BRIEF COMMUNICATION |
Mutations in BRAF and KRAS Characterize the Development of Low-Grade Ovarian Serous Carcinoma
Gad Singer,
Robert Oldt, III,
Yoram Cohen,
Brant G. Wang,
David Sidransky,
Robert J. Kurman,
Ie-Ming Shih
Affiliations of authors: G. Singer, R. Oldt III, B. G. Wang (Department of Pathology), Y. Cohen, D. Sidransky (Head and Neck Cancer Research Division), R. J. Kurman, I.-M. Shih (Departments of Pathology and Gynecology and Obstetrics), The Johns Hopkins University School of Medicine, Baltimore, MD.
Correspondence to: Ie-Ming Shih, M.D., Ph.D., Department of Pathology, The Johns Hopkins University School of Medicine, 418 N. Bond St., B-315, Baltimore, MD 21231 (e-mail: ishih{at}jhmi.edu).
ABSTRACT
Activating mutations in KRAS and in one of its downstream mediators, BRAF, have been identified in a variety of human cancers. To determine the role of mutations in BRAF and KRAS in ovarian carcinoma, we analyzed both genes for three common mutations (at codon 599 of BRAF and codons 12 and 13 of KRAS). Mutations in either codon 599 of BRAF or codons 12 and 13 of KRAS occurred in 15 of 22 (68%) invasive micropapillary serous carcinomas (MPSCs; low-grade tumors) and in 31 of 51 (61%) serous borderline tumors (precursor lesions to invasive MPSCs). None of the tumors contained a mutation in both BRAF and KRAS. In contrast, none of the 72 conventional aggressive high-grade serous carcinomas analyzed contained the BRAF codon 599 mutation or either of the two KRAS mutations. The apparent restriction of these BRAF and KRAS mutations to low-grade serous ovarian carcinoma and its precursors suggests that low-grade and high-grade ovarian serous carcinomas develop through independent pathways.
The kinase cascade involving RAS, RAF, mitogen/extracellular signal-regulated kinase (MEK), extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase (MAPK) mediates the transmission of growth signals into the nucleus (1). One of the three RAF members, BRAF, has been recently reported to be activated by somatic mutation in many human cancers, with mutations in BRAF occurring at a particularly high rate in cutaneous melanoma and papillary carcinoma of the thyroid (2,3). All known BRAF mutations occur within the kinase domain, with a single substitution of A for the T at nucleotide position 1796 (1796T/A) accounting for at least 80% of BRAF mutations (2,4,5). This mutation converts a valine residue at amino acid position 599 to a glutamic acid (V599E); the mutant protein has elevated kinase activity and is able to transform NIH3T3 cells independent of RAS function (2). Similarly, activating mutations in codons 12 and 13 of KRAS occur frequently in carcinomas and result in constitutive activation of KRAS that contributes to tumorigenesis (1).
To investigate the role of BRAF and KRAS mutations in ovarian carcinoma, we analyzed different types of ovarian carcinomas for three common mutations in these genesthe BRAF mutation at codon 599 and the KRAS mutations at codons 12 and 13. Ovarian carcinoma, one of the major cancer types and the most lethal gynecologic malignancy, comprises a heterogeneous group of tumors with distinctly different histologic types, molecular features, and clinical behavior (68). The most common type of ovarian cancer is serous carcinoma which, in our previous study (9), we further divided into high-grade conventional serous carcinoma and a low-grade tumor, invasive micropapillary serous carcinoma (MPSC). All serous carcinomas are believed to develop from ovarian surface epithelium or inclusion cysts (10). In contrast to conventional serous carcinoma, for which morphologically recognizable precursor lesions have not been identified, invasive MPSC develops in a stepwise fashion from a noninvasive group of neoplasms termed serous borderline tumors. Based on our extensive morphologic and molecular studies, serous borderline tumors include a benign precursor (atypical proliferative serous tumor) and a noninvasive carcinoma designated noninvasive MPSC (9,1114). The non-serous types of ovarian carcinoma include endometrioid carcinoma and clear-cell carcinoma, which are less common than serous carcinoma and appear to develop from endometriosis (15).
