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201. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

Author

Purrington, Kristen S. Slager, Susan Eccles, Diana and Yannoukakos, Drakoulis Fasching, Peter A. Miron, Penelope and Carpenter, Jane Chang-Claude, Jenny Martin, Nicholas G. and Montgomery, Grant W. Kristensen, Vessela Anton-Culver, Hoda and Goodfellow, Paul Tapper, William J. Rafiq, Sajjad Gerty, Susan M. Durcan, Lorraine Konstantopoulou, Irene Fostira, Florentia Vratimos, Athanassios Apostolou, Paraskevi and Konstanta, Irene Kotoula, Vassiliki Lakis, Sotiris and Dimopoulos, Meletios A. Skarlos, Dimosthenis Pectasides, Dimitrios Fountzilas, George Beckmann, Matthias W. Hein, Alexander Ruebner, Matthias Ekici, Arif B. Hartmann, Arndt and Schulz-Wendtland, Ruediger Renner, Stefan P. Janni, Wolfgang and Rack, Brigitte Scholz, Christoph Neugebauer, Julia and Andergassen, Ulrich Lux, Michael P. Haeberle, Lothar Clarke, Christine Pathmanathan, Nirmala Rudolph, Anja Flesch-Janys, Dieter Nickels, Stefan Olson, Janet E. Ingle, James N. and Olswold, Curtis Slettedahl, Seth Eckel-Passow, Jeanette E. and Anderson, S. Keith Visscher, Daniel W. Cafourek, Victoria L. and Sicotte, Hugues Prodduturi, Naresh Weiderpass, Elisabete and Bernstein, Leslie Ziogas, Argyrios Ivanovich, Jennifer and Giles, Graham G. Baglietto, Laura Southey, Melissa Kosma, Veli-Matti Fischer, Hans-Peter Reed, Malcom W. R. Cross, Simon S. Deming-Halverson, Sandra Shrubsole, Martha Cai, Qiuyin Shu, Xiao-Ou Daly, Mary Weaver, JoEllen Ross, Eric Klemp, Jennifer Sharma, Priyanka Torres, Diana and Rudiger, Thomas Wolfing, Heidrun Ulmer, Hans-Ulrich Forsti, Asta Khoury, Thaer Kumar, Shicha Pilarski, Robert and Shapiro, Charles L. Greco, Dario Heikkila, Paivi Aittomaki, Kristiina Blomqvist, Carl Irwanto, Astrid Liu, Jianjun and Pankratz, Vernon Shane Wang, Xianshu Severi, Gianluca and Mannermaa, Arto Easton, Douglas Hall, Per Brauch, Hiltrud and Cox, Angela Zheng, Wei Godwin, Andrew K. Hamann, Ute and Ambrosone, Christine Toland, Amanda Ewart Nevanlinna, Heli and Vachon, Celine M. Couch, Fergus J. GENICA Network and Purrington, Kristen S. Slager, Susan Eccles, Diana and Yannoukakos, Drakoulis Fasching, Peter A. Miron, Penelope and Carpenter, Jane Chang-Claude, Jenny Martin, Nicholas G. and Montgomery, Grant W. Kristensen, Vessela Anton-Culver, Hoda and Goodfellow, Paul Tapper, William J. Rafiq, Sajjad Gerty, Susan M. Durcan, Lorraine Konstantopoulou, Irene Fostira, Florentia Vratimos, Athanassios Apostolou, Paraskevi and Konstanta, Irene Kotoula, Vassiliki Lakis, Sotiris and Dimopoulos, Meletios A. Skarlos, Dimosthenis Pectasides, Dimitrios Fountzilas, George Beckmann, Matthias W. Hein, Alexander Ruebner, Matthias Ekici, Arif B. Hartmann, Arndt and Schulz-Wendtland, Ruediger Renner, Stefan P. Janni, Wolfgang and Rack, Brigitte Scholz, Christoph Neugebauer, Julia and Andergassen, Ulrich Lux, Michael P. Haeberle, Lothar Clarke, Christine Pathmanathan, Nirmala Rudolph, Anja Flesch-Janys, Dieter Nickels, Stefan Olson, Janet E. Ingle, James N. and Olswold, Curtis Slettedahl, Seth Eckel-Passow, Jeanette E. and Anderson, S. Keith Visscher, Daniel W. Cafourek, Victoria L. and Sicotte, Hugues Prodduturi, Naresh Weiderpass, Elisabete and Bernstein, Leslie Ziogas, Argyrios Ivanovich, Jennifer and Giles, Graham G. Baglietto, Laura Southey, Melissa Kosma, Veli-Matti Fischer, Hans-Peter Reed, Malcom W. R. Cross, Simon S. Deming-Halverson, Sandra Shrubsole, Martha Cai, Qiuyin Shu, Xiao-Ou Daly, Mary Weaver, JoEllen Ross, Eric Klemp, Jennifer Sharma, Priyanka Torres, Diana and Rudiger, Thomas Wolfing, Heidrun Ulmer, Hans-Ulrich Forsti, Asta Khoury, Thaer Kumar, Shicha Pilarski, Robert and Shapiro, Charles L. Greco, Dario Heikkila, Paivi Aittomaki, Kristiina Blomqvist, Carl Irwanto, Astrid Liu, Jianjun and Pankratz, Vernon Shane Wang, Xianshu Severi, Gianluca and Mannermaa, Arto Easton, Douglas Hall, Per Brauch, Hiltrud and Cox, Angela Zheng, Wei Godwin, Andrew K. Hamann, Ute and Ambrosone, Christine Toland, Amanda Ewart Nevanlinna, Heli and Vachon, Celine M. Couch, Fergus J. GENICA Network

