Cancer ◽  
Residual Disease ◽  
Early Stage ◽  
Recurrence Risk ◽  
Early Response ◽  
Circulating Tumor Dna ◽  
Response To Treatment ◽  
Molecular Profile ◽  
Liquid Biopsies ◽  
Tissue Biopsy

Abstract:: Circulating tumour DNA (ctDNA) is a novel tool that has being investigated in several types of tumours, includ-ing colorectal cancer (CRC). In fact, the techniques based on liquid biopsies are proposed as appealing non-invasive alter-natives to tissue biopsy, adding more insights into tumour molecular profile, heterogeneity and for cancer detection and monitoring. Additionally, some analysis showed that in CRC patients ctDNA seems to act as biomarker able to predict the outcome (prognostic role) and the response to treatments (predictive role). In particular, in the early stage CRC (stage I-III) it could represent a time marker of adjuvant therapy benefit as well as a marker of minimal residual disease and recurrence risk in addition to the already recognized risk factors. In metastatic CRC, the analysis of molecular tumour profile by ctDNA has shown to have high concordance with the tissue biopsy at diagnosis. Additionally, some studies demonstrated that ctDNA level during the treatment was linked with early response to treatment and prognosis. Finally, the quantitative anal-ysis of ctDNA and copy number alterations may be useful in order to detect resistance to therapy at the time of progression of disease and to help in finding new therapeutic targets.

scholarly journals Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3975
Author(s):  
Marco A. De Velasco ◽  
Yurie Kura ◽  
Naomi Ando ◽  
Noriko Sako ◽  
Eri Banno ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Late Stage ◽  
Early Stage ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Molecular Features ◽  
Context Specific

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

scholarly journals Higher EU-TIRADS-Score Correlated with BRAF V600E Positivity in the Early Stage of Papillary Thyroid Carcinoma

2021 ◽  
Vol 10 (11) ◽  
pp. 2304
Author(s):  
Karolina Skubisz ◽  
Joanna Januszkiewicz-Caulier ◽  
Patrycja Cybula ◽  
Elwira Bakuła-Zalewska ◽  
Krzysztof Goryca ◽  
...  
Keyword(s):  
Early Stage ◽  
Braf V600e ◽  
P Value ◽  
Dna And Rna ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Ion Proton ◽  
Indolent Disease ◽  
Next Generation Sequencing Ngs ◽  
Formalin Fixed

The data demonstrating a correlation between sonographic markers of malignancy of thyroid cancer (TC) and its genetic status are scarce. This study aimed to assess whether the addition of genetic analysis at the preoperative step of TC patients’ stratification could aid their clinical management. The material consisted of formalin-fixed paraffin-embedded tumor fragments of 49 patients who underwent thyroidectomy during the early stages of papillary TC (PTC). Tumor DNA and RNA were subjected to next-generation sequencing (NGS) on Ion Proton using the Oncomine™ Comprehensive Assay panel. We observed a significant correlation between BRAF V600E and a higher EU-TIRADS score (p-value = 0.02) with a correlation between hypoechogenicity and taller-than-wide tumor shape in analysed patients. There were no other significant associations between the identified genetic variants and other clinicopathological features. For TC patient’s stratification, a strong suspicion of BRAF V600E negativity in preoperative management of TC patients could limit the over-treatment of asymptomatic, very low-risk, indolent disease and leave room for active surveillance.

scholarly journals Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1234
Author(s):  
Jérôme Raffenne ◽  
Fernando A. Martin ◽  
Rémy Nicolle ◽  
Marina Konta ◽  
Yuna Blum ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Protein Identification ◽  
Molecular Profile ◽  
Global Methylation ◽  
Old Patients ◽  
Molecular Features ◽  
Age Related ◽  
Clinical Difference ◽  
Dna Repair Gene

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is known to impact DNA methylation and proteome integrity through carbonylation-related oxidative damages. We therefore aimed to assess the global molecular features of EOT. We compared 176 EOT (≤55 y.o.) and 316 LOT (≥70 y.o.) from three distinct surgical cohorts at the clinical/genomic/epigenomic/transcriptomic level. Furthermore, we assessed oxidative stress responses and oxidative proteome damages using 2D gel electrophoresis followed by mass spectrometry protein identification. There was no consistent clinical difference between EOT and LOT across the three cohorts. The mutational landscape of key driver genes and the global methylation profile were similar in the two groups. LOT did display age-related features such as enriched DNA repair gene signatures and upregulation of oxidative stress defenses together with increased proteome carbonylation. However, these age-related differences were more preeminent in non-tumor tissues while tumor proteome and proteome damages were fairly comparable. In conclusion, this multi-omics comparison showed that EOT harbor a comparable molecular profile to that of LOT.

