scholarly journals The Landscape of Genetic Alterations Stratified Prognosis in Oriental Pancreatic Cancer Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Shiwei Guo ◽  
Xiaohan Shi ◽  
Suizhi Gao ◽  
Qunxing Hou ◽  
Lisha Jiang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Tumor Biology ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Genomic Alteration ◽  
Solid Pseudopapillary Tumor ◽  
Specific Gene ◽  
Platinum Drug ◽  
Resistance Pathway

BackgroundPancreatic cancer is a life-threatening malignant disease with significant diversity among geographic regions and races leading to distinct carcinogenesis and prognosis. Previous studies mainly focused on Western patients, while the genomic landscape of Oriental patients, especially Chinese, remained less investigated.MethodsA total of 408 pancreatic cancer patients were enrolled. A panel containing 436 cancer-related genes was used to detect genetic alterations in tumor samples.ResultsWe profiled the genomic alteration landscape of pancreatic duct adenocarcinoma (PDAC), intraductal papillary mucinous neoplasm (IPMN), periampullary carcinoma (PVC), and solid-pseudopapillary tumor (SPT). Comparison with a public database revealed specific gene mutations in Oriental PDAC patients including higher mutation rates of DNA damage repair-related genes. Analysis of mutational signatures showed potential heterogenous carcinogenic factors caused by diabetes mellitus. KRAS mutation, especially KRAS G12D mutation, was associated with poor survival, while patients not harboring the 17 significant copy number variations (CNVs) had a better prognosis. We further identified multiple correlations between clinicopathologic variables and genetic mutations, as well as CNVs. Finally, by network-based stratification, three classes of PDAC patients were robustly clustered. Among these, class 1 (characterized by the Fanconi anemia pathway) achieved the best outcome, while class 2 (involved in the platinum drug resistance pathway) suffered from the worst prognosis.ConclusionsIn this study, we reported for the first time the genetic alteration landscape of Oriental PDAC patients identifying many Oriental-specific alterations. The relationship between genetic alterations and clinicopathological factors as well as prognosis demonstrated important genomic impact on tumor biology. This study will help to optimize clinical treatment of Oriental PDAC patients and improve their survival.

Circulating tumor DNA molecular profiling in rare cancer patients from the MASTER KEY Project.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14532-e14532
Author(s):  
Hitomi Sumiyoshi Okuma ◽  
Kan Yonemori ◽  
Takuji Seo ◽  
Emi Noguchi ◽  
Keiko Wakakuwa ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Salivary Gland Tumor ◽  
Circulating Tumor Dna ◽  
Genetic Alterations ◽  
Unknown Primary ◽  
Genomic Alteration ◽  
Cancer Type ◽  
Rare Cancer ◽  
Registry Study ◽  
Tumor Dna

e14532 Background: In April 2017, MASTER KEY Project, composed of a prospective registry study part and a multiple clinical trials part, was established to promote treatment development for rare cancers, which is lacking standard or investigational therapeutic options. Circulating tumor DNA (ctDNA) analysis by next-generation sequencing (NGS) has provided new insight into personalized medicine in a more accessible, non-invasive manner; however, most reports are focused on common cancers. We report genetic alterations detected by ctDNA NGS analysis in rare solid cancers. Methods: Prospectively consented patients (pts), also enrolled in MASTER KEY registry study, had ctDNA NGS testing at a CLIA-certified lab (Guardant360) for point mutations, indels, copy number amplifications, fusions, and microsatellite instability. Alterations were assessed for incidence according to cancer type, functional impact, therapeutic implications, and comparison with tissue NGS. Main inclusion criteria: 1) age ≥16, 2) histological diagnosis of rare cancer (annual incidence less than 6 cases per 100,000 population), cancer of unknown primary (CUP), or rare tissue subtypes of common cancers, 3) active metastatic / unresectable cancer, 4) a written consent. Results: From Nov. 2018 to Jan 2019, 50 pts had Guardant360 testing. Diseases included: soft tissue sarcoma (28), ovarian carc. (7), CUP (4), salivary gland tumor (3), thyroid carc. (2), GIST (1), adrenal cortical carc. (1), rare subtype of GI tract (1), malignant mesothelioma (1), nephroblastoma (1), NET (1), NUT carc. (1). All Japanese, male/female = 14/36, median age 61, ECOG performance status 0/1/2/3 = 30/19/0/1. 76% of pts (38/50) had ≥1 alteration detected, with median number of 2 alterations (range: 0-9), with VAF(0.1-60.3%); 87%(33/38) of those pts had a variant most likely pathogenic; 61% (20/33) of those pts had a variant potential for clinical action. Mean TAT was 10.3 days. 19 pts had tissue NGS testing and in 3 pts, alterations were detected by ctDNA NGS but not by tissue NGS. Updated results of 100 patients will be presented at the conference. Conclusions: Most rare cancer patients with advanced disease had a detectable genomic alteration by Guardant360. Clinical trial information: UMIN000034394.