Abstract

In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 x 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 x 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 x 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 x 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

Published
2014

202. Comparative DNA methylome analysis of endometrial carcinoma reveals complex and distinct deregulation of cancer promoters and enhancers

Author

Zhang, Bo, primary, Xing, XiaoYun, additional, Li, Jing, additional, Lowdon, Rebecca F, additional, Zhou, Yan, additional, Lin, Nan, additional, Zhang, Baoxue, additional, Sundaram, Vasavi, additional, Chiappinelli, Katherine B, additional, Hagemann, Ian S, additional, Mutch, David G, additional, Goodfellow, Paul J, additional, and Wang, Ting, additional

Published
2014
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203. Abstract 1376: EpCAM-mediated hypomethylation of BMP and cell adhesion genes is associated with advanced endometrial cancer

Author

Hsu, Ya-Ting, primary, Gu, Fei, additional, Huang, Yi-Wen, additional, Liu, Joseph, additional, Ruan, Jianhua, additional, Huang, Rui-Lan, additional, Wang, Chiou-Miin, additional, Chen, Chun-Liang, additional, Jadhav, Rohit R., additional, Wang, Yao, additional, Jin, Victor X., additional, Lai, Hung-Cheng, additional, Mutch, David G., additional, Goodfellow, Paul J., additional, Thompson, Ian M., additional, Kirma, Nameer B., additional, and Huang, Tim H.M., additional

Published
2014
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204. Abstract 3266: Expression quantitative trait locus analysis of triple negative breast cancer

Author

Purrington, Kristen S., primary, Yannoukakos, Drakoulis, additional, Carpenter, Jane, additional, Nevanlinna, Heli, additional, Cox, Angela, additional, Severi, Gianluca, additional, Ambrosone, Christine, additional, Toland, Amanda Ewart, additional, Godwin, Andrew K., additional, Brauch, Hiltrud, additional, Fasching, Peter A., additional, Miron, Penelope, additional, Chang-Claude, Jenny, additional, Martin, Nicholas G., additional, Montgomery, Grant W., additional, Kristensen, Vessela, additional, Anton-Culver, Hoda, additional, Goodfellow, Paul, additional, Olson, Janet E., additional, Sicotte, Hugues, additional, Prodduturi, Naresh, additional, Visscher, Daniel W., additional, Eckel-Passow, Jeanette E., additional, Anderson, S. Keith, additional, Slettedahl, Seth, additional, Olswold, Curtis, additional, Wang, Xianshu, additional, Pankratz, V. Shane, additional, Slager, Susan, additional, Zheng, Wei, additional, Mannermaa, Arto, additional, Hamann, Ute, additional, Eccles, Diana M., additional, Vachon, Celine M., additional, and Couch, Fergus J., additional

Published
2014
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209. FGFR2 point mutations in 466 endometrioid endometrial tumors: Relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features

Author

Byron, Sara, Gartside, Michael, Powell, Matthew, Wellens, Candice, Gao, Feng, Mutch, David, Goodfellow, Paul, Pollock, Pamela, Byron, Sara, Gartside, Michael, Powell, Matthew, Wellens, Candice, Gao, Feng, Mutch, David, Goodfellow, Paul, and Pollock, Pamela

Abstract

Mutations in multiple oncogenes including KRAS, CTNNB1, PIK3CA and FGFR2 have been identified in endometrial cancer. The aim of this study was to provide insight into the clinicopathological features associated with patterns of mutation in these genes, a necessary step in planning targeted therapies for endometrial cancer. 466 endometrioid endometrial tumors were tested for mutations in FGFR2, KRAS, CTNNB1, and PIK3CA. The relationships between mutation status, tumor microsatellite instability (MSI) and clinicopathological features including overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Mutations were identified in FGFR2 (48/466); KRAS (87/464); CTNNB1 (88/454) and PIK3CA (104/464). KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors. KRAS and FGFR2 occurred in a near mutually exclusive pattern (p = 0.05) and, surprisingly, mutations in KRAS and CTNNB1 also occurred in a near mutually exclusive pattern (p = 0.0002). Multivariate analysis revealed that mutation in KRAS and FGFR2 showed a trend (p = 0.06) towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II), FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025) and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045). In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology. This has implications for the implementation of anti-FGFR or anti-MEK biologic therapies.