Formalin-fixed, paraffin-embedded tissue samples of 182 ovarian tumor tissues were obtained from the surgical pathology file of the Johns Hopkins Hospital. Genomic DNA was purified from the microdissected tumor component, as previously described (9). The ovarian tumors (51 serous borderline tumors, 21 invasive MPSCs, 69 conventional serous carcinomas, 21 endometrioid carcinomas, and 20 clear-cell carcinomas), three conventional serous carcinoma cell lines (SKOV-3, OVCAR-3 and HTB-75), and one primary culture of an invasive MPSC were analyzed for the codon 599 mutation in BRAF and the codon 12 and 13 mutations in KRAS. Five normal ovarian tissues and 10 serous cystadenomas were also included in the mutation analysis. The KRAS mutation status of some of the tumor samples (22 of the serous borderline tumors, 15 of the invasive MPSCs, and 20 of the conventional serous carcinomas) has already been reported (9). Waiver of patients consent was approved by the local Institutional Review Board. All the cases were reviewed by three gynecologic pathologists (R. J. Kurman, G. Singer, and I.-M. Shih), who concurred with the diagnoses before microdissection.
Analysis of the 1796T/A status in BRAF was performed using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) technique (3). For this method, the BRAF PCR product of exon 15, which contains nucleotide position 1796, was digested with TspR1 (New England Biolabs, Inc., Beverly, MA) at 65 °C for 3 hours. The PCR products were electrophoresed on a 10% polyacrylamide gel and were also sequenced to validate the RFLP results. As shown in Fig. 1
, BRAF mutations were found in 33% of the invasive MPSCs (including the primary culture of an invasive MPSC) and in 28% of their precursor lesions, serous borderline tumors. The BRAF mutation was not detected in the histologically normal-appearing cyst epithelium adjacent to a borderline tumor that contained the BRAF mutation (data not shown), indicating that BRAF mutations occur during progression of serous borderline tumors.

View larger version (11K):
[in this window]
[in a new window]
|
Fig. 1. Mutations of BRAF and KRAS in ovarian carcinomas. Mutational analysis of codon 599 of BRAF (gray bars) and codons 12 and 13 of KRAS (black bars) was performed in several types of ovarian neoplasm, including serous borderline tumors (SBT), invasive micropapillary serous carcinomas (iMPSC, low-grade carcinomas), conventional high-grade serous carcinomas (CSC), endometrioid carcinomas (EM), and clear-cell carcinomas (CC). The number of tumors of each type that were analyzed is indicated. None of the tumors showed both BRAF and KRAS mutations. iMPSCs and their precursor lesions, serous borderline tumors, demonstrate the highest frequency of mutations in BRAF and KRAS.
|
|
KRAS mutational status at codon 12 or 13 was analyzed either by digital PCR (9,16,17) or direct sequencing. In combination with our previous results (9), KRAS mutations were found in 35% of invasive MPSCs and 33% of serous borderline tumors. None of the tumors contained a mutation in both BRAF and KRAS; thus, considering the two genes together, a mutation in one of them was found in 68% of invasive MPSCs and in 61% of serous borderline tumors. There was no correlation between the presence of the BRAF or KRAS mutations and patient age, clinical stage, tumor size, and mismatch repair deficiency status (two-sided Spearmans rank-order correlation) (data not shown). In contrast to invasive MPSCs and their precursors, all 69 specimens of clinically aggressive conventional serous carcinomas, as well as three well-established cell lines, contained wild-type BRAF and KRAS sequences at the analyzed sites in both genes. As controls, all five normal ovarian tissues and all 10 serous cystadenomas analyzed contained wild-type BRAF and KRAS.