Molecular characterization of urothelial carcinoma of bladder and upper urinary tract.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 361-361 ◽  
Author(s):  
In Gyu Hwang ◽  
Mi Hwa Heo ◽  
Hee Kyung Kim ◽  
Hansang Lee ◽  
Jinhyun Cho ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Somatic Mutation ◽  
Clinical Decision Making ◽  
Small Sample Size ◽  
Unmet Need ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Small Sample ◽  
Genomic Alteration ◽  
Single Nucleotide Variants

361 Background: It is a considerable unmet need to increase understanding of the molecular basis of urothelial carcinoma (UC) to refine the clinical decision-making process. We also aim to assess that whether we can apply similar principles in the management of upper tract UC (UTUC) based on the behavior of urinary bladder UC (UBUC). Methods: To study the molecular nature of UC, we performed next-generation sequencing to investigate the mutational and transcriptional profiles of commonly mutated genes using the Ampliseq v2. Copy number variations (CNVs) were detected with nCounter assay. Genetic alterations between UTUC and UBUC were compared. Results: Tumor samples from 34 UTUC and 63 UBUC patients were eligible for analyses. Two groups showed similar clinicopathologic features including tumor grade and stage. Median survival was, although statistically insignificant, longer in UTUC than UBUC patients (59 vs. 41 months, P = 0.63). In total, we found 920 genetic alterations from 97 samples: most common type of somatic mutation was single nucleotide variants (SNVs; 494/525, 94.1%). After analyzing total genomic alteration frequency, we found that the frequency of CNVs was not significantly different between UTUC and UBUC group: most commonly observed mutation in the UBUC patients was TP53 (18.9%), followed by KDR (7.2%), FGFR3 (4.1%) and PIK3CA (4.1%). In the UTUC patients, TP53 (22.9%), KDR (6.5%), NOTCH1 (5.3%) and FGFR3 (4.1%) are most frequentl somatic mutations. We also identified five translocations in total UC cohort including one case with FGFR3–TACC3 (Chr4) fusion. Conclusions: Within the limitation of small sample size, we found no relevant differences in somatic mutation frequencies between UTUC and UBUC, indicating a basis for similar management strategies.

Clinical significance of monitoring KRAS in tissue and serum of pancreatic cancer patients.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 286-286
Author(s):  
Fumiaki Watanabe ◽  
Koichi Suzuki ◽  
Hideki Ishikawa ◽  
Yuhei Endo ◽  
Kosuke Ichida ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Clinical Significance ◽  
Kras Mutation ◽  
Tumor Biology ◽  
Pancreatic Tumors ◽  
Curative Surgery ◽  
Kras Mutations ◽  
Tumor Tissues ◽  
Predictive And Prognostic Biomarker

286 Background: KRAS monitoring provides valuable information for early diagnosis and prediction of treatment outcome in colorectal cancer. KRAS mutation is observed in only half of colon cancer patients, whereas it is detected in 90% of pancreatic cancer patients. Therefore, investigating tumor DNA in serum by KRAS monitoring may be even more valuable in pancreatic cancer patients. In this study, we elucidated the clinical significance of KRAS monitoring in pancreatic cancer patients during treatment. Methods: KRAS in tumor tissues was analyzed for mutations by Scorpion ARMS or RASKET in 69 patients with pancreatic tumors. KRAS in serum was analyzed for mutations (G12D, G12V, G12C, G12A, G12S, G12R, G13D, Q61L, and Q61H) using droplet digital polymerase chain reaction in 58 patients who underwent the curative surgery (N = 39) or the chemotherapy (N = 19) and who had KRAS mutation in their tissues. Results: KRAS mutation in tumor tissues was detected in 62 of 69 patients (92.5%). These 62 patients showed significantly poorer prognosis (3years overall survival; 43.9%) than the seven patients without mutation (p = 0.03), who were all alive. Monitoring of KRAS in serum revealed KRAS mutation in 22 of 58 patients (37.9%). In patients who underwent the chemotherapy (N = 19), 2years OS of patients who detected KRAS mutation in serum (N = 9) was 0% and them which not detected it (N = 10) was 46.7% (p = 0.01). And in the curative resection group (N = 39), we detected KRAS mutations in serum among recurrent patients after surgery, but did not detect them among non-recurrent patients. Conclusions: KRAS mutation in serum could be a valuable predictive and prognostic biomarker in pancreatic cancer patients. Additionally, assessment of KRAS in tumor tissues may provide information about individual tumor biology. So, monitoring KRAS status of patients with pancreatic cancer may be useful of the treatment strategy.