Published
2012

210. Case report. Squamous cell carcinoma or diabetic foot ulcer?

Author

McIntyre, Kaye, Goodfellow, Paul, and Bristow, Ivan

Subjects
Diagnosis, Care and treatment, Research, Case studies, Risk factors, Patient outcomes, Diabetic foot -- Risk factors -- Diagnosis -- Care and treatment -- Patient outcomes -- Case studies -- Research, Squamous cell carcinoma -- Risk factors -- Diagnosis -- Research -- Case studies -- Care and treatment -- Patient outcomes
Abstract

Article points 1. Squamous cell carcinoma (SCC) is the second most common skin tumour in humans; however, it rarely affects the foot. 3. Any wound that does not heal or [...]

Published
2008

211. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer

Author

Haiman, Christopher A. Chen, Gary K. Vachon, Celine M. and Canzian, Federico Dunning, Alison Millikan, Robert C. Wang, Xianshu Ademuyiwa, Foluso Ahmed, Shahana Ambrosone, Christine B. Baglietto, Laura Balleine, Rosemary Bandera, Elisa V. Beckmann, Matthias W. Berg, Christine D. Bernstein, Leslie Blomqvist, Carl Blot, William J. Brauch, Hiltrud and Buring, Julie E. Carey, Lisa A. Carpenter, Jane E. and Chang-Claude, Jenny Chanock, Stephen J. Chasman, Daniel I. and Clarke, Christine L. Cox, Angela Cross, Simon S. Deming, Sandra L. Diasio, Robert B. Dimopoulos, Athanasios M. and Driver, W. Ryan Duennebier, Thomas Durcan, Lorraine Eccles, Diana Edlund, Christopher K. Ekici, Arif B. Fasching, Peter A. Feigelson, Heather S. Flesch-Janys, Dieter Fostira, Florentia Foersti, Asta Fountzilas, George Gerty, Susan M. and Giles, Graham G. Godwin, Andrew K. Goodfellow, Paul and Graham, Nikki Greco, Dario Hamann, Ute Hankinson, Susan E. and Hartmann, Arndt Hein, Rebecca Heinz, Judith Holbrook, Andrea Hoover, Robert N. Hu, Jennifer J. Hunter, David J. and Ingles, Sue A. Irwanto, Astrid Ivanovich, Jennifer John, Esther M. Johnson, Nicola Jukkola-Vuorinen, Arja Kaaks, Rudolf Ko, Yon-Dschun Kolonel, Laurence N. Konstantopoulou, Irene Kosma, Veli-Matti Kulkarni, Swati Lambrechts, Diether and Lee, Adam M. Le Marchand, Loic Lesnick, Timothy Liu, Jianjun Lindstrom, Sara Mannermaa, Arto Margolin, Sara and Martin, Nicholas G. Miron, Penelope Montgomery, Grant W. and Nevanlinna, Heli Nickels, Stephan Nyante, Sarah Olswold, Curtis Palmer, Julie Pathak, Harsh Pectasides, Dimitrios and Perou, Charles M. Peto, Julian Pharoah, Paul D. P. Pooler, Loreall C. Press, Michael F. Pylkas, Katri Rebbeck, Timothy R. Rodriguez-Gil, Jorge L. Rosenberg, Lynn Ross, Eric and Ruediger, Thomas Silva, Isabel dos Santos Sawyer, Elinor and Schmidt, Marjanka K. Schulz-Wendtland, Ruediger Schumacher, Fredrick Severi, Gianluca Sheng, Xin Signorello, Lisa B. and Sinn, Hans-Peter Stevens, Kristen N. Southey, Melissa C. and Haiman, Christopher A. Chen, Gary K. Vachon, Celine M. and Canzian, Federico Dunning, Alison Millikan, Robert C. Wang, Xianshu Ademuyiwa, Foluso Ahmed, Shahana Ambrosone, Christine B. Baglietto, Laura Balleine, Rosemary Bandera, Elisa V. Beckmann, Matthias W. Berg, Christine D. Bernstein, Leslie Blomqvist, Carl Blot, William J. Brauch, Hiltrud and Buring, Julie E. Carey, Lisa A. Carpenter, Jane E. and Chang-Claude, Jenny Chanock, Stephen J. Chasman, Daniel I. and Clarke, Christine L. Cox, Angela Cross, Simon S. Deming, Sandra L. Diasio, Robert B. Dimopoulos, Athanasios M. and Driver, W. Ryan Duennebier, Thomas Durcan, Lorraine Eccles, Diana Edlund, Christopher K. Ekici, Arif B. Fasching, Peter A. Feigelson, Heather S. Flesch-Janys, Dieter Fostira, Florentia Foersti, Asta Fountzilas, George Gerty, Susan M. and Giles, Graham G. Godwin, Andrew K. Goodfellow, Paul and Graham, Nikki Greco, Dario Hamann, Ute Hankinson, Susan E. and Hartmann, Arndt Hein, Rebecca Heinz, Judith Holbrook, Andrea Hoover, Robert N. Hu, Jennifer J. Hunter, David J. and Ingles, Sue A. Irwanto, Astrid Ivanovich, Jennifer John, Esther M. Johnson, Nicola Jukkola-Vuorinen, Arja Kaaks, Rudolf Ko, Yon-Dschun Kolonel, Laurence N. Konstantopoulou, Irene Kosma, Veli-Matti Kulkarni, Swati Lambrechts, Diether and Lee, Adam M. Le Marchand, Loic Lesnick, Timothy Liu, Jianjun Lindstrom, Sara Mannermaa, Arto Margolin, Sara and Martin, Nicholas G. Miron, Penelope Montgomery, Grant W. and Nevanlinna, Heli Nickels, Stephan Nyante, Sarah Olswold, Curtis Palmer, Julie Pathak, Harsh Pectasides, Dimitrios and Perou, Charles M. Peto, Julian Pharoah, Paul D. P. Pooler, Loreall C. Press, Michael F. Pylkas, Katri Rebbeck, Timothy R. Rodriguez-Gil, Jorge L. Rosenberg, Lynn Ross, Eric and Ruediger, Thomas Silva, Isabel dos Santos Sawyer, Elinor and Schmidt, Marjanka K. Schulz-Wendtland, Ruediger Schumacher, Fredrick Severi, Gianluca Sheng, Xin Signorello, Lisa B. and Sinn, Hans-Peter Stevens, Kristen N. Southey, Melissa C.