The mutually exclusive nature of BRAF at codon 599 and KRAS mutations at codons 12 and 13 in ovarian carcinoma is consistent with a similar finding in melanoma and colorectal carcinoma and lends strong support for the view that BRAF and KRAS mutations have equivalent effects on tumorigenesis (2,5). Although the possibility that other members of the RAF family or downstream targets of RAF are mutated in conventional high-grade serous carcinomas must be investigated, it would appear that the development of high-grade conventional serous carcinomas involves a pathway distinct from the RAS signaling pathway. For example, mutations in TP53 are common in high-grade ovarian serous carcinomas (18).
We also analyzed codon 599 of BRAF and codons 12 and 13 of KRAS in less common, non-serous types of ovarian cancer, including endometrioid and clear-cell carcinomas. We did not include mucinous carcinomas involving the ovary because we had previously found that most such carcinomas are metastases from other primary sites (19,20). We detected BRAF mutations in 24% of endometrioid carcinomas but in none of the clear-cell carcinomas. No other gene has such a high mutation rate in ovarian endometrioid carcinomas, except PTEN, which is mutated in 20% of ovarian endometrioid carcinomas (21). Only one clear-cell carcinoma and one endometrioid carcinoma had a KRAS mutation. This finding is similar to that in a previous report, which also analyzed KRAS in a small number of cases (22). Again, among the tumors we analyzed, the BRAF mutation and KRAS mutations were never both present in the same tumor.
Our results demonstrate that the mutational status of BRAF and KRAS is distinctly different among various histologic types of ovarian serous carcinoma, occurring most frequently in invasive MPSC, a clinically indolent neoplasm, and its precursors, serous borderline tumors. Thus, it appears that different histologic types of ovarian carcinomas have distinctive molecular pathways in tumor development. In addition, our analysis has extended a previous finding of BRAF mutations in four of 10 "low malignant potential" and one of 25 "malignant epithelial" ovarian neoplasms (2). Our results also have potential implications for the treatment of invasive MPSC; such lesions, unlike conventional high-grade serous carcinomas, generally do not respond well to conventional chemotherapy. Conceivably, blocking KRASBRAF signaling may provide more effective therapy (2).
NOTES
G. Singer, R. Oldt III, and Y. Cohen contributed equally to this work.
Supported by research grant OC010017 from the Department of Defense; Public Health Service grant CA97527 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; and the Swiss National Science Foundation (GS).
REFERENCES
1 Peyssonnaux C, Eychene A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 2001;93:5362.[CrossRef][Medline]
2 Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:94954.[CrossRef][Medline]
3 Cohen Y, Zhao XM, Mambo E, Guo Z, Wu G, Trink B, et al. BRAF mutation occurs in a majority of papillary thyroid carcinoma. J Natl Cancer Inst. In press 2003.
4 Pollock PM, Meltzer PS. A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell 2002;2:57.[CrossRef][Medline]
5 Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002;418:934.[CrossRef][Medline]
6 Schwartz DR, Kardia SL, Shedden KA, Kuick R, Michailidis G, Taylor JM, et al. Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res 2002;62:47229.[Abstract/Free Full Text]
7 Hough CD, Sherman-Baust CA, Pizer ES, Montz FJ, Im DD, Rosenshein NB, et al. Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res 2000;60:62817.[Abstract/Free Full Text]
8 Sugiyama T, Kamura T, Kigawa J, Terakawa N, Kikuchi Y, Kita T, et al. Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer 2000;88:25849.[CrossRef][Medline]
9 Singer G, Kurman RJ, Chang HW, Cho SK, Shih IM. Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol 2002;160:12238.[Abstract/Free Full Text]
10 Auersperg N, Edelson MI, Mok SC, Johnson SW, Hamilton TC. The biology of ovarian cancer. Semin Oncol 1998;25:281304.[Medline]
11 Seidman JD, Kurman RJ. Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators. Hum Pathol 2000;31:53957.[Medline]
12 Seidman JD, Kurman RJ. Subclassification of serous borderline tumors of the ovary into benign and malignant types. A clinicopathologic study of 65 advanced stage cases. Am J Surg Pathol 1996;20:133145.[CrossRef][Medline]
13 Burks RT, Sherman ME, Kurman RJ. Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors. Am J Surg Pathol 1996;20:131930.[CrossRef][Medline]
14 Sehdev AE, Sehdev PS, Kurman RJ. Noninvasive and invasive miropapillary serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases. Am J Surg Pathol. In press 2003.
