Cancer Research and Treatment

Original Articles

Sarcoma

Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study: Joonha Kwon, Jun Hyeong Lee, Young Han Lee, Jeeyun Lee, Jin-Hee Ahn, Se Hyun Kim, Seung Hyun Kim, Tae Il Kim, Kum-Hee Yun, Young Suk Park, Jeong Eun Kim, Kyu Sang Lee, Jung Kyoon Choi, Hyo Song Kim; Cancer Res Treat. 2022;54(4):1240-1255. Published online January 17, 2022; DOI: https://doi.org/10.4143/crt.2021.1194

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Purpose
Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to treat desmoid tumor. However, the molecular mechanism of why imatinib works remains unclear. Here, we describe potential roles of NOTCH2 and HES1 in clinical response to imatinib at genome and transcriptome levels.
Materials and Methods
We identified somatic mutations in coding and noncoding regions via whole-genome sequencing. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale whole-genome sequencing and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response.
Results
Among 20 patients, four (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥ 1 year. With gene-wise functional analyses, we detected a significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on Pan-Cancer Analysis of Whole Genomes data analyses, NOTCH2 mutations affect expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate between responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders.
Conclusion
Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, and an important therapeutic consideration for desmoid tumor.

Citations

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Therapeutical potential of natural products in treatment of pancreatic cancer: a review
Sanjeev Kumar Sahu, Pranav Kumar Prabhakar, Manish Vyas
Molecular Biology Reports.2025;[Epub] CrossRef
Advancing Precision Medicine: The Role of Genetic Testing and Sequencing Technologies in Identifying Biological Markers for Rare Cancers
Joviana Farhat, Lara Alzyoud, Mohammad AlWahsh, Animesh Acharjee, Basem Al‐Omari
Cancer Medicine.2025;[Epub] CrossRef
The Notch signaling pathway in desmoid tumor: Recent advances and the therapeutic prospects
Chuanxi Zheng, Jianghong Huang, Gang Xu, Wei Li, Xin Weng, Shiquan Zhang
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2024; 1870(1): 166907. CrossRef
Long‐term result of 125I seed brachytherapy for pediatric desmoid tumor in the head and neck
Yi‐Wei Zhong, Xiao‐Ming Lyu, Yan Shi, Chuan‐Bin Guo, Jian‐Guo Zhang, Lei Zheng
Pediatric Blood & Cancer.2023;[Epub] CrossRef
Update on Familial Adenomatous Polyposis-Associated Desmoid Tumors
Wanjun Yang, Pei-Rong Ding
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Multimodality Imaging Assessment of Desmoid Tumors: The Great Mime in the Era of Multidisciplinary Teams
Igino Simonetti, Federico Bruno, Roberta Fusco, Carmen Cutolo, Sergio Venanzio Setola, Renato Patrone, Carlo Masciocchi, Pierpaolo Palumbo, Francesco Arrigoni, Carmine Picone, Andrea Belli, Roberta Grassi, Francesca Grassi, Antonio Barile, Francesco Izzo,
Journal of Personalized Medicine.2022; 12(7): 1153. CrossRef

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Breast cancer

Implication and Influence of Multigene Panel Testing with Genetic Counseling in Korean Patients with BRCA1/2 Mutation-Negative Breast Cancer: Ji Soo Park, Saeam Shin, Yoon Jung Lee, Seung-Tae Lee, Eun Ji Nam, Jung Woo Han, Sun Hwa Lee, Tae Il Kim, Hyung Seok Park; Cancer Res Treat. 2022;54(4):1099-1110. Published online November 17, 2021; DOI: https://doi.org/10.4143/crt.2021.978

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Purpose
The aim of the study was to evaluate the clinical implication of multigene panel testing of beyond BRCA genes in Korean patients with BRCA1/2 mutation-negative breast cancer.
Materials and Methods
Between 2016 and 2019, a total of 700 BRCA1/2 mutation-negative breast cancer patients received comprehensive multigene panel testing and genetic counseling. Among them, 347 patients completed a questionnaire about cancer worry, genetic knowledge, and preference for the method of genetic tests during pre- and post-genetic test counseling. The frequency of pathogenic and likely pathogenic variants (PV/LPV) were analyzed.
Results
At least one PV/LPV of 26 genes was found in 76 out of 700 patients (10.9 %). The rate for PV/LPV was 3.4% for high-risk genes (17 PALB2, 6 TP53, and 1 PTEN). PV/LPVs of clinical actionable genes for breast cancer management, high-risk genes and other moderate-risk genes such as ATM, BARD1, BRIP, CHEK2, NF1, and RAD51D, were observed in 7.4%. Patients who completed the questionnaire showed decreased concerns about the risk of additional cancer development (average score, 4.21 to 3.94; p < 0.001), influence on mood (3.27 to 3.13; p < 0.001), influence on daily functioning (3.03 to 2.94; p=0.006); and increased knowledge about hereditary cancer syndrome (66.9 to 68.8; p=0.025) in post-test genetic counseling. High cancer worry scales (CWSs) were associated with age ≤ 40 years and the identification of PV/LPV. Low CWSs were related to the satisfaction of the counselee.
Conclusion
Comprehensive multigene panel test with genetic counseling is clinically applicable. It should be based on interpretable genetic information, consideration of potential psychological consequences, and proper preventive strategies.