Abstract

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

Published
2011

212. FGFR2 mutations are rare across histologic subtypes of ovarian cancer

Author

Byron, Sara, Gartside, Michael, Wellens, Candice, Goodfellow, Paul, Birrer, Michael, Campbell, Ian, Pollock, Pamela, Byron, Sara, Gartside, Michael, Wellens, Candice, Goodfellow, Paul, Birrer, Michael, Campbell, Ian, and Pollock, Pamela

Abstract

OBJECTIVE: Ovarian cancer is the leading cause of death from gynecologic malignancies in the Western world. Fibroblast growth factor receptor (FGFR) signaling has been implicated to play a role in ovarian tumorigenesis. Mutational activation of one member of this receptor family, FGFR2, is a frequent event in endometrioid endometrial cancer. Given the similarities in the histologic and molecular genetics of ovarian and endometrial cancers, we hypothesized that activating FGFR2 mutations may occur in a subset of endometrioid ovarian tumors, and possibly other histotypes. METHODS: Six FGFR2 exons were sequenced in 120 primary ovarian tumors representing the major histologic subtypes. RESULTS: FGFR2 mutation was detected at low frequency in endometrioid (1/46, 2.2%) and serous (1/41, 2.4%) ovarian cancer. No mutations were detected in clear cell, mucinous, or mixed histology tumors or in the ovarian cancer cell lines tested. Functional characterization of the FGFR2 mutations confirmed that the mutations detected in ovarian cancer result in receptor activation. CONCLUSIONS: Despite the low incidence of FGFR2 mutations in ovarian cancer, the two FGFR2 mutations identified in ovarian tumors (S252W, Y376C) overlap with the oncogenic mutations previously identified in endometrial tumors, suggesting activated FGFR2 may contribute to ovarian cancer pathogenesis in a small subset of ovarian tumors.

Published
2010

213. Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing.

Author

Varley, Katherine E, Mutch, David G, Edmonston, Tina B, Goodfellow, Paul J, Mitra, Robi D, Varley, Katherine E, Mutch, David G, Edmonston, Tina B, Goodfellow, Paul J, and Mitra, Robi D

Abstract

A single tumor may contain cells with different somatic mutations. By characterizing this genetic heterogeneity within tumors, advances have been made in the prognosis, treatment and understanding of tumorigenesis. In contrast, the extent of epigenetic intra-tumor heterogeneity and how it influences tumor biology is under-explored. We have characterized epigenetic heterogeneity within individual tumors using next-generation sequencing. We used deep single molecule bisulfite sequencing and sample-specific DNA barcodes to determine the spectrum of MLH1 promoter methylation across an average of 1000 molecules in each of 33 individual samples in parallel, including endometrial cancer, matched blood and normal endometrium. This first glimpse, deep into each tumor, revealed unexpectedly heterogeneous patterns of methylation at the MLH1 promoter within a subset of endometrial tumors. This high-resolution analysis allowed us to measure the clonality of methylation in individual tumors and gain insight into the accumulation of aberrant promoter methylation on both alleles during tumorigenesis.