scholarly journals Genomic Profiling of KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer Patients Reveals Novel Mutations in Genes Potentially Associated with Resistance to Anti-EGFR Agents

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 859 ◽  
Author(s):  
Anna Maria Rachiglio ◽  
Matilde Lambiase ◽  
Francesca Fenizia ◽  
Cristin Roma ◽  
Claudia Cardone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
De Novo ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Wild Type ◽  
Single Nucleotide Variants ◽  
Colorectal Cancer Patients ◽  
De Novo Resistance

Previous findings suggest that metastatic colorectal carcinoma (mCRC) patients with KRAS/NRAS/BRAF/PIK3CA wild-type (quadruple-wt) tumors are highly sensitive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). However, additional molecular alterations might be involved in the de novo resistance to these drugs. We performed a comprehensive molecular profiling of 21 quadruple-wt tumors from mCRC patients enrolled in the “Cetuximab After Progression in KRAS wild-type colorectal cancer patients” (CAPRI-GOIM) trial of first line FOLFIRI plus cetuximab. Tumor samples were analyzed with a targeted sequencing panel covering single nucleotide variants (SNVs), insertions/deletions (Indels), copy number variations (CNVs), and gene fusions in 143 cancer-related genes. The analysis revealed in all 21 patients the presence of at least one SNV/Indel and in 10/21 cases (48%) the presence of at least one CNV. Furthermore, 17/21 (81%) patients had co-existing SNVs/Indels in different genes. Quadruple-wt mCRC from patients with the shorter progression free survival (PFS) were enriched with peculiar genetic alterations in KRAS, FBXW7, MAP2K1, and NF1 genes as compared with patients with longer PFS. These data suggest that a wide genetic profiling of quadruple-wt mCRC patients might help to identify novel markers of de novo resistance to anti-EGFR MoAbs.

Personalizing cancer treatment of combined targeting of PI3K/AKT and MAPK pathways in advanced cancer patients harboring simultaneous oncogenic alterations in both signaling pathways.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13025-e13025
Author(s):  
Toshio Shimizu ◽  
Anthony W. Tolcher ◽  
Kyriakos P. Papadopoulos ◽  
Muralidhar Beeram ◽  
Drew Warren Rasco ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathways ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Kras Mutation ◽  
Mapk Pathway ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Advanced Cancer Patients ◽  
Mapk Pathways

e13025 Background: Frequent coactivation of both PI3K/AKT and MAPK pathways has been seen in a number of different tumor types. Preclinical studies also provide a clear rationale for the co-inhibition of these, "semi-parallel" pathways. Methods: We reviewed the records of 1,672 consecutive advanced cancer patients (pts) in our Phase I Clinical Trials Program and investigated the clinical impact of simultaneous blockade of both PI3K/AKT and MAPK pathways in patients with oncogenic alterations in both signaling pathways from 317 pts who received PI3K pathway inhibitor and/or MAPK pathway inhibitor. Results: 163 of 317 pts (51.4%) were tested for comprehensive tumor genomic analysis using DNA array-based CGH/PCR-based DNA sequencing. PI3K pathway genetic alterations (PIK3CA mutation, n=3; PTEN deletion, n=18; AKT amplification, n=10) were detected in 29 of the 163 (17.8%) pts. RAS/RAF pathway genetic alterations (KRAS mutation, n=33; HRAS mutation, n=4; BRAF mutation, n=6) were detected in 43 of the 163 (26.4%) pts. Simultaneous oncogenic alterations in both PI3K/AKT and MAPK pathways were detected in 12 pts (colorectal cancer, n=7; pancreatic cancer, n=2; melanoma, n=2; non-seminomatous germ cell tumor, n=1). Six of 8 (75%) pts treated with personalized treatment based on dual pathways inhibition had tumor regression with prolonged duration of time to treatment failure compared to that of pts treated with single pathway inhibition. A pt with pancreatic cancer harboring simultaneous KRAS mutation and AKT2 amplification treated with combination MEK1/2 inhibitor and AKT inhibitor showed central cavitations of numerous lung metastatic lesions along with a decrease in CA19-9, which may reflect treatment effect. Conclusions: These data could serve as a platform for therapeutic decision making. The strategy of targeting parallel pathways may be especially important in pts with coexisting PI3K/AKT and MAPK pathway genetic alterations. The data also suggest the need to further investigate the role of molecular profiling and matching pts with targeted drugs for personalized treatment.

