Assessment of hepatocyte growth factor in ovarian cancer mortality

Ellen L Goode; Georgia Chenevix-Trench; Lynn C Hartmann; Brooke L Fridley; Kimberly R Kalli; Robert A Vierkant; Melissa C Larson; Kristin L White; Gary L Keeney; Trynda N Oberg; Julie M Cunningham; Jonathan Beesley; Sharon E Johnatty; Xiaoqing Chen; Katelyn E Goodman; Sebastian M Armasu; David N Rider; Hugues Sicotte; Michele M Schmidt; Elaine A Elliott; Estrid Høgdall; Susanne Krüger Kjær; Peter A Fasching; Arif B Ekici; Diether Lambrechts; Evelyn Despierre; Claus Høgdall; Lene Lundvall; Beth Y Karlan; Jenny Gross; Robert Brown; Jeremy Chien; David J Duggan; Ya-Yu Tsai; Catherine M Phelan; Linda E Kelemen; Prema P Peethambaram; Joellen M Schildkraut; Vijayalakshmi Shridhar; Rebecca Sutphen; Fergus J Couch; Thomas A Sellers; Ovarian Cancer Association Consortium

doi:http://dx.doi.org/10.1158/1055-9965.EPI-11-0455

Assessment of hepatocyte growth factor in ovarian cancer mortality

Ellen L Goode, Georgia Chenevix-Trench, Lynn C Hartmann, Brooke L Fridley, Kimberly R Kalli, Robert A Vierkant, Melissa C Larson, Kristin L White, Gary L Keeney, Trynda N Oberg, Julie M Cunningham, Jonathan Beesley, Sharon E Johnatty, Xiaoqing Chen, Katelyn E Goodman, Sebastian M Armasu, David N Rider, Hugues Sicotte, Michele M Schmidt, Elaine A ElliottEstrid Høgdall, Susanne Krüger Kjær, Peter A Fasching, Arif B Ekici, Diether Lambrechts, Evelyn Despierre, Claus Høgdall, Lene Lundvall, Beth Y Karlan, Jenny Gross, Robert Brown, Jeremy Chien, David J Duggan, Ya-Yu Tsai, Catherine M Phelan, Linda E Kelemen, Prema P Peethambaram, Joellen M Schildkraut, Vijayalakshmi Shridhar, Rebecca Sutphen, Fergus J Couch, Thomas A Sellers, Ovarian Cancer Association Consortium

Faculty of Health and Medical Sciences

30 Citations (Scopus)

Abstract

Background: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. Methods: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths). Results: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3-2.2, P = 2.0 × 10 ^-5) and with overall variation in HGF (gene-level test, P = 3.7 × 10 ^-4). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r ² = 0.96 \with rs1800793): TCGA HR = 2.4, CI = 1.4-4.1, P = 2.2 × 10 ^-3; Mayo Clinic + TCGA HR = 1.6, CI = 1.3-1.9, P = 7.0 × 10 ^-5] and suggested genotype correlation with reduced HGF mRNAlevels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9-1.1, P = 0.87). Conclusions: Weconclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression. Impact: Our study shows the utility of multiple data types and multiple data sets in observational studies.

Original language	English
Journal	Cancer Epidemiology, Biomarkers & Prevention
Volume	20
Issue number	8
Pages (from-to)	1638-48
Number of pages	11
ISSN	1055-9965
DOIs	https://doi.org/10.1158/1055-9965.EPI-11-0455
Publication status	Published - Aug 2011

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Goode, E. L., Chenevix-Trench, G., Hartmann, L. C., Fridley, B. L., Kalli, K. R., Vierkant, R. A., Larson, M. C., White, K. L., Keeney, G. L., Oberg, T. N., Cunningham, J. M., Beesley, J., Johnatty, S. E., Chen, X., Goodman, K. E., Armasu, S. M., Rider, D. N., Sicotte, H., Schmidt, M. M., ... Ovarian Cancer Association Consortium (2011). Assessment of hepatocyte growth factor in ovarian cancer mortality. Cancer Epidemiology, Biomarkers & Prevention, 20(8), 1638-48. https://doi.org/10.1158/1055-9965.EPI-11-0455

Goode, EL, Chenevix-Trench, G, Hartmann, LC, Fridley, BL, Kalli, KR, Vierkant, RA, Larson, MC, White, KL, Keeney, GL, Oberg, TN, Cunningham, JM, Beesley, J, Johnatty, SE, Chen, X, Goodman, KE, Armasu, SM, Rider, DN, Sicotte, H, Schmidt, MM, Elliott, EA, Høgdall, E, Kjær, SK, Fasching, PA, Ekici, AB, Lambrechts, D, Despierre, E, Høgdall, C, Lundvall, L, Karlan, BY, Gross, J, Brown, R, Chien, J, Duggan, DJ, Tsai, Y-Y, Phelan, CM, Kelemen, LE, Peethambaram, PP, Schildkraut, JM, Shridhar, V, Sutphen, R, Couch, FJ, Sellers, TA & Ovarian Cancer Association Consortium 2011, 'Assessment of hepatocyte growth factor in ovarian cancer mortality', Cancer Epidemiology, Biomarkers & Prevention, vol. 20, no. 8, pp. 1638-48. https://doi.org/10.1158/1055-9965.EPI-11-0455

