Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients

Bray, Steven M.; Lee, Jeeyun; Kim, Seung Tae; Hur, Joon Young; Ebert, Philip J.; Calley, John N.; Wulur, Isabella H.; Gopalappa, Thejaswini; Wong, Suei Nee; Qian, Hui; Ting, Jason C.; Liu, Jiangang; Willard, Melinda D.; Novosiadly, Ruslan D.; Park, Young Suk; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Aggarwal, Amit; Kim, Hee Cheol; Reinhard, Christoph

doi:10.1038/s41598-019-51981-5

Cited by 59 publications

(48 citation statements)

References 54 publications

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“…Entrez gene models were used to assign copy number to genes located on a segmented copy number region. For this study, gene's copy numbers were classified into 5 categories: deletion (CN < 1.0), loss ( Sample Preparation Kit v2 as described previously 54 . Paired-end sequencing with a read length of 100 bp and targeted read depth of 50 million reads/sample was performed.…”

Section: Scientific Reports |mentioning

confidence: 99%

Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis

Liu

Cho

Hong

et al. 2020

Sci Rep

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Metastasis is the primary cause of cancer mortality. the primary tumors of colorectal cancer (cRc) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. thirteen patients have primary tumors without distant metastasis and matched normal tissues. characterization of these samples was conducted by whole-exome and RnA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasiscorrelated gene networks of immune-suppression, epithelial-mesenchymal transition (eMt) and angiogenesis as the key events and potentially synergistic drivers associated with cRc metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. the gene networks of eMt, angiogenesis, immune-suppression and t cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic cRc. CRC is the third most common cancer in world with second highest cancer-related mortality worldwide 1. In US alone, it is estimated that approximately 137,000 people are diagnosed, and more than 50,000 are dead from CRC each year. CRC primary tumors often metastasize to the liver, which accounts for most of CRC related death. The molecular mechanism of tumor metastasis remains poorly understood. It is believed to be a multiple step process that includes cells to detach from their original site and invade the neighboring submucosa, extravasate and survive in the vasculature and metastatic site, and eventually reestablish tumor in alien organ 2. Prevention

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Section: Scientific Reports |mentioning

confidence: 99%

Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis

Liu

Cho

Hong

et al. 2020

Sci Rep

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“…Mutational assessment of cfDNA in blood has the potential to predict recurrence or patient metastasis. KRAS mutations is acquired after chemotherapy as a resistance mechanism (16,17). In the pre-and postoperative serum monitoring performed in this study, three patients exhibited conversion of postoperative serum KRAS G12/13 mutation status from preoperative wild type to postoperative mutant.…”

Section: Discussionmentioning

confidence: 74%

Serum-Based KRASG12/G13 Mutation Detection Using Droplet Digital PCR: Clinical Implications and Limitations in Colorectal Adenocarcinoma With Tumor Heterogeneity

et al. 2021

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BackgroundCell-free DNA (cfDNA) has arisen as an alternative target for evaluating somatic mutations in cancer. KRAS mutation status is critical for targeted therapy in colorectal adenocarcinoma (CRAC). We evaluated KRASG12/G13 mutations in cfDNA extracted from serum and compared the results with KRASG12/G13 mutations detected in tissue samples. We assessed the clinical significance of KRASG12/G13 mutation in serum in regard to recurrence and metastasis of CRAC.MethodsA total of 146 CRAC patients were enrolled, and KRASG12/G13 mutations were evaluated in 146 pairs of serum and tissue samples. In addition, 35 pairs of primary and metastatic CRAC tissue samples were evaluated for KRASG12/G13 mutational status.ResultsDetection of KRASG12/13 mutation from serum and tissue had a 55% concordance rate, and serum detection had a sensitivity of 39.8%. Detection of the KRASG12/13 mutation yielded a 14% discordance rate between primary and metastatic tissue. CRAC patients with mutant KRASG12/13 mutation in serum but wild-type KRASG12/13 in tissue had concurrent KRASG12/13-mutant metastatic tumors, indicating spatial genetic heterogeneity. Changes in serum KRASG12/G13 mutation status during postoperative follow-up were associated with recurrence. Conclusion: Although serum detection of the KRASG12/13 mutation cannot substitute for detection in tissue, serum testing can support the interpretation of a CRAC patient’s status in regard to concurrent metastasis. Dynamic changes in serum KRASG12/13 mutation status during follow-up indicated that cfDNA from serum represents a potential source for monitoring recurrence in CRAC patients.

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“…Thus, in the course of tumor progression and subsequent therapy, additional mutations may occur providing the resistance of tumor cells to the drugs. Among chemotherapy-induced mutations, mutations in genes of the EGFR-dependent signaling pathway (EGFR, HER2, RAS) targeted by the drugs are common [58][59][60][61]. In addition to mutations that lead to a decrease in the effectiveness of targeted therapy, some mutations decrease the effects of less specific chemotherapeutic drugs through the regulation of DNA repair or inhibition of apoptosis.…”

Section: Intracellular Mechanisms Of Acquired Therapy Resistancementioning

confidence: 99%

New Insights into Therapy-Induced Progression of Cancer

Shnaider

Ivanova

Malyants

et al. 2020

IJMS

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The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.

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Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients

Cited by 59 publications

References 54 publications

Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis

Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis

Serum-Based KRASG12/G13 Mutation Detection Using Droplet Digital PCR: Clinical Implications and Limitations in Colorectal Adenocarcinoma With Tumor Heterogeneity

New Insights into Therapy-Induced Progression of Cancer

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