Published
2009

214. Integrated analysis of germline and somatic variants in ovarian cancer

Author

Kanchi, Krishna L., primary, Johnson, Kimberly J., additional, Lu, Charles, additional, McLellan, Michael D., additional, Leiserson, Mark D. M., additional, Wendl, Michael C., additional, Zhang, Qunyuan, additional, Koboldt, Daniel C., additional, Xie, Mingchao, additional, Kandoth, Cyriac, additional, McMichael, Joshua F., additional, Wyczalkowski, Matthew A., additional, Larson, David E., additional, Schmidt, Heather K., additional, Miller, Christopher A., additional, Fulton, Robert S., additional, Spellman, Paul T., additional, Mardis, Elaine R., additional, Druley, Todd E., additional, Graubert, Timothy A., additional, Goodfellow, Paul J., additional, Raphael, Benjamin J., additional, Wilson, Richard K., additional, and Ding, Li, additional

Published
2014
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215. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation

Author

Byron, Sara, Gartside, Michael, Wellens, Candice, Mallon, Mary, Keenan, Jack, Powell, Matthew, Goodfellow, Paul, Pollock, Pamela, Byron, Sara, Gartside, Michael, Wellens, Candice, Mallon, Mary, Keenan, Jack, Powell, Matthew, Goodfellow, Paul, and Pollock, Pamela

Abstract

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.

Published
2008

216. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

Author

Purrington, Kristen S., primary, Slager, Susan, additional, Eccles, Diana, additional, Yannoukakos, Drakoulis, additional, Fasching, Peter A., additional, Miron, Penelope, additional, Carpenter, Jane, additional, Chang-Claude, Jenny, additional, Martin, Nicholas G., additional, Montgomery, Grant W., additional, Kristensen, Vessela, additional, Anton-Culver, Hoda, additional, Goodfellow, Paul, additional, Tapper, William J., additional, Rafiq, Sajjad, additional, Gerty, Susan M., additional, Durcan, Lorraine, additional, Konstantopoulou, Irene, additional, Fostira, Florentia, additional, Vratimos, Athanassios, additional, Apostolou, Paraskevi, additional, Konstanta, Irene, additional, Kotoula, Vassiliki, additional, Lakis, Sotiris, additional, Dimopoulos, Meletios A., additional, Skarlos, Dimosthenis, additional, Pectasides, Dimitrios, additional, Fountzilas, George, additional, Beckmann, Matthias W., additional, Hein, Alexander, additional, Ruebner, Matthias, additional, Ekici, Arif B., additional, Hartmann, Arndt, additional, Schulz-Wendtland, Ruediger, additional, Renner, Stefan P., additional, Janni, Wolfgang, additional, Rack, Brigitte, additional, Scholz, Christoph, additional, Neugebauer, Julia, additional, Andergassen, Ulrich, additional, Lux, Michael P., additional, Haeberle, Lothar, additional, Clarke, Christine, additional, Pathmanathan, Nirmala, additional, Rudolph, Anja, additional, Flesch-Janys, Dieter, additional, Nickels, Stefan, additional, Olson, Janet E., additional, Ingle, James N., additional, Olswold, Curtis, additional, Slettedahl, Seth, additional, Eckel-Passow, Jeanette E., additional, Anderson, S.Keith, additional, Visscher, Daniel W., additional, Cafourek, Victoria L., additional, Sicotte, Hugues, additional, Prodduturi, Naresh, additional, Weiderpass, Elisabete, additional, Bernstein, Leslie, additional, Ziogas, Argyrios, additional, Ivanovich, Jennifer, additional, Giles, Graham G., additional, Baglietto, Laura, additional, Southey, Melissa, additional, Kosma, Veli-Matti, additional, Fischer, Hans-Peter, additional, Reed, Malcom W.R., additional, Cross, Simon S., additional, Deming-Halverson, Sandra, additional, Shrubsole, Martha, additional, Cai, Qiuyin, additional, Shu, Xiao-Ou, additional, Daly, Mary, additional, Weaver, JoEllen, additional, Ross, Eric, additional, Klemp, Jennifer, additional, Sharma, Priyanka, additional, Torres, Diana, additional, Rüdiger, Thomas, additional, Wölfing, Heidrun, additional, Ulmer, Hans-Ulrich, additional, Försti, Asta, additional, Khoury, Thaer, additional, Kumar, Shicha, additional, Pilarski, Robert, additional, Shapiro, Charles L., additional, Greco, Dario, additional, Heikkilä, Päivi, additional, Aittomäki, Kristiina, additional, Blomqvist, Carl, additional, Irwanto, Astrid, additional, Liu, Jianjun, additional, Pankratz, Vernon Shane, additional, Wang, Xianshu, additional, Severi, Gianluca, additional, Mannermaa, Arto, additional, Easton, Douglas, additional, Hall, Per, additional, Brauch, Hiltrud, additional, Cox, Angela, additional, Zheng, Wei, additional, Godwin, Andrew K., additional, Hamann, Ute, additional, Ambrosone, Christine, additional, Toland, Amanda Ewart, additional, Nevanlinna, Heli, additional, Vachon, Celine M., additional, and Couch, Fergus J., additional