Citations

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Katerina Nikitara, Maria Luis Cardoso, Astrid Moura Vicente, Célia Maria Batalha Silva Rasga, Roberta De Angelis, Zeina Chamoun Morel, Arcangela De Nicolo, Maria Nomikou, Christina Karamanidou, Christine Kakalou
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PALB2 germline pathogenic variants: frequency, clinical features, and functional analysis of c.3350+5G>A variant in 3987 Korean cancer patients
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Yoo-Na Kim, Yun Soo Chung, Eunhyang Park, Seung Tae Lee, Jung-Yun Lee
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Yung-Huyn Hwang, Tae-Kyung Yoo, Sae Byul Lee, Jisun Kim, Beom Seok Ko, Hee Jeong Kim, Jong Won Lee, Byung Ho Son, Il Yong Chung
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Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families
Ava Kwong, Cecilia Yuen Sze Ho, Chun Hang Au, Sze Keong Tey, Edmond Shiu Kwan Ma
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Prevalence Estimation of the PALB2 Germline Variant in East Asians and Koreans through Population Database Analysis
Jong Eun Park, Min-Chae Kang, Taeheon Lee, Eun Hye Cho, Mi-Ae Jang, Dongju Won, Boyoung Park, Chang-Seok Ki, Sun-Young Kong
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Min-Chae Kang, R.N., Jong Eun Park, Mi-Ae Jang, Dongju Won, Boyoung Park, Seeyoun Lee, Dong Ock Lee, Kum Hei Ryu, Yoon-Jung Chang, Sun-Young Kong
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Impact of High-to-Moderate Penetrance Genes on Genetic Testing: Looking over Breast Cancer
Antonella Turchiano, Marilidia Piglionica, Stefania Martino, Rosanna Bagnulo, Antonella Garganese, Annunziata De Luisi, Stefania Chirulli, Matteo Iacoviello, Michele Stasi, Ornella Tabaku, Eleonora Meneleo, Martina Capurso, Silvia Crocetta, Simone Lattaru
Genes.2023; 14(8): 1530. CrossRef

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Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls: Ji Soo Park, Eun Ji Nam, Hyung Seok Park, Jung Woo Han, Jung-Yun Lee, Jieun Kim, Tae Il Kim, Seung-Tae Lee; Cancer Res Treat. 2017;49(4):1012-1021. Published online January 17, 2017; DOI: https://doi.org/10.4143/crt.2016.433

Abstract PDF Supplementary Material PubReader ePub

Purpose
Comparison of variant frequencies in the general population has become an essential part of the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for interpreting sequence variants. We determined the optimal number of relevant ethnic controls that should be used to accurately calculate the odds ratio (OR) of genetic variants.
Materials and Methods
Using the ACMG guidelines, we reclassified BRCA1 and BRCA2 mutations and variants of unknown significance in 745 Korean patients susceptible to hereditary breast and ovarian cancer compared with 1,314 Korean population controls.
Results
We observed that the ORs were falsely inflated when we analyzed several variants using non-Korean population data. Our simulation indicated that the number of controls needed for the lower limit of a 95% confidence interval to exceed 1.0 varied according to the frequency of the variant in each patient group, with more than 820 controls needed for a variant existing in 1% of cases. Using a sufficient number of relevant population data, we could efficiently classify variants and identified the BRCA1 p.Leu1780Pro mutation as a possible pathogenic founder mutation in Korean patients.
Conclusion
Our study suggests that BRCA1 p.Leu1780Pro is a novel pathogenic mutation found in Korean patients. We also determined the optimal number of relevant ethnic controls needed for accurate variant classification according to the ACMG guidelines.

