Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Nicola S Meagher; Kylie L Gorringe; Matthew Wakefield; Adelyn Bolithon; Chi Nam Ignatius Pang; Derek S Chiu; Michael S Anglesio; Kylie-Ann Mallitt; Jennifer A Doherty; Holly R Harris; Joellen M Schildkraut; Andrew Berchuck; Kara L Cushing-Haugen; Ksenia Chezar; Angela Chou; Adeline Tan; Jennifer Alsop; Ellen Barlow; Matthias W Beckmann; Jessica Boros; David D L Bowtell; Alison H Brand; James D Brenton; Ian Campbell; Dane Cheasley; Joshua Cohen; Cezary Cybulski; Esther Elishaev; Ramona Erber; Rhonda Farrell; Anna Fischer; Zhuxuan Fu; Blake Gilks; Anthony J Gill; Charlie Gourley; Marcel Grube; Paul R Harnett; Arndt Hartmann; Anusha Hettiaratchi; Claus K Høgdall; Tomasz Huzarski; Anna Jakubowska; Mercedes Jimenez-Linan; Catherine J Kennedy; Byoung-Gie Kim; Jae-Weon Kim; Jae-Hoon Kim; Kayla Klett; Jennifer M Koziak; AOCS group; Estrid Høgdall

doi:10.1158/1078-0432.CCR-22-1206

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Nicola S Meagher^*, Kylie L Gorringe, Matthew Wakefield, Adelyn Bolithon, Chi Nam Ignatius Pang, Derek S Chiu, Michael S Anglesio, Kylie-Ann Mallitt, Jennifer A Doherty, Holly R Harris, Joellen M Schildkraut, Andrew Berchuck, Kara L Cushing-Haugen, Ksenia Chezar, Angela Chou, Adeline Tan, Jennifer Alsop, Ellen Barlow, Matthias W Beckmann, Jessica BorosDavid D L Bowtell, Alison H Brand, James D Brenton, Ian Campbell, Dane Cheasley, Joshua Cohen, Cezary Cybulski, Esther Elishaev, Ramona Erber, Rhonda Farrell, Anna Fischer, Zhuxuan Fu, Blake Gilks, Anthony J Gill, Charlie Gourley, Marcel Grube, Paul R Harnett, Arndt Hartmann, Anusha Hettiaratchi, Claus K Høgdall, Tomasz Huzarski, Anna Jakubowska, Mercedes Jimenez-Linan, Catherine J Kennedy, Byoung-Gie Kim, Jae-Weon Kim, Jae-Hoon Kim, Kayla Klett, Jennifer M Koziak, AOCS group, Estrid Høgdall

^*Corresponding author for this work

Department of Pathology

20 Citations (Scopus)

Abstract

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.

EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).

RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).

CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Original language	English
Journal	Clinical Cancer Research
Volume	28
Issue number	24
Pages (from-to)	5383-5395
Number of pages	13
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.CCR-22-1206
Publication status	Published - 15 Dec 2022

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Meagher, N. S., Gorringe, K. L., Wakefield, M., Bolithon, A., Pang, C. N. I., Chiu, D. S., Anglesio, M. S., Mallitt, K.-A., Doherty, J. A., Harris, H. R., Schildkraut, J. M., Berchuck, A., Cushing-Haugen, K. L., Chezar, K., Chou, A., Tan, A., Alsop, J., Barlow, E., Beckmann, M. W., ... Høgdall, E. (2022). Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes. Clinical Cancer Research, 28(24), 5383-5395. https://doi.org/10.1158/1078-0432.CCR-22-1206

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes. / Meagher, Nicola S; Gorringe, Kylie L; Wakefield, Matthew et al.
In: Clinical Cancer Research, Vol. 28, No. 24, 15.12.2022, p. 5383-5395.

Research output: Contribution to journal › Journal article › Research › peer-review

Meagher, NS, Gorringe, KL, Wakefield, M, Bolithon, A, Pang, CNI, Chiu, DS, Anglesio, MS, Mallitt, K-A, Doherty, JA, Harris, HR, Schildkraut, JM, Berchuck, A, Cushing-Haugen, KL, Chezar, K, Chou, A, Tan, A, Alsop, J, Barlow, E, Beckmann, MW, Boros, J, Bowtell, DDL, Brand, AH, Brenton, JD, Campbell, I, Cheasley, D, Cohen, J, Cybulski, C, Elishaev, E, Erber, R, Farrell, R, Fischer, A, Fu, Z, Gilks, B, Gill, AJ, Gourley, C, Grube, M, Harnett, PR, Hartmann, A, Hettiaratchi, A, Høgdall, CK, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kim, B-G, Kim, J-W, Kim, J-H, Klett, K, Koziak, JM, AOCS group & Høgdall, E 2022, 'Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes', Clinical Cancer Research, vol. 28, no. 24, pp. 5383-5395. https://doi.org/10.1158/1078-0432.CCR-22-1206