Published
2013
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217. Promoter Hypomethylation of EpCAM-Regulated Bone Morphogenetic Protein Gene Family in Recurrent Endometrial Cancer

Author

Hsu, Ya-Ting, primary, Gu, Fei, additional, Huang, Yi-Wen, additional, Liu, Joseph, additional, Ruan, Jianhua, additional, Huang, Rui-Lan, additional, Wang, Chiou-Miin, additional, Chen, Chun-Liang, additional, Jadhav, Rohit R., additional, Lai, Hung-Cheng, additional, Mutch, David G., additional, Goodfellow, Paul J., additional, Thompson, Ian M., additional, Kirma, Nameer B., additional, and Huang, Tim Hui-Ming, additional

Published
2013
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219. Gynecologic Cancer InterGroup (GCIG) Endometrial Cancer Clinical Trials Planning Meeting

Author

Creutzberg, Carien L., primary, Kitchener, Henry C., additional, Birrer, Michael J., additional, Landoni, Fabio, additional, Lu, Karen H., additional, Powell, Melanie, additional, Aghajanian, Carol, additional, Edmondson, Richard, additional, Goodfellow, Paul J., additional, Quinn, Michael, additional, Salvesen, Helga B., additional, and Thomas, Gillian, additional

Published
2013
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223. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes

Author

Pollock, Pamela, Gartside, Michael, Dejeza, L., Powell, Matthew, Mallon, M., Davies, H., Mohammadi, Moosa, Futreal, P., Stratton, Michael, Trent, Jeffrey, Goodfellow, Paul, Pollock, Pamela, Gartside, Michael, Dejeza, L., Powell, Matthew, Mallon, M., Davies, H., Mohammadi, Moosa, Futreal, P., Stratton, Michael, Trent, Jeffrey, and Goodfellow, Paul

Abstract

Endometrial carcinoma is the most common gynecological malignancy in the United States. Although most women present with early disease confined to the uterus, the majority of persistent or recurrent tumors are refractory to current chemotherapies. We have identified a total of 11 different FGFR2 mutations in 3/10 (30%) of endometrial cell lines and 19/187 (10%) of primary uterine tumors. Mutations were seen primarily in tumors of the endometrioid histologic subtype (18/115 cases investigated, 16%). The majority of the somatic mutations identified were identical to germline activating mutations in FGFR2 and FGFR3 that cause Apert Syndrome, Beare-Stevenson Syndrome, hypochondroplasia, achondroplasia and SADDAN syndrome. The two most common somatic mutations identified were S252W (in eight tumors) and N550K (in five samples). Four novel mutations were identified, three of which are also likely to result in receptor gain-of-function. Extensive functional analyses have already been performed on many of these mutations, demonstrating they result in receptor activation through a variety of mechanisms. The discovery of activating FGFR2 mutations in endometrial carcinoma raises the possibility of employing anti-FGFR molecularly targeted therapies in patients with advanced or recurrent endometrial carcinoma.

Published
2007

224. Role of the ARF Tumor Suppressor in Prostate Cancer

Author

WASHINGTON UNIV ST LOUIS MO, Maggi ,Jr., Leonard B., Weber, Jason D., Chinnaiyan, Arul M., Goodfellow, Paul J., Kibel, Adam S., Milbrandt, Jeffrey D., Humphrey, Peter A., WASHINGTON UNIV ST LOUIS MO, Maggi ,Jr., Leonard B., Weber, Jason D., Chinnaiyan, Arul M., Goodfellow, Paul J., Kibel, Adam S., Milbrandt, Jeffrey D., and Humphrey, Peter A.