Citations

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Junhwan Kim, So-Yeon Park, Ju-Hyun Kim, Shin-Wha Lee, Jeong-Yeol Park, Jong-Hyeok Kim, Yong-Man Kim, Dae-Yeon Kim
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Genomic disparity impacts variant classification of cancer susceptibility genes in Turkish breast cancer patients
Nihat B. Agaoglu, Busra Unal, Connor P. Hayes, McKenzie Walker, Ozden Hatirnaz Ng, Levent Doganay, Nisan D. Can, Huma Q. Rana, Arezou A. Ghazani
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Human Genomics.2023;[Epub] CrossRef
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Jeong Dong Lee, Won-Ji Ryu, Hyun Ju Han, Tae Yeong Kim, Min Hwan Kim, Joohyuk Sohn
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Won Kyung Kwon, Hyeok-Jae Jang, Jeong Eon Lee, Yeon Hee Park, Jai Min Ryu, Jonghan Yu, Ja-Hyun Jang, Jong-Won Kim
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Hereditary variants of unknown significance in African American women with breast cancer
J. Tyson McDonald, Luisel J. Ricks-Santi, Alvaro Galli
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Dan Li, Yujian Shi, Ang Li, Dandan Cao, Huijun Su, Haiqi Yang, Qihuan Zhi, Yuchen Yang, Zhaoji Lan, Tianliangwen Zhou, Xiaobin You, Guifang Hu
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Hyung Seok Park, Jai Min Ryu, Ji Soo Park, Seock-Ah Im, So-Youn Jung, Eun-Kyu Kim, Woo-Chan Park, Jun Won Min, Jeeyeon Lee, Ji Young You, Jeong Eon Lee, Sung-Won Kim
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Se Ik Kim, Maria Lee, Hee Seung Kim, Hyun Hoon Chung, Jae-Weon Kim, Noh Hyun Park, Yong-Sang Song
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Ji Soo Park, Seung-Tae Lee, Jung Woo Han, Tae Il Kim, Eun Ji Nam, Hyung Seok Park
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Jee-Soo Lee, Sohee Oh, Sue Kyung Park, Min-Hyuk Lee, Jong Won Lee, Sung-Won Kim, Byung Ho Son, Dong-Young Noh, Jeong Eon Lee, Hai-Lin Park, Man Jin Kim, Sung Im Cho, Young Kyung Lee, Sung Sup Park, Moon-Woo Seong
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p16 Hypermethylation and KRAS Mutation Are Independent Predictors of Cetuximab Plus FOLFIRI Chemotherapy in Patients with Metastatic Colorectal Cancer: Se Hyun Kim, Kyu Hyun Park, Sang Joon Shin, Kang Young Lee, Tae Il Kim, Nam Kyu Kim, Sun Young Rha, Jae Kyung Roh, Joong Bae Ahn; Cancer Res Treat. 2016;48(1):208-215. Published online April 24, 2015; DOI: https://doi.org/10.4143/crt.2014.314

Abstract PDF PubReader ePub

Purpose
Hypermethylation of the CpG island of p16INK4a occurs in a significant proportion of colorectal cancer (CRC). We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), and cetuximab.
Materials and Methods
Pyrosequencing was used to identify KRASmutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, and hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype (CIMP) markers including p16 and clinical outcome.
Results
Hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6%) and showed significant association with KRASmutation (Fisher exact, p=0.01) and CIMP positivity (Fisher exact, p=0.002). Patients with p16-unmethylated tumors had significantly longer time to progression (TTP; median, 9.0 months vs. 3.5 months; log-rank, p=0.001) and overall survival (median, 44.9 months vs. 16.4 months; log-rank, p=0.008) than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy (n=6) had markedly shortened TTP (median, 2.8 months) compared to those with either KRAS or p16 aberrancy (n=11; median, 8.6 months; p=0.021) or those with neither (n=32; median, 9.0 months; p < 0.0001). In multivariate analysis, KRAS mutation and p16 methylation showed independent association with shorter TTP (KRAS mutation: hazard ratio [HR], 3.21; p=0.017; p16 methylation: HR, 2.97; p=0.027).
Conclusion
Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.

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Chih-Hsiung Hsu, Cheng-Wen Hsiao, Chien-An Sun, Wen-Chih Wu, Tsan Yang, Je-Ming Hu, Yu-Chan Liao, Chi-Hua Huang, Chao-Yang Chen, Fu-Huang Lin, Yu-Ching Chou
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Klara Cervena, Anna Siskova, Tomas Buchler, Pavel Vodicka, Veronika Vymetalkova
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CpG Island Methylator Phenotype and Methylation of Wnt Pathway Genes Together Predict Survival in Patients with Colorectal Cancer
Se Hyun Kim, Kyu Hyun Park, Sang Joon Shin, Kang Young Lee, Tae Il Kim, Nam Kyu Kim, Sun Young Rha, Joong Bae Ahn
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Recent advances in understanding colorectal cancer
Sebastian Stintzing
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Clinical and prognosis value of the CIMP status combined with MLH1 or p16 INK4a methylation in colorectal cancer
Amana Saadallah-Kallel, Rania Abdelmaksoud-Dammak, Mouna Triki, Slim Charfi, Abdelmajid Khabir, Tahia Sallemi-Boudawara, Raja Mokdad-Gargouri
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DNA methylation of CMTM3 , SSTR2 , and MDFI genes in colorectal cancer
Jinyun Li, Cheng Chen, Xuer Bi, Chongchang Zhou, Tao Huang, Chao Ni, Ping Yang, Si Chen, Meng Ye, Shiwei Duan
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