15 Stern RC, Dash R, Bentley RC, Snyder MJ, Haney AF, Robboy SJ. Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol 2001;20:1339.[Medline]
16 Vogelstein B, Kinzler KW. Digital PCR. Proc Natl Acad Sci U S A 1999;96:923641.[Abstract/Free Full Text]
17 Shih IM, Yan H, Speyrer D, Shmookler BM, Sugarbaker PH, Ronnett BM. Molecular genetic analysis of appendiceal mucinous adenomas in identical twins, including one with pseudomyxoma peritonei. Am J Surg Pathol 2001;25:10959.[CrossRef][Medline]
18 Milner BJ, Allan LA, Eccles DM, Kitchener HC, Leonard RC, Kelly KF, et al. p53 mutation is a common genetic event in ovarian carcinoma. Cancer Res 1993;53:212832.[Abstract]
19 Riopel MA, Ronnett BM, Kurman RJ. Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas. Am J Surg Pathol 1999;23:61735.[CrossRef][Medline]
20 Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol. In press 2003.
21 Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y, Kubo T, et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 2000;60:70526.[Abstract/Free Full Text]
22 Hough CD, Cho KR, Zonderman AB, Schwartz DR, Morin PJ. Coordinately up-regulated genes in ovarian cancer. Cancer Res 2001;61:386976.[Abstract/Free Full Text]
Manuscript received September 23, 2002;
revised January 7, 2003;
accepted January 15, 2003.
This article has been cited by other articles in HighWire Press-hosted journals:
-
McPhillips, F., Mullen, P., MacLeod, K. G., Sewell, J. M., Monia, B. P., Cameron, D. A., Smyth, J. F., Langdon, S. P.
(2006). Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells. Carcinogenesis
27: 729-739
[Abstract]
[Full Text]
-
Kim, I.-J., Kang, H. C., Jang, S.-G., Kim, K., Ahn, S.-A, Yoon, H.-J., Yoon, S. N., Park, J.-G.
(2006). Oligonucleotide microarray analysis of distinct gene expression patterns in colorectal cancer tissues harboring BRAF and K-ras mutations. Carcinogenesis
27: 392-404
[Abstract]
[Full Text]
-
Sapio, M. R., Posca, D., Troncone, G., Pettinato, G., Palombini, L., Rossi, G., Fenzi, G., Vitale, M.
(2006). Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA). eur j endocrinol
154: 341-348
[Abstract]
[Full Text]
-
Yen, M. J., Hsu, C.-Y., Mao, T.-L., Wu, T-C., Roden, R., Wang, T.-L., Shih, I.-M.
(2006). Diffuse Mesothelin Expression Correlates with Prolonged Patient Survival in Ovarian Serous Carcinoma. Clin Cancer Res
12: 827-831
[Abstract]
[Full Text]
-
Mercer, K., Giblett, S., Green, S., Lloyd, D., DaRocha Dias, S., Plumb, M., Marais, R., Pritchard, C.
(2005). Expression of Endogenous Oncogenic V600EB-raf Induces Proliferation and Developmental Defects in Mice and Transformation of Primary Fibroblasts. Cancer Res
65: 11493-11500
[Abstract]
[Full Text]
-
Bonome, T., Lee, J.-Y., Park, D.-C., Radonovich, M., Pise-Masison, C., Brady, J., Gardner, G. J., Hao, K., Wong, W. H., Barrett, J. C., Lu, K. H., Sood, A. K., Gershenson, D. M., Mok, S. C., Birrer, M. J.