Abstract

The nucleolar tumor suppressor ARF plays an important role in the tumor surveillance of human cancer. We have found that ARF expression is absent from highly proliferative prostate adenocarcinomas and this correlates with the increased expression of the p53-independent target of NPM. We have created and characterized an immortalized ARF-null prostate epithelial cell line. In addition we have shown that alterations in NPM levels can have dramatic affects on the androgen-dependent cancer cell line, LNCaP, but not PC3 cells which are androgen-independent. We have previously shown that ARF inhibits NPM's nuclear export and cell cycle progression in a p53-indpendent manner. Under this proposal we have defined the mechanism by which this happens. Specifically, ARF binds to NPM preventing its ability to carry both small and large ribosomal subunits out of the nucleus. This results in a decrease in protein synthesis and growth rates contributing to ARF's tumor suppressor function. We are beginning to further define the role of ARF in prostate cell growth. These studies are opening the door to new therapeutic targets in prostate cancer; namely protein synthesis., The original document contains color images.

Published
2006

226. Reply to Vance et al

Author

Yee, Woon-Chee, Elliott, Jeffrey L., Kwon, Jennifer M., and Goodfellow, Paul

Subjects
Letters to the Editor
Published
1996

227. Low allele frequency of MLH1 D132H in American colorectal and endometrial cancer patients.

Author

Shin, Brian Y, Shin, Brian Y, Chen, Huiping, Rozek, Laura S, Paxton, Leslie, Peel, David J, Anton-Culver, Hoda, Rennert, Gad, Mutch, David G, Goodfellow, Paul J, Gruber, Stephen B, Lipkin, Steve M, Shin, Brian Y, Shin, Brian Y, Chen, Huiping, Rozek, Laura S, Paxton, Leslie, Peel, David J, Anton-Culver, Hoda, Rennert, Gad, Mutch, David G, Goodfellow, Paul J, Gruber, Stephen B, and Lipkin, Steve M

Abstract

PurposeHereditary nonpolyposis colon cancer is caused by mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2. Classic MLH1 mutations cause an approximately 20-fold increase in colorectal cancer susceptibility. Recently, we identified a hypomorphic allele, MLH1 D132H , which impairs, but does not completely eliminate the function of MLH1 in tumor suppression. MLH1 D132H confers an approximately fivefold increase in colorectal cancer susceptibility and was first described in a cohort of Israeli colorectal cancer patients, with an estimated allele frequency of 1.3 percent. Because MLH1 D132H has only recently been described, the ethnic distribution of this risk allele is not well understood. This study was undertaken to determine both the frequencies of this risk allele in ethnic groups outside of Israel and whether families harboring this mutation have susceptibility to extracolonic cancers in the hereditary nonpolyposis colon cancer spectrum.MethodsWe genotyped two independent cohorts: 629 population-based colorectal cancer patients ascertained from clinics in Orange, Imperial, and San Diego Counties, and 515 endometrial cancer patients ascertained from gynecologic oncology clinics in the Midwestern United States.ResultsMLH1 D132H was not detected in either study cohort, which together totaled more than 1,100 American colorectal cancer and endometrial cancer patients.ConclusionsThe MLH1 D132H risk variant has significantly lower allele frequency in American compared with Israeli cancer patients and, alone, is unlikely to explain significant amounts of American sporadic colorectal cancer or uterine cancer susceptibility. Genetic testing for the MLH1 D132H allele exclusively is therefore unlikely to be cost effective for genetic risk assessment in American population-based and clinic-based colorectal cancer and endometrial cancer patients.

Published
2005

229. BRCA1,TP53, andCHEK2germline mutations in uterine serous carcinoma

Author

Pennington, Kathryn P., primary, Walsh, Tom, additional, Lee, Ming, additional, Pennil, Christopher, additional, Novetsky, Akiva P., additional, Agnew, Kathy J., additional, Thornton, Anne, additional, Garcia, Rochelle, additional, Mutch, David, additional, King, Mary-Claire, additional, Goodfellow, Paul, additional, and Swisher, Elizabeth M., additional

Published
2012
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230. Use of mutation profiles to refine the classification of endometrial carcinomas

Author

McConechy, Melissa K, primary, Ding, Jiarui, additional, Cheang, Maggie CU, additional, Wiegand, Kimberly C, additional, Senz, Janine, additional, Tone, Alicia A, additional, Yang, Winnie, additional, Prentice, Leah M, additional, Tse, Kane, additional, Zeng, Thomas, additional, McDonald, Helen, additional, Schmidt, Amy P, additional, Mutch, David G, additional, McAlpine, Jessica N, additional, Hirst, Martin, additional, Shah, Sohrab P, additional, Lee, Cheng-Han, additional, Goodfellow, Paul J, additional, Gilks, C Blake, additional, and Huntsman, David G, additional

Published
2012
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231. ColoSeq Provides Comprehensive Lynch and Polyposis Syndrome Mutational Analysis Using Massively Parallel Sequencing

Author

Pritchard, Colin C., primary, Smith, Christina, additional, Salipante, Stephen J., additional, Lee, Ming K., additional, Thornton, Anne M., additional, Nord, Alex S., additional, Gulden, Cassandra, additional, Kupfer, Sonia S., additional, Swisher, Elizabeth M., additional, Bennett, Robin L., additional, Novetsky, Akiva P., additional, Jarvik, Gail P., additional, Olopade, Olufunmilayo I., additional, Goodfellow, Paul J., additional, King, Mary-Claire, additional, Tait, Jonathan F., additional, and Walsh, Tom, additional

