SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features

Tingting Li, Xiaoyun Liao, Paul Lochhead, Teppei Morikawa, Mai Yamauchi, Reiko Nishihara, Kentaro Inamura, Sun A Kim, Kosuke Mima, Yasutaka Sukawa, Aya Kuchiba, Yu Imamura, Yoshifumi Baba, Kaori Shima, Jeffrey A Meyerhardt, Andrew T Chan, Charles S Fuchs, Shuji Ogino, Zhi Rong Qian

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

BACKGROUND: Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear.

METHODS: Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1.

RESULTS: SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34-0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35-0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13-0.95; P interaction = 0.035, for SMO and CIMP status).

CONCLUSIONS: Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed.

Original languageEnglish
Pages (from-to)4164-4173
Number of pages10
JournalAnnals of Surgical Oncology
Volume21
Issue number13
Early online date15 Jul 2014
DOIs
Publication statusPublished - Dec 2014

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CpG Islands
Colorectal Neoplasms
Phenotype
Neoplasms
Confidence Intervals
Odds Ratio
Frizzled Receptors
Microsatellite Instability
Survival
Health
Diphosphonates
Rectal Neoplasms
Phosphatidylinositols
Colonic Neoplasms
Methylation
Phosphotransferases
Logistic Models
Immunohistochemistry
Nurses
Regression Analysis

Keywords

  • surgical oncology
  • oncology
  • surgery

Cite this

Li, T., Liao, X., Lochhead, P., Morikawa, T., Yamauchi, M., Nishihara, R., ... Qian, Z. R. (2014). SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features. Annals of Surgical Oncology, 21(13), 4164-4173. https://doi.org/10.1245/s10434-014-3888-y

SMO Expression in Colorectal Cancer : Associations with Clinical, Pathological, and Molecular Features. / Li, Tingting; Liao, Xiaoyun; Lochhead, Paul; Morikawa, Teppei; Yamauchi, Mai; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A; Mima, Kosuke; Sukawa, Yasutaka; Kuchiba, Aya; Imamura, Yu; Baba, Yoshifumi; Shima, Kaori; Meyerhardt, Jeffrey A; Chan, Andrew T; Fuchs, Charles S; Ogino, Shuji; Qian, Zhi Rong.

In: Annals of Surgical Oncology, Vol. 21, No. 13, 12.2014, p. 4164-4173.

Research output: Contribution to journalArticle

Li, T, Liao, X, Lochhead, P, Morikawa, T, Yamauchi, M, Nishihara, R, Inamura, K, Kim, SA, Mima, K, Sukawa, Y, Kuchiba, A, Imamura, Y, Baba, Y, Shima, K, Meyerhardt, JA, Chan, AT, Fuchs, CS, Ogino, S & Qian, ZR 2014, 'SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features', Annals of Surgical Oncology, vol. 21, no. 13, pp. 4164-4173. https://doi.org/10.1245/s10434-014-3888-y
Li, Tingting ; Liao, Xiaoyun ; Lochhead, Paul ; Morikawa, Teppei ; Yamauchi, Mai ; Nishihara, Reiko ; Inamura, Kentaro ; Kim, Sun A ; Mima, Kosuke ; Sukawa, Yasutaka ; Kuchiba, Aya ; Imamura, Yu ; Baba, Yoshifumi ; Shima, Kaori ; Meyerhardt, Jeffrey A ; Chan, Andrew T ; Fuchs, Charles S ; Ogino, Shuji ; Qian, Zhi Rong. / SMO Expression in Colorectal Cancer : Associations with Clinical, Pathological, and Molecular Features. In: Annals of Surgical Oncology. 2014 ; Vol. 21, No. 13. pp. 4164-4173.
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abstract = "BACKGROUND: Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear.METHODS: Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1.RESULTS: SMO expression was detected in 370 tumors (50 {\%}). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 {\%} confidence interval (CI) 0.34-0.67] and CTNNB1 nuclear localization (OR 0.48; 95 {\%} CI 0.35-0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 {\%} CI 0.13-0.95; P interaction = 0.035, for SMO and CIMP status).CONCLUSIONS: Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed.",
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author = "Tingting Li and Xiaoyun Liao and Paul Lochhead and Teppei Morikawa and Mai Yamauchi and Reiko Nishihara and Kentaro Inamura and Kim, {Sun A} and Kosuke Mima and Yasutaka Sukawa and Aya Kuchiba and Yu Imamura and Yoshifumi Baba and Kaori Shima and Meyerhardt, {Jeffrey A} and Chan, {Andrew T} and Fuchs, {Charles S} and Shuji Ogino and Qian, {Zhi Rong}",
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TY - JOUR

T1 - SMO Expression in Colorectal Cancer

T2 - Associations with Clinical, Pathological, and Molecular Features

AU - Li, Tingting

AU - Liao, Xiaoyun

AU - Lochhead, Paul

AU - Morikawa, Teppei

AU - Yamauchi, Mai

AU - Nishihara, Reiko

AU - Inamura, Kentaro

AU - Kim, Sun A

AU - Mima, Kosuke

AU - Sukawa, Yasutaka

AU - Kuchiba, Aya

AU - Imamura, Yu

AU - Baba, Yoshifumi

AU - Shima, Kaori

AU - Meyerhardt, Jeffrey A

AU - Chan, Andrew T

AU - Fuchs, Charles S

AU - Ogino, Shuji

AU - Qian, Zhi Rong

PY - 2014/12

Y1 - 2014/12

N2 - BACKGROUND: Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear.METHODS: Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1.RESULTS: SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34-0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35-0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13-0.95; P interaction = 0.035, for SMO and CIMP status).CONCLUSIONS: Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed.

AB - BACKGROUND: Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear.METHODS: Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1.RESULTS: SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34-0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35-0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13-0.95; P interaction = 0.035, for SMO and CIMP status).CONCLUSIONS: Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed.

KW - surgical oncology

KW - oncology

KW - surgery

U2 - 10.1245/s10434-014-3888-y

DO - 10.1245/s10434-014-3888-y

M3 - Article

C2 - 25023548

VL - 21

SP - 4164

EP - 4173

JO - Annals of Surgical Oncology

JF - Annals of Surgical Oncology

SN - 1068-9265

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ER -