(2005). Expression Profiling of Serous Low Malignant Potential, Low-Grade, and High-Grade Tumors of the Ovary. Cancer Res
65: 10602-10612
[Abstract]
[Full Text]
-
Shih, I.-M., Kurman, R. J.
(2005). Molecular Pathogenesis of Ovarian Borderline Tumors: New Insights and Old Challenges. Clin Cancer Res
11: 7273-7279
[Abstract]
[Full Text]
-
Rahmani, M., Davis, E. M., Bauer, C., Dent, P., Grant, S.
(2005). Apoptosis Induced by the Kinase Inhibitor BAY 43-9006 in Human Leukemia Cells Involves Down-regulation of Mcl-1 through Inhibition of Translation. J. Biol. Chem.
280: 35217-35227
[Abstract]
[Full Text]
-
Sieben, N. L.G., Oosting, J., Flanagan, A. M., Prat, J., Roemen, G. M.J.M., Kolkman-Uljee, S. M., van Eijk, R., Cornelisse, C. J., Fleuren, G. J., van Engeland, M.
(2005). Differential Gene Expression in Ovarian Tumors Reveals Dusp 4 and Serpina 5 As Key Regulators for Benign Behavior of Serous Borderline Tumors. J Clin Oncol
23: 7257-7264
[Abstract]
[Full Text]
-
Beeram, M., Patnaik, A., Rowinsky, E. K.
(2005). Raf: A Strategic Target for Therapeutic Development Against Cancer. J Clin Oncol
23: 6771-6790
[Abstract]
[Full Text]
-
Marquez, R. T., Baggerly, K. A., Patterson, A. P., Liu, J., Broaddus, R., Frumovitz, M., Atkinson, E. N., Smith, D. I., Hartmann, L., Fishman, D., Berchuck, A., Whitaker, R., Gershenson, D. M., Mills, G. B., Bast, R. C. Jr., Lu, K. H.
(2005). Patterns of Gene Expression in Different Histotypes of Epithelial Ovarian Cancer Correlate with Those in Normal Fallopian Tube, Endometrium, and Colon. Clin Cancer Res
11: 6116-6126
[Abstract]
[Full Text]
-
Kobel, M., Pohl, G., Schmitt, W. D., Hauptmann, S., Wang, T.-L., Shih, I.-M.
(2005). Activation of Mitogen-Activated Protein Kinase Is Required for Migration and Invasion of Placental Site Trophoblastic Tumor. Am J Pathol
167: 879-885
[Abstract]
[Full Text]
-
Adjei, A. A., Hidalgo, M.
(2005). Intracellular Signal Transduction Pathway Proteins As Targets for Cancer Therapy. J Clin Oncol
23: 5386-5403
[Abstract]
[Full Text]
-
Xing, M
(2005). BRAF mutation in thyroid cancer. Endocr Relat Cancer
12: 245-262
[Abstract]
[Full Text]
-
Pohl, G., Ho, C.-L., Kurman, R. J., Bristow, R., Wang, T.-L., Shih, I.-M.
(2005). Inactivation of the Mitogen-Activated Protein Kinase Pathway as a Potential Target-Based Therapy in Ovarian Serous Tumors with KRAS or BRAF Mutations. Cancer Res
65: 1994-2000
[Abstract]
[Full Text]
-
Chen, Y.-C., Pohl, G., Wang, T.-L., Morin, P. J., Risberg, B., Kristensen, G. B., Yu, A., Davidson, B., Shih, I.-M.
(2005). Apolipoprotein E Is Required for Cell Proliferation and Survival in Ovarian Cancer. Cancer Res
65: 331-337
[Abstract]
[Full Text]
-
Penson, R. T., Sahani, D., Bell, D. A.
(2004). Case 37-2004 - A 52-Year-Old Woman with Postmenopausal Bleeding and a Cystic Ovarian Mass. NEJM
351: 2531-2538
[Full Text]
-
Hsu, C.-Y., Bristow, R., Cha, M. S., Wang, B. G., Ho, C.-L., Kurman, R. J., Wang, T.-L., Shih, I.-M.