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title = "Assessment of hepatocyte growth factor in ovarian cancer mortality",

abstract = "Background: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. Methods: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths). Results: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3-2.2, P = 2.0 × 10 -5) and with overall variation in HGF (gene-level test, P = 3.7 × 10 -4). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r 2 = 0.96 \with rs1800793): TCGA HR = 2.4, CI = 1.4-4.1, P = 2.2 × 10 -3; Mayo Clinic + TCGA HR = 1.6, CI = 1.3-1.9, P = 7.0 × 10 -5] and suggested genotype correlation with reduced HGF mRNAlevels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9-1.1, P = 0.87). Conclusions: Weconclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression. Impact: Our study shows the utility of multiple data types and multiple data sets in observational studies.",

author = "Goode, {Ellen L} and Georgia Chenevix-Trench and Hartmann, {Lynn C} and Fridley, {Brooke L} and Kalli, {Kimberly R} and Vierkant, {Robert A} and Larson, {Melissa C} and White, {Kristin L} and Keeney, {Gary L} and Oberg, {Trynda N} and Cunningham, {Julie M} and Jonathan Beesley and Johnatty, {Sharon E} and Xiaoqing Chen and Goodman, {Katelyn E} and Armasu, {Sebastian M} and Rider, {David N} and Hugues Sicotte and Schmidt, {Michele M} and Elliott, {Elaine A} and Estrid H{\o}gdall and Kj{\ae}r, {Susanne Kr{\"u}ger} and Fasching, {Peter A} and Ekici, {Arif B} and Diether Lambrechts and Evelyn Despierre and Claus H{\o}gdall and Lene Lundvall and Karlan, {Beth Y} and Jenny Gross and Robert Brown and Jeremy Chien and Duggan, {David J} and Ya-Yu Tsai and Phelan, {Catherine M} and Kelemen, {Linda E} and Peethambaram, {Prema P} and Schildkraut, {Joellen M} and Vijayalakshmi Shridhar and Rebecca Sutphen and Couch, {Fergus J} and Sellers, {Thomas A} and H{\o}gdall, {Claus Kim}",

note = "{\textcopyright}2011 AACR.",

year = "2011",

month = aug,

doi = "http://dx.doi.org/10.1158/1055-9965.EPI-11-0455",

language = "English",

volume = "20",

pages = "1638--48",

journal = "Cancer Epidemiology, Biomarkers & Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research (A A C R)",

number = "8",

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TY - JOUR

T1 - Assessment of hepatocyte growth factor in ovarian cancer mortality

AU - Goode, Ellen L

AU - Chenevix-Trench, Georgia

AU - Hartmann, Lynn C

AU - Fridley, Brooke L

AU - Kalli, Kimberly R

AU - Vierkant, Robert A

AU - Larson, Melissa C

AU - White, Kristin L

AU - Keeney, Gary L

AU - Oberg, Trynda N

AU - Cunningham, Julie M

AU - Beesley, Jonathan

AU - Johnatty, Sharon E

AU - Chen, Xiaoqing

AU - Goodman, Katelyn E

AU - Armasu, Sebastian M

AU - Rider, David N

AU - Sicotte, Hugues

AU - Schmidt, Michele M

AU - Elliott, Elaine A

AU - Høgdall, Estrid

AU - Kjær, Susanne Krüger

AU - Fasching, Peter A

AU - Ekici, Arif B

AU - Lambrechts, Diether

AU - Despierre, Evelyn

AU - Høgdall, Claus

AU - Lundvall, Lene

AU - Karlan, Beth Y

AU - Gross, Jenny

AU - Brown, Robert

AU - Chien, Jeremy

AU - Duggan, David J

AU - Tsai, Ya-Yu

AU - Phelan, Catherine M

AU - Kelemen, Linda E

AU - Peethambaram, Prema P

AU - Schildkraut, Joellen M

AU - Shridhar, Vijayalakshmi

AU - Sutphen, Rebecca

AU - Couch, Fergus J

AU - Sellers, Thomas A

AU - Ovarian Cancer Association Consortium

PY - 2011/8

Y1 - 2011/8

N2 - Background: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. Methods: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths). Results: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3-2.2, P = 2.0 × 10 -5) and with overall variation in HGF (gene-level test, P = 3.7 × 10 -4). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r 2 = 0.96 \with rs1800793): TCGA HR = 2.4, CI = 1.4-4.1, P = 2.2 × 10 -3; Mayo Clinic + TCGA HR = 1.6, CI = 1.3-1.9, P = 7.0 × 10 -5] and suggested genotype correlation with reduced HGF mRNAlevels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9-1.1, P = 0.87). Conclusions: Weconclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression. Impact: Our study shows the utility of multiple data types and multiple data sets in observational studies.

AB - Background: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. Methods: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths). Results: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3-2.2, P = 2.0 × 10 -5) and with overall variation in HGF (gene-level test, P = 3.7 × 10 -4). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r 2 = 0.96 \with rs1800793): TCGA HR = 2.4, CI = 1.4-4.1, P = 2.2 × 10 -3; Mayo Clinic + TCGA HR = 1.6, CI = 1.3-1.9, P = 7.0 × 10 -5] and suggested genotype correlation with reduced HGF mRNAlevels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9-1.1, P = 0.87). Conclusions: Weconclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression. Impact: Our study shows the utility of multiple data types and multiple data sets in observational studies.

U2 - http://dx.doi.org/10.1158/1055-9965.EPI-11-0455

DO - http://dx.doi.org/10.1158/1055-9965.EPI-11-0455

M3 - Journal article

SN - 1055-9965

VL - 20

SP - 1638

EP - 1648

JO - Cancer Epidemiology, Biomarkers & Prevention

JF - Cancer Epidemiology, Biomarkers & Prevention

IS - 8

ER -

Assessment of hepatocyte growth factor in ovarian cancer mortality

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