Abstract C106: New therapeutic strategy by integrative analysis of germline, somatic genetic alterations and tumor mutational burden (TMB) in deficient mismatch repair (dMMR) gastric cancer

2019 ◽  
Author(s):  
Garden Lee ◽  
Jihyun Hwang ◽  
Sejung Park ◽  
Woo Sun Kwon ◽  
Jinseul Park ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Mismatch Repair ◽  
Therapeutic Strategy ◽  
Genetic Alterations ◽  
Integrative Analysis ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Deficient Mismatch Repair

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

Microsatellite frameshift variants in SGO1 of gastric cancer are not always associated with MSI status

2020 ◽  
pp. jclinpath-2020-206934
Author(s):  
Tomohiro Sugiyama ◽  
Moriya Iwaizumi ◽  
Terumi Taniguchi ◽  
Satoshi Suzuki ◽  
Shinya Tani ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Gastrointestinal Cancer ◽  
Early Stage ◽  
Stage Iv ◽  
Cancer Resection ◽  
Deficient Mismatch Repair ◽  
Gastric Cancer Resection ◽  
Genemapper Software

AimsAlthough frameshift variants in the microsatellite area of shugoshin 1 (SGO1) have been reported in the context of microsatellite instability-high (MSI-H)/deficient mismatch repair gastrointestinal cancer, most have been evaluated only in early stage I–III patients, and only two of its five microsatellite regions have been evaluated. Therefore, we investigated the frequency and MSI status of microsatellite frameshift variants in gastric cancer cases, including stage IV.MethodsIn a total of 55 cases, 30 gastric cancer resection and 25 non-resection cases, DNA was extracted from both tumour and normal parts and PCR was performed. The variant was confirmed by TA cloning, and MSI was evaluated using GeneMapper software.ResultsA frameshift variant of c.973delA was observed in 16 of the 45 evaluable cases. Its frequency was 35.6%. Of the 25 cases that could be assessed for MSI status, two cases of MSI-H were associated with the c.973delA SGO1 variant. However, c.973delA SGO1 variant was also observed in four cases of microsatellite stable.ConclusionOur study shows that SGO1 frameshift variants are not always associated with MSI status.

scholarly journals Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 445 ◽  
Author(s):  
David Vossen ◽  
Caroline Verhagen ◽  
Martijn van der Heijden ◽  
Paul Essers ◽  
Harry Bartelink ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Head And Neck ◽  
Genetic Alterations ◽  
Hypopharyngeal Carcinoma ◽  
Advanced Stage ◽  
Biopsy Material ◽  
Tumor Biopsy ◽  
Mutational Burden ◽  
Hpv Status ◽  
Tumor Mutational Burden

About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies.

scholarly journals Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities

2020 ◽  
Vol 21 (15) ◽  
pp. 5500
Author(s):  
Matteo Canale ◽  
Andrea Casadei-Gardini ◽  
Paola Ulivi ◽  
Maria Arechederra ◽  
Carmen Berasain ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Therapeutic Strategy ◽  
Complex Disease ◽  
Genetic Alterations ◽  
Epigenetic Mechanisms ◽  
Disease Heterogeneity ◽  
Cancer Heterogeneity ◽  
Epigenetic Events ◽  
Epigenetic Machinery ◽  
Gastric Cancer Treatment

Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.

scholarly journals Influence of Tumor Mutational Burden on Immune-infiltrating Cells in Stomach Adenocarcinoma

2020 ◽  
Author(s):  
Zongxian Zhao ◽  
Shilong Li ◽  
Shuliang Li ◽  
Huaxiang Yang ◽  
Daohan Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Receptor Interaction ◽  
Nucleotide Polymorphisms ◽  
Systematic Analysis ◽  
Btb Domain ◽  
Matrix Metalloproteinase 13 ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Stomach Adenocarcinoma ◽  
N Stage

Abstract Background: Gastric cancer (GC) is one of the most common and fatal cancers worldwide. Tumor mutational burden (TMB) is described as a novel powerful signature to predict response to immunotherapy in gastric cancer. Nevertheless, tumor-infiltrating immune cells (TIICs) in different TMB GC remains unknown.Results: (1) The most common missense were single nucleotide polymorphisms and C>T. Furthermore, titin (TTN), tumor protein p53 (TP53), and mucin 16 (MUC16) had a higher rate of mutations in STAD. (2) TMB-high and -low groups were not associated with survival, T stage, M stage, and grade of patients with stomach adenocarcinoma (STAD) (Psurvival=0.086, PT=0.331, PM=0.804, Pgrade=0.695). However, TMB groupings were related with N stage and sex (PN=0.003, Psex=0.003). (3) There were intricate differences in immune infiltration cells (eg, T cells, monocytes, and mast cells) between the TMB-high and TMB-low groups. (4) A total of 458 genes were identified as DEGs; Dynein cytoplasmic 1 intermediate chain 1(DYNC1I1), matrix metalloproteinase 13 (MMP13) and zinc finger and BTB domain containing 16 (ZBTB16) were correlated with overall survival (OS). (5) DEGs were mainly involved in the regulation of the extracellular matrix-receptor interaction, and the Wnt and PI3K-AKT signaling pathways.Conclusion: The present study provides a comprehensive and systematic analysis of TMB and its clinical significance, and reveals the complicated differences of 22 TIICs between TMB-high and TMB-low groups in STAD.

scholarly journals A PD-L1 Negative Advanced Gastric Cancer Patient With a Long Response to PD-1 Blockade After Failure of Systematic Treatment: A Case Report

2021 ◽  
Vol 12 ◽  
Author(s):  
Fangyuan Zhang ◽  
Jieying Zhang ◽  
Lei Zhao ◽  
Menglan Zhai ◽  
Tao Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patient ◽  
Gastric Cancer Patient ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Systematic Treatment ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Gastric Cancer Patients

BackgroundIt was widely accepted that programmed death-ligand 1 (PD-L1) positive, tumor mutational burden-high (TMB-H) or microsatellite instability-high (MSI-H) tumor are prone to have better treatment response to immune checkpoint blockade. The value of immune checkpoint blockade in PD-L1 negative gastric cancer patients has been questioned due to lower objective response rate (ORR).Case PresentationWe report an unusual case of a PD-L1 negative, proficient mismatch repair (pMMR)/microsatellite stability (MSS), tumor mutational burden-low (TMB-L) gastric cancer patient who achieved good response to immune checkpoint blockade after failure of systematic treatment. Multiple lymph nodes and bone metastases are the main characteristics of this patient. The patient survived for more than 30 months after diagnosis.ConclusionsThis case suggested that PD-L1 negative gastric cancer patient may also benefit from immune checkpoint blockade. In gastric cancer, patients with lymph node metastasis may be potential beneficiaries.

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