(2004). Characterization of Active Mitogen-Activated Protein Kinase in Ovarian Serous Carcinomas. Clin Cancer Res
10: 6432-6436
[Abstract]
[Full Text]
-
Ho, C.-L., Kurman, R. J., Dehari, R., Wang, T.-L., Shih, I.-M.
(2004). Mutations of BRAF and KRAS Precede the Development of Ovarian Serous Borderline Tumors. Cancer Res
64: 6915-6918
[Abstract]
[Full Text]
-
Steinmetz, R., Wagoner, H. A., Zeng, P., Hammond, J. R., Hannon, T. S., Meyers, J. L., Pescovitz, O. H.
(2004). Mechanisms Regulating the Constitutive Activation of the Extracellular Signal-Regulated Kinase (ERK) Signaling Pathway in Ovarian Cancer and the Effect of Ribonucleic Acid Interference for ERK1/2 on Cancer Cell Proliferation. Mol Endocrinol
18: 2570-2582
[Abstract]
[Full Text]
-
Lima, J., Trovisco, V., Soares, P., Maximo, V., Magalhaes, J., Salvatore, G., Santoro, M., Bogdanova, T., Tronko, M., Abrosimov, A., Jeremiah, S., Thomas, G., Williams, D., Sobrinho-Simoes, M.
(2004). BRAF Mutations Are Not a Major Event in Post-Chernobyl Childhood Thyroid Carcinomas. J Clin Endocrinol Metab
89: 4267-4271
[Abstract]
[Full Text]
-
VDOVICHENKO, K K, MARKOVA, S I, BELOKHVOSTOV, A S
(2004). Mutant Form of BRAF Gene in Blood Plasma of Cancer Patients. Annals NYAS Online
1022: 228-231
[Full Text]
-
Kambara, T, Simms, L A, Whitehall, V L J, Spring, K J, Wynter, C V A, Walsh, M D, Barker, M A, Arnold, S, McGivern, A, Matsubara, N, Tanaka, N, Higuchi, T, Young, J, Jass, J R, Leggett, B A
(2004). BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut
53: 1137-1144
[Abstract]
[Full Text]
-
Young, T. W., Mei, F. C., Yang, G., Thompson-Lanza, J. A., Liu, J., Cheng, X.
(2004). Activation of Antioxidant Pathways in Ras-Mediated Oncogenic Transformation of Human Surface Ovarian Epithelial Cells Revealed by Functional Proteomics and Mass Spectrometry. Cancer Res
64: 4577-4584
[Abstract]
[Full Text]
-
Cohen, Y., Rosenbaum, E., Begum, S., Goldenberg, D., Esche, C., Lavie, O., Sidransky, D., Westra, W. H.
(2004). Exon 15 BRAF Mutations Are Uncommon in Melanomas Arising in Nonsun-Exposed Sites. Clin Cancer Res
10: 3444-3447
[Abstract]
[Full Text]
-
Ikenoue, T., Hikiba, Y., Kanai, F., Aragaki, J., Tanaka, Y., Imamura, J., Imamura, T., Ohta, M., Ijichi, H., Tateishi, K., Kawakami, T., Matsumura, M., Kawabe, T., Omata, M.
(2004). Different Effects of Point Mutations within the B-Raf Glycine-Rich Loop in Colorectal Tumors on Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase and Nuclear Factor {kappa}B Pathway and Cellular Transformation. Cancer Res
64: 3428-3435
[Abstract]
[Full Text]
-
Puxeddu, E., Moretti, S., Elisei, R., Romei, C., Pascucci, R., Martinelli, M., Marino, C., Avenia, N., Rossi, E. D., Fadda, G., Cavaliere, A., Ribacchi, R., Falorni, A., Pontecorvi, A., Pacini, F., Pinchera, A., Santeusanio, F.
(2004). BRAFV599E Mutation Is the Leading Genetic Event in Adult Sporadic Papillary Thyroid Carcinomas. J Clin Endocrinol Metab
89: 2414-2420
[Abstract]
[Full Text]
-
Shih, I.-M., Kurman, R. J.