scholarly journals Integrative genomics approach identifies molecular features associated with early-stage ovarian carcinoma histotypes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hanna Engqvist ◽  
Toshima Z. Parris ◽  
Jana Biermann ◽  
Elisabeth Werner Rönnerman ◽  
Peter Larsson ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Early Stage ◽  
Integrative Genomics ◽  
Molecular Features

Uncommon Breast Malignancies: Presentation Pattern, Prognostic Issue and Treatment Outcome in an Italian Single Institution Experience

2013 ◽  
Vol 99 (1) ◽  
pp. 39-44
Author(s):  
Claudia Maria Regina Bareggi ◽  
Dario Consonni ◽  
Barbara Galassi ◽  
Donatella Gambini ◽  
Elisa Locatelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Outcome ◽  
Invasive Ductal Carcinoma ◽  
Ductal Carcinoma ◽  
Early Stage ◽  
Medullary Carcinoma ◽  
Mucinous Carcinoma ◽  
Lymph Node Involvement ◽  
Tubular Carcinoma ◽  
Breast Malignancies

Aims and background Often neglected by large clinical trials, patients with uncommon breast malignancies have been rarely analyzed in large series. Patients and methods Of 2,052 patients diagnosed with breast cancer and followed in our Institution from January 1985 to December 2009, we retrospectively collected data on those with uncommon histotypes, with the aim of investigating their presentation characteristics and treatment outcome. Results Rare histotypes were identified in 146 patients (7.1% of our total breast cancer population), being classified as follows: tubular carcinoma in 75 (51.4%), mucinous carcinoma in 36 (24.7%), medullary carcinoma in 25 (17.1%) and papillary carcinoma in 10 patients (6.8%). Whereas age at diagnosis was not significantly different among the diverse diagnostic groups, patients with medullary and papillary subtypes had a higher rate of lymph node involvement, similar to that of invasive ductal carcinoma. Early stage diagnosis was frequent, except for medullary carcinoma. Overall, in comparison with our invasive ductal carcinoma patients, those with rare histotypes showed a significantly lower risk of recurrence, with a hazard ratio of 0.28 (95% CI, 0.12–0.62; P = 0.002). Conclusions According to our analysis, patients with uncommon breast malignancies are often diagnosed at an early stage, resulting in a good prognosis with standard treatment.

scholarly journals Effective Early Treatment of AChR Antibody-Positive Myasthenia Gravis with Rituximab; the Experience from a Neuroimmunology Clinic in a Developing Country

2021 ◽  
Vol 13 ◽  
pp. 117957352110160
Author(s):  
Thomas Mathew ◽  
Kurian Thomas ◽  
Saji K John ◽  
Shruthi Venkatesh ◽  
Raghunandan Nadig ◽  
...  
Keyword(s):  
Observational Study ◽  
Myasthenia Gravis ◽  
Treatment Option ◽  
Early Treatment ◽  
Early Stage ◽  
Tertiary Care ◽  
Response To Treatment ◽  
Myasthenic Crisis ◽  
Achr Antibody ◽  
Significant Difference

Background: Rituximab is reserved for treating refractory myasthenia gravis (MG) patients. Here we report our experience with rituximab in AChR antibody positive generalized MG (gMG) and impending myasthenic crisis (IMC). Methods: This retrospective, observational study, conducted at a tertiary care, neuroimmunology clinic, analyzed the data of patients with AChR antibody positive gMG, treated with rituximab between 1st January 2016 and 30th October 2018. Results: Eleven patients with AChR antibody positive gMG received rituximab. Mean age of the cohort was 50.54 ± 18.71 years with 9 males. Seven out of 11 patients received rituximab in the early stage (<2 years from onset) and had good response to treatment. Four of the 5 patients with IMC improved with rituximab alone. In the 10 patients who regularly followed up, there was a significant difference between the QMG scores at baseline and at 1, 2, 6, 12, and 18 months ( P < .0001). Conclusion: Rituximab appears to be a potentially effective early treatment option for AChR antibody positive generalized MG and impending myasthenic crisis.

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