• Journal of Gastric Cancer
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• 제23권1호
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• pp.224-249
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• 2023

Gastric cancer is heterogeneous in morphology, biology, genomics, and treatment response. Alterations in human epidermal growth factor receptor 2 (HER2) overexpression, microsatellite instability (MSI) status, programmed death-ligand 1 (PD-L1) levels, and fibroblast growth factor receptor 2 (FGFR2) can be used as biomarkers. Since the combination of fluoropyrimidine/platinum plus trastuzumab that was investigated in the ToGA trial was approved as a standard of care in HER2-positive patients in 2010, no other agents showed efficacy in the first- (HELOISE, LOGiC, JACOB trials) and second- (TyTAN, GATSBY, T-ACT trials) line treatments. Despite the success in treating breast cancer, various anti-HER2 agents, including a monoclonal antibody (pertuzumab), an antibody-drug conjugate (ADC; trastuzumab emtansine [T-DM1]), and a small molecule (lapatinib) failed to translate into clinical benefits until the KEYNOTE-811 (first-line) and DESTINY-Gastri01 (≥second-line) trials were conducted. The incorporation of HER2-directed treatment with immune checkpoint inhibitors in the form of a monoclonal antibody or ADC is now approved as a standard treatment. Despite the promising results of new agents (engineered monoclonal antibodies, bi-specific antibodies, fusion proteins, and small molecules) in the early phase of development, the management of HER2-positive gastric cancer requires further optimization to achieve precision medicine with a chemotherapeutic backbone. Treatment resistance is a complex process that can be overcome using a combination of chemotherapy, targeted agents, and immune checkpoint inhibitors, including novel agents. HER2 status must be reassessed in patients undergoing anti-HER2 treatment with disease progression after the first-line treatment. As a general guideline, patients who need systemic treatment should receive chemotherapy plus targeted agents, anti-angiogenic agents, immune checkpoint inhibitors, or their combinations.

• Asian Pacific Journal of Cancer Prevention
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• 제13권6호
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• pp.2629-2633
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• 2012

Background: Raw betel nut (RBN) chewing is an important contributing factor for esophageal squamous cell carcinoma (ESCC), although associated genomic changes remain unclear. One difficulty in assessing the effects of exclusively RBN induced genetic alterations has been that earlier studies were performed with samples of patients commonly using tobacco and alcohol, in addition to betel-quid. Both CDKN2A (at 9p21) and Rb1 gene (at 13q14.2) are regarded as tumor suppressors involved in the development of ESCC. Therefore, the present study aimed to verify the RBN's ability to induce ESCC and assess the involvement of CDKN2A and Rb1 genes. Methods: A panel of dinucelotide polymorphic markers were chosen for loss of heterozygosity studies in 93 samples of which 34 were collected from patients with only RBN-chewing habit. Promoter hypermethylation was also investigated. Results: Loss in microsatellite markers D9S1748 and D9S1749, located close to exon $1{\beta}$ of CDKN2A/ARF gene at 9p21, was noted in 40% ESCC samples with the habit of RBN-chewing alone. Involvement of a novel site in the 9p23 region was also observed. Promoter hypermethylation of CDKN2A gene in the samples with the habit of only RBN-chewing alone was significantly higher (p=0.01) than Rb1 gene, also from the samples having the habit of use both RBN and tobacco (p=0.047). Conclusions: The data indicate that the disruption of 9p21 where CDKN2A gene resides, is the most frequent critical genetic event in RBN-associated carcinogenesis. The involvement of 9p23 as well as 13q14.2 could be required in later stages in RBN-mediated carcinogenesis.

• BMB Reports
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• 제57권2호
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• pp.110-115
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• 2024

Alterations in DNA methylation play an important pathophysiological role in the development and progression of colorectal cancer. We comprehensively profiled DNA methylation alterations in 165 Korean patients with colorectal cancer (CRC), and conducted an in-depth investigation of cancer-specific methylation patterns. Our analysis of the tumor samples revealed a significant presence of hypomethylated probes, primarily within the gene body regions; few hypermethylated sites were observed, which were mostly enriched in promoter-like and CpG island regions. The CpG Island Methylator Phenotype-High (CIMP-H) exhibited notable enrichment of microsatellite instability-high (MSI-H). Additionally, our findings indicated a significant correlation between methylation of the MLH1 gene and MSI-H status. Furthermore, we found that the CIMP-H had a higher tendency to affect the right-side of the colon tissues and was slightly more prevalent among older patients. Through our methylome profile analysis, we successfully verified the methylation patterns and clinical characteristics of Korean patients with CRC. This valuable dataset lays a strong foundation for exploring novel molecular insights and potential therapeutic targets for the treatment of CRC.

• Tuberculosis and Respiratory Diseases
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• 제50권6호
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• pp.668-675
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• 2001

연구배경 : 제21번 염색체가 3개(trisomy)인 다운 증후군(Down syndrome) 에서는 폐암을 포함한 고형종양의 빈도가 일반인에 비해 유의하게 낮다. 이와 같이 디운증후군에서 폐암 위험도가 낮은 것은 여분의 21번 염색체가 존재함에 따른 유전자-용량 효과(gene-dosage effect) 때문일 가능성이 있으며 이는 폐암의 발생과정에 관여하는 종양억제유전자가 21번 염색체에 있음을 의미한다. 저자들은 21번 염색체의 종양억제 유전자 발굴을 위한 선행연구로 21번 염색체 장암의 LOH 빈도와 LOH 유 무에 따른 임상상을 비교하였다. 방 법 : 근치적 절제술을 받은 비소세포폐암 39예를 대상으로 하였다. 동결된 폐암조직과 환자의 림프구에서 DNA를 추출한 후 21q의 5개의 현미부수체 표지자를 이용하여 PCR을 시행하고 6% polyacrylamide-8M urea gel에서 전기영동 한 후 silver 염색을 하였다. LOH는 암조직의 대립유전자 signal이 림프구의 50%이하로 감소된 경우로 판정하였으며 종양의 fractional allelic loss(FAL)는 informative 표지자 수에 대한 LOH가 발견된 표지자 수의 비로 계산하였다. 결 과 : 대상환자 39예 가운데 21예(53.8%)에서 한 개 이상의 표시자에서 LOH가 관찰되었다. LOH는 편평상피세포암의 경우 23예 가운데 15예(65.2%)에서, 선암의 경우는 16예 가운데 6예(37.5%)에서 관찰되어 편평상피세포암에서 LOH의 빈도가 높은 경향이 있었다. 편평상피세포암에서 LOH 빈도는 I 기 53.8%와 II-III기 80.0%로 진행된 병기에서 높은 경향이 있었으나 통계적 유의성은 없었다. 종양에서 대립 유전자 소실의 축적 정도를 반영하는 지표인 FAL치는 편평상피세포암의 경우 0.431(${\pm}0.375$)로 선암의 0.192(${\pm}0.276$)에 비해 통계적으로 유의하게 높았다. 편평상피세포암에서 FAL치는 I 기 0.391(${\pm}0.427$)인데 비해 II-III기는 0.484(${\pm}0.310$)로 통계적 유의성은 없었으나 진행된 병기에서 높은 경향을 보였다. 결 론 : 비소세포폐암에서 21q의 LOH가 흔히 관찰되었으며 이러한 결과는 비소세포폐암의 발암과정에 관여하는 종양억제유전자가 21q에 존재할 가능성을 강력히 시사한다. 21q에 존재하는 LOH의 역할을 규명하기 위해서는 향후 보다 많은 예를 대상으로 한 연구가 필요할 것으로 생각된다.