Clinical significance of monitoring KRAS in the blood of pancreatic cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23042-e23042
Author(s):  
Fumiaki Watanabe ◽  
Koichi Suzuki ◽  
Kosuke Ichida ◽  
Yuji Takayama ◽  
Taro Fukui ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Clinical Significance ◽  
Kras Mutation ◽  
Tumor Biology ◽  
Pancreatic Tumors ◽  
Tumor Tissues ◽  
Polymerase Chain ◽  
Predictive And Prognostic Biomarker ◽  
Digital Polymerase Chain Reaction

e23042 Background: KRAS monitoring provides valuable information for early diagnosis and prediction of treatment outcome in colorectal cancer. KRAS mutation is observed in only half of colon cancer patients, whereas it is detected in 90% of pancreatic cancer patients. Therefore, investigating tumor DNA in blood by KRAS monitoring may be even more valuable in pancreatic cancer patients. In this study, we elucidated the clinical significance of KRAS monitoring in pancreatic cancer patients during treatment. Methods: KRAS in tumor tissues was analyzed for mutations by Scorpion ARMS or RASKET in 38 patients with pancreatic tumors. KRAS in blood was analyzed for mutations (G12D, G12V, G12C, G12A, G12S, G12R, G13D, Q61L, and Q61H) using droplet digital polymerase chain reaction in 23 patients who underwent chemotherapy and who had KRAS mutation in their tissues. Results: KRAS mutation in tumor tissues was detected in 27 of 38 patients (71.1%). These 27 patients showed significantly poorer prognosis (24.4 months median overall survival time [MST]) than the six patients without mutation (p = 0.04), who were all alive. Patients with mutation of 12D in tumor tissues showed better prognosis than patients with other types of mutation; thus, mutation of 12D may have a different biological effect to other mutations. Monitoring of KRAS in blood revealed KRAS mutation in 14 of 23 patients (60.9%). These 14 patients exhibited significantly poorer treatment outcomes than patients without mutation. The MST of patients with KRAS mutation in their blood was significantly shorter than that of patients without KRAS mutation (17.7 months vs. 44.3 months, p = 0.03). Conclusions: KRAS mutation in blood could be a valuable predictive and prognostic biomarker in pancreatic cancer patients who undergo chemotherapy. Additionally, assessment of KRAS in tumor tissues may provide information about individual tumor biology.

scholarly journals PATH-40. INTRAGENIC DMD DELETIONS ARE THE MOST COMMON RECURRENT GENOMIC ALTERATIONS IN ESTHESIONEUROBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii173-ii173
Author(s):  
Tareq Juratli ◽  
Naema Nayyar ◽  
Michael Young ◽  
Megha Subramanian ◽  
Priscilla Brastianos ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Copy Number Variations ◽  
Genomic Alteration ◽  
Metastatic Lesions ◽  
Tert Promoter ◽  
Whole Exome ◽  
Tert Promoter Mutations ◽  
Multiple Metastases ◽  
Intragenic Deletions ◽  
Promoter Mutations

Abstract INTRODUCTION Esthesioneuroblastoma (ENB) is a rare, malignant neuroectodermal tumor of the olfactory epithelium. To date, a few recurrent genetic alterations have been identified in ENB. Here, we sought to examine the genomic signature on a series of clinically well-characterized aggressive ENB samples. METHODS We performed whole-exome sequencing in a cohort of 26 ENB samples from 12 patients, containing 11 matched primary-metastatic samples. Additionally, targeted sequencing was carried out in all samples to determine TERT promoter hotspot mutations. Furthermore, we performed immunohistochemistry (IHC) using an antibody that recognizes the dystrophin central rod domain in all available specimens. RESULTS Our cohort consisted of 9 male and 3 female patients with a median age of 66 years at first diagnosis (4- 77 years). One patient was staged Kadish B at the time of diagnosis and eleven were staged Kadish C. The median overall survival was 3.85 years (0.3 – 16 years). Consistent with previous findings, each tumor exhibited a different mutational signature and the mutational landscape appears to be predominantly driven by copy number variations. Interestingly, we detected intragenic deletions in dystrophin (DMD) as the most common and consistent alteration in ENB patients (in 11 of 12 patients, 91.6%). DMD deletions, when identified within the primary ENB, were preserved in all subsequent metastatic lesions. Moreover, DMD deletions where concurrently identified in three cases with multiple metastases. IHC revealed the concurrent loss of dystrophin expression, the protein encoded by DMD, in all cases with DMD deletions. Otherwise, no other recurrent genomic findings were detected, including TERT promoter mutations. CONCLUSIONS Our findings validate previously described DMD deletions as the most common recurrent genomic alteration in primary ENB. Furthermore, our data demonstrate that DMD deletions were perpetuated in subsequent metastatic lesions, and when identified in any metastasis, were present in other metastases from the same patient.