Published
2012
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238. Uterine Serous Carcinoma: Increased Familial Risk for Lynch-Associated Malignancies

Author

Dewdney, Summer B., primary, Kizer, Nora T., additional, Andaya, Abegail A., additional, Babb, Sheri A., additional, Luo, Jingqin, additional, Mutch, David G., additional, Schmidt, Amy P., additional, Brinton, Louise A., additional, Broaddus, Russell R., additional, Ramirez, Nilsa C., additional, Huettner, Phyllis C., additional, McMeekin, Donald Scott, additional, Darcy, Kathleen, additional, Ali, Shamshad, additional, Judson, Patricia L., additional, Mannel, Robert S., additional, Lele, Shashikant B., additional, O'Malley, David M., additional, and Goodfellow, Paul J., additional

Published
2012
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243. Complete characterization of the microRNAome in a patient with acute myeloid leukemia

Author

Ramsingh, Giridharan, primary, Koboldt, Daniel C., additional, Trissal, Maria, additional, Chiappinelli, Katherine B., additional, Wylie, Todd, additional, Koul, Sunita, additional, Chang, Li-Wei, additional, Nagarajan, Rakesh, additional, Fehniger, Todd A., additional, Goodfellow, Paul, additional, Magrini, Vincent, additional, Wilson, Richard K., additional, Ding, Li, additional, Ley, Timothy J., additional, Mardis, Elaine R., additional, and Link, Daniel C., additional

Published
2010
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246. Abstract B12: Complete characterization of the “microRNAome” of a human acute myeloid leukemia

Author

Ramsingh, Giridharan, primary, Koboldt, Daniel C., additional, Trissal, Maria, additional, Chiappinelli, Katherine B., additional, Wylie, Todd, additional, Koul, Sunita, additional, Chang, Li-Wei, additional, Nagarajan, Rakesh, additional, Fehniger, Todd A., additional, Goodfellow, Paul, additional, Magrini, Vincent, additional, Wilson, Richard K., additional, Ding, Li, additional, Ley, Timothy J., additional, Mardis, Elaine R., additional, and Link, Daniel C., additional

Published
2010
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249. Genome remodelling in a basal-like breast cancer metastasis and xenograft

Author

Ding, Li, primary, Ellis, Matthew J., additional, Li, Shunqiang, additional, Larson, David E., additional, Chen, Ken, additional, Wallis, John W., additional, Harris, Christopher C., additional, McLellan, Michael D., additional, Fulton, Robert S., additional, Fulton, Lucinda L., additional, Abbott, Rachel M., additional, Hoog, Jeremy, additional, Dooling, David J., additional, Koboldt, Daniel C., additional, Schmidt, Heather, additional, Kalicki, Joelle, additional, Zhang, Qunyuan, additional, Chen, Lei, additional, Lin, Ling, additional, Wendl, Michael C., additional, McMichael, Joshua F., additional, Magrini, Vincent J., additional, Cook, Lisa, additional, McGrath, Sean D., additional, Vickery, Tammi L., additional, Appelbaum, Elizabeth, additional, DeSchryver, Katherine, additional, Davies, Sherri, additional, Guintoli, Therese, additional, Lin, Li, additional, Crowder, Robert, additional, Tao, Yu, additional, Snider, Jacqueline E., additional, Smith, Scott M., additional, Dukes, Adam F., additional, Sanderson, Gabriel E., additional, Pohl, Craig S., additional, Delehaunty, Kim D., additional, Fronick, Catrina C., additional, Pape, Kimberley A., additional, Reed, Jerry S., additional, Robinson, Jody S., additional, Hodges, Jennifer S., additional, Schierding, William, additional, Dees, Nathan D., additional, Shen, Dong, additional, Locke, Devin P., additional, Wiechert, Madeline E., additional, Eldred, James M., additional, Peck, Josh B., additional, Oberkfell, Benjamin J., additional, Lolofie, Justin T., additional, Du, Feiyu, additional, Hawkins, Amy E., additional, O’Laughlin, Michelle D., additional, Bernard, Kelly E., additional, Cunningham, Mark, additional, Elliott, Glendoria, additional, Mason, Mark D., additional, Thompson Jr, Dominic M., additional, Ivanovich, Jennifer L., additional, Goodfellow, Paul J., additional, Perou, Charles M., additional, Weinstock, George M., additional, Aft, Rebecca, additional, Watson, Mark, additional, Ley, Timothy J., additional, Wilson, Richard K., additional, and Mardis, Elaine R., additional

Published
2010
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