@article{03fb6ad099c146c8be75913dde1574f5,

title = "Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes",

abstract = "PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95\% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95\% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95\% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26\%) of MOCs, but only 8 of 243 (3\%) were also infiltrative (4/39, 10\%) or stage III/IV (4/31, 13\%).CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.",

author = "Meagher, \{Nicola S\} and Gorringe, \{Kylie L\} and Matthew Wakefield and Adelyn Bolithon and Pang, \{Chi Nam Ignatius\} and Chiu, \{Derek S\} and Anglesio, \{Michael S\} and Kylie-Ann Mallitt and Doherty, \{Jennifer A\} and Harris, \{Holly R\} and Schildkraut, \{Joellen M\} and Andrew Berchuck and Cushing-Haugen, \{Kara L\} and Ksenia Chezar and Angela Chou and Adeline Tan and Jennifer Alsop and Ellen Barlow and Beckmann, \{Matthias W\} and Jessica Boros and Bowtell, \{David D L\} and Brand, \{Alison H\} and Brenton, \{James D\} and Ian Campbell and Dane Cheasley and Joshua Cohen and Cezary Cybulski and Esther Elishaev and Ramona Erber and Rhonda Farrell and Anna Fischer and Zhuxuan Fu and Blake Gilks and Gill, \{Anthony J\} and Charlie Gourley and Marcel Grube and Harnett, \{Paul R\} and Arndt Hartmann and Anusha Hettiaratchi and H{\o}gdall, \{Claus K\} and Tomasz Huzarski and Anna Jakubowska and Mercedes Jimenez-Linan and Kennedy, \{Catherine J\} and Byoung-Gie Kim and Jae-Weon Kim and Jae-Hoon Kim and Kayla Klett and Koziak, \{Jennifer M\} and \{AOCS group\} and Estrid H{\o}gdall",

note = "{\textcopyright}2022 The Authors; Published by the American Association for Cancer Research.",

year = "2022",

month = dec,

day = "15",

doi = "10.1158/1078-0432.CCR-22-1206",

language = "English",

volume = "28",

pages = "5383--5395",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "24",

}

TY - JOUR

T1 - Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

AU - Meagher, Nicola S

AU - Gorringe, Kylie L

AU - Wakefield, Matthew

AU - Bolithon, Adelyn

AU - Pang, Chi Nam Ignatius

AU - Chiu, Derek S

AU - Anglesio, Michael S

AU - Mallitt, Kylie-Ann

AU - Doherty, Jennifer A

AU - Harris, Holly R

AU - Schildkraut, Joellen M

AU - Berchuck, Andrew

AU - Cushing-Haugen, Kara L

AU - Chezar, Ksenia

AU - Chou, Angela

AU - Tan, Adeline

AU - Alsop, Jennifer

AU - Barlow, Ellen

AU - Beckmann, Matthias W

AU - Boros, Jessica

AU - Bowtell, David D L

AU - Brand, Alison H

AU - Brenton, James D

AU - Campbell, Ian

AU - Cheasley, Dane

AU - Cohen, Joshua

AU - Cybulski, Cezary

AU - Elishaev, Esther

AU - Erber, Ramona

AU - Farrell, Rhonda

AU - Fischer, Anna

AU - Fu, Zhuxuan

AU - Gilks, Blake

AU - Gill, Anthony J

AU - Gourley, Charlie

AU - Grube, Marcel

AU - Harnett, Paul R

AU - Hartmann, Arndt

AU - Hettiaratchi, Anusha

AU - Høgdall, Claus K

AU - Huzarski, Tomasz

AU - Jakubowska, Anna

AU - Jimenez-Linan, Mercedes

AU - Kennedy, Catherine J

AU - Kim, Byoung-Gie

AU - Kim, Jae-Weon

AU - Kim, Jae-Hoon

AU - Klett, Kayla

AU - Koziak, Jennifer M

AU - AOCS group

AU - Høgdall, Estrid

PY - 2022/12/15

Y1 - 2022/12/15

N2 - PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

AB - PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

UR - https://www.scopus.com/pages/publications/85141531275

U2 - 10.1158/1078-0432.CCR-22-1206

DO - 10.1158/1078-0432.CCR-22-1206

M3 - Journal article

C2 - 36222710

SN - 1078-0432

VL - 28

SP - 5383

EP - 5395

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 24

ER -

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

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