scholarly journals Pre-Clinical and Clinical Applications of Small Interfering RNAs (siRNA) and Co-Delivery Systems for Pancreatic Cancer Therapy

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3348
Author(s):  
Sepideh Mirzaei ◽  
Mohammad Hossein Gholami ◽  
Hui Li Ang ◽  
Farid Hashemi ◽  
Ali Zarrabi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Targeted Delivery ◽  
Polymeric Nanoparticles ◽  
Genetic Alterations ◽  
Delivery Systems ◽  
Metal Nanostructures ◽  
Specific Gene ◽  
Small Interfering Rnas ◽  
Pancreatic Cancer Therapy ◽  
Interfering Rna

Pancreatic cancer (PC) is one of the leading causes of death and is the fourth most malignant tumor in men. The epigenetic and genetic alterations appear to be responsible for development of PC. Small interfering RNA (siRNA) is a powerful genetic tool that can bind to its target and reduces expression level of a specific gene. The various critical genes involved in PC progression can be effectively targeted using diverse siRNAs. Moreover, siRNAs can enhance efficacy of chemotherapy and radiotherapy in inhibiting PC progression. However, siRNAs suffer from different off target effects and their degradation by enzymes in serum can diminish their potential in gene silencing. Loading siRNAs on nanoparticles can effectively protect them against degradation and can inhibit off target actions by facilitating targeted delivery. This leads to enhanced efficacy of siRNAs in PC therapy. Moreover, different kinds of nanoparticles such as polymeric nanoparticles, lipid nanoparticles and metal nanostructures have been applied for optimal delivery of siRNAs that are discussed in this article. This review also reveals that how naked siRNAs and their delivery systems can be exploited in treatment of PC and as siRNAs are currently being applied in clinical trials, significant progress can be made by translating the current findings into the clinical settings.

scholarly journals The Role of BRCA2 Mutation Status as Diagnostic, Predictive, and Prognosis Biomarker for Pancreatic Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Javier Martinez-Useros ◽  
Jesus Garcia-Foncillas
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cancer Patients ◽  
Brca2 Mutation ◽  
Acquired Resistance ◽  
Predictive Biomarker ◽  
Parp Inhibitors ◽  
Genetic Alterations ◽  
Mutation Status

Pancreatic cancer is one of the deadliest cancers worldwide, and life expectancy after diagnosis is often short. Most pancreatic tumours appear sporadically and have been highly related to habits such as cigarette smoking, high alcohol intake, high carbohydrate, and sugar consumption. Other observational studies have suggested the association between pancreatic cancer and exposure to arsenic, lead, or cadmium. Aside from these factors, chronic pancreatitis and diabetes have also come to be considered as risk factors for these kinds of tumours. Studies have found that 10% of pancreatic cancer cases arise from an inherited syndrome related to some genetic alterations. One of these alterations includes mutation inBRCA2gene.BRCA2mutations impair DNA damage response and homologous recombination by direct regulation of RAD51. In light of these findings that link genetic factors to tumour development, DNA damage agents have been proposed as target therapies for pancreatic cancer patients carryingBRCA2mutations. Some of these drugs include platinum-based agents and PARP inhibitors. However, the acquired resistance to PARP inhibitors has created a need for new chemotherapeutic strategies to targetBRCA2.The present systematic review collects and analyses the role ofBRCA2alterations to be used in early diagnosis of an inherited syndrome associated with familiar cancer and as a prognostic and predictive biomarker for the management of pancreatic cancer patients.

FEASIBILITY OF ORAL AND DUODENAL MICROBIOTA ANALYSIS OF PANCREATIC CANCER PATIENTS AND CONTROLS

2020 ◽  
Author(s):  
L Archibugi ◽  
MC Petrone ◽  
G Rossi ◽  
A Mariani ◽  
SGG Testoni ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Microbiota Analysis
Sign in / Sign up

Export Citation Format

Share Document