Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer

Dae Won Lee; Sae Won Han; Yongjun Cha; Jeong Mo Bae; Hwang Phill Kim; Jaemyun Lyu; Hyojun Han; Hyoki Kim; Hoon Jang; Duhee Bang; Iksoo Huh; Taesung Park; Jae Kyung Won; Seung Yong Jeong; Kyu Joo Park; Gyeong Hoon Kang; Tae You Kim

doi:10.1002/cncr.30760

Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer

Dae Won Lee, Sae Won Han, Yongjun Cha, Jeong Mo Bae, Hwang Phill Kim, Jaemyun Lyu, Hyojun Han, Hyoki Kim, Hoon Jang, Duhee Bang, Iksoo Huh, Taesung Park, Jae Kyung Won, Seung Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, Tae You Kim

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

38 Citations (Scopus)

Abstract

BACKGROUND: Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. METHODS: Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor β [TGF-β]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse-free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. RESULTS: The mutation rates for the WNT, P53, RTK-RAS, PI3K, and TGF-β pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.99), whereas a mutation in the RTK-RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01-2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and B-Raf proto-oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors. CONCLUSIONS: A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK-RAS pathway mutation was associated with worse RFS. The significance of the prognostic impact differed according to the tumor location. Cancer 2017;123:3513-23.

Original language	English
Pages (from-to)	3513-3523
Number of pages	11
Journal	Cancer
Volume	123
Issue number	18
DOIs	https://doi.org/10.1002/cncr.30760
Publication status	Published - 2017 Sept 15

Bibliographical note

Funding Information:
This research was supported by the Seoul National University Hospital Research Fund (03-2014-0440) and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, which is funded by the Ministry of Health and Welfare of the Republic of Korea (grants HI14C1277, HI13C2163, and HI13C2096000013).

Publisher Copyright:
© 2017 American Cancer Society

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/cncr.30760

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Lee, D. W., Han, S. W., Cha, Y., Bae, J. M., Kim, H. P., Lyu, J., Han, H., Kim, H., Jang, H., Bang, D., Huh, I., Park, T., Won, J. K., Jeong, S. Y., Park, K. J., Kang, G. H., & Kim, T. Y. (2017). Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer. Cancer, 123(18), 3513-3523. https://doi.org/10.1002/cncr.30760

@article{25e4c6f2e4424df4ae4c6db246cd794d,

title = "Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer",

abstract = "BACKGROUND: Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. METHODS: Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor β [TGF-β]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse-free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. RESULTS: The mutation rates for the WNT, P53, RTK-RAS, PI3K, and TGF-β pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.99), whereas a mutation in the RTK-RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01-2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and B-Raf proto-oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors. CONCLUSIONS: A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK-RAS pathway mutation was associated with worse RFS. The significance of the prognostic impact differed according to the tumor location. Cancer 2017;123:3513-23.",

author = "Lee, {Dae Won} and Han, {Sae Won} and Yongjun Cha and Bae, {Jeong Mo} and Kim, {Hwang Phill} and Jaemyun Lyu and Hyojun Han and Hyoki Kim and Hoon Jang and Duhee Bang and Iksoo Huh and Taesung Park and Won, {Jae Kyung} and Jeong, {Seung Yong} and Park, {Kyu Joo} and Kang, {Gyeong Hoon} and Kim, {Tae You}",

note = "Funding Information: This research was supported by the Seoul National University Hospital Research Fund (03-2014-0440) and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, which is funded by the Ministry of Health and Welfare of the Republic of Korea (grants HI14C1277, HI13C2163, and HI13C2096000013). Publisher Copyright: {\textcopyright} 2017 American Cancer Society",

year = "2017",

month = sep,

day = "15",

doi = "10.1002/cncr.30760",

language = "English",

volume = "123",

pages = "3513--3523",

journal = "Cancer",

issn = "0008-543X",

publisher = "John Wiley and Sons Inc.",

number = "18",

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TY - JOUR

T1 - Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer

AU - Lee, Dae Won

AU - Han, Sae Won

AU - Cha, Yongjun

AU - Bae, Jeong Mo

AU - Kim, Hwang Phill

AU - Lyu, Jaemyun

AU - Han, Hyojun

AU - Kim, Hyoki

AU - Jang, Hoon

AU - Bang, Duhee

AU - Huh, Iksoo

AU - Park, Taesung

AU - Won, Jae Kyung

AU - Jeong, Seung Yong

AU - Park, Kyu Joo

AU - Kang, Gyeong Hoon

AU - Kim, Tae You

N1 - Funding Information: This research was supported by the Seoul National University Hospital Research Fund (03-2014-0440) and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, which is funded by the Ministry of Health and Welfare of the Republic of Korea (grants HI14C1277, HI13C2163, and HI13C2096000013). Publisher Copyright: © 2017 American Cancer Society

PY - 2017/9/15

Y1 - 2017/9/15

N2 - BACKGROUND: Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. METHODS: Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor β [TGF-β]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse-free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. RESULTS: The mutation rates for the WNT, P53, RTK-RAS, PI3K, and TGF-β pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.99), whereas a mutation in the RTK-RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01-2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and B-Raf proto-oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors. CONCLUSIONS: A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK-RAS pathway mutation was associated with worse RFS. The significance of the prognostic impact differed according to the tumor location. Cancer 2017;123:3513-23.

AB - BACKGROUND: Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. METHODS: Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor β [TGF-β]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse-free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. RESULTS: The mutation rates for the WNT, P53, RTK-RAS, PI3K, and TGF-β pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.99), whereas a mutation in the RTK-RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01-2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and B-Raf proto-oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors. CONCLUSIONS: A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK-RAS pathway mutation was associated with worse RFS. The significance of the prognostic impact differed according to the tumor location. Cancer 2017;123:3513-23.

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Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer

Abstract

Bibliographical note

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UN SDGs

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