(2004). Ovarian Tumorigenesis: A Proposed Model Based on Morphological and Molecular Genetic Analysis. Am J Pathol
164: 1511-1518
[Abstract]
[Full Text]
-
Edwards, R H, Ward, M R, Wu, H, Medina, C A, Brose, M S, Volpe, P, Nussen-Lee, S, Haupt, H M, Martin, A M, Herlyn, M, Lessin, S R, Weber, B L
(2004). Absence of BRAF mutations in UV-protected mucosal melanomas. J. Med. Genet.
41: 270-272
[Abstract]
[Full Text]
-
Hogg, R., Friedlander, M.
(2004). Biology of Epithelial Ovarian Cancer: Implications for Screening Women at High Genetic Risk. J Clin Oncol
22: 1315-1327
[Abstract]
[Full Text]
-
Xing, M., Cohen, Y., Mambo, E., Tallini, G., Udelsman, R., Ladenson, P. W., Sidransky, D.
(2004). Early Occurrence of RASSF1A Hypermethylation and Its Mutual Exclusion with BRAF Mutation in Thyroid Tumorigenesis. Cancer Res
64: 1664-1668
[Abstract]
[Full Text]
-
Liu, J., Yang, G., Thompson-Lanza, J. A., Glassman, A., Hayes, K., Patterson, A., Marquez, R. T., Auersperg, N., Yu, Y., Hahn, W. C., Mills, G. B., Bast, R. C. Jr.
(2004). A Genetically Defined Model for Human Ovarian Cancer. Cancer Res
64: 1655-1663
[Abstract]
[Full Text]
-
Ulku, A. S., Schafer, R., Der, C. J.
(2003). Essential Role of Raf in Ras Transformation and Deregulation of Matrix Metalloproteinase Expression in Ovarian Epithelial Cells. Mol Cancer Res
1: 1077-1088
[Abstract]
[Full Text]
-
Omholt, K., Platz, A., Kanter, L., Ringborg, U., Hansson, J.
(2003). NRAS and BRAF Mutations Arise Early during Melanoma Pathogenesis and Are Preserved throughout Tumor Progression. Clin Cancer Res
9: 6483-6488
[Abstract]
[Full Text]
-
Ikenoue, T., Hikiba, Y., Kanai, F., Tanaka, Y., Imamura, J., Imamura, T., Ohta, M., Ijichi, H., Tateishi, K., Kawakami, T., Aragaki, J., Matsumura, M., Kawabe, T., Omata, M.
(2003). Functional Analysis of Mutations within the Kinase Activation Segment of B-Raf in Human Colorectal Tumors. Cancer Res
63: 8132-8137
[Abstract]
[Full Text]
-
Cruz, F. III, Rubin, B. P., Wilson, D., Town, A., Schroeder, A., Haley, A., Bainbridge, T., Heinrich, M. C., Corless, C. L.
(2003). Absence of BRAF and NRAS Mutations in Uveal Melanoma. Cancer Res
63: 5761-5766
[Abstract]
[Full Text]
-
Calhoun, E. S., Jones, J. B., Ashfaq, R., Adsay, V., Baker, S. J., Valentine, V., Hempen, P. M., Hilgers, W., Yeo, C. J., Hruban, R. H., Kern, S. E.
(2003). BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) Mutations in Distinct Subsets of Pancreatic Cancer: Potential Therapeutic Targets. Am J Pathol
163: 1255-1260
[Abstract]
[Full Text]
-
Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., Hemminki, K.
(2003). BRAF Mutations in Metastatic Melanoma: A Possible Association with Clinical Outcome. Clin Cancer Res
9: 3362-3368
[Abstract]
[Full Text]
-
Wang, B. G., Huang, H.-Y., Chen, Y.-C., Bristow, R. E., Kassauei, K., Cheng, C.-C., Roden, R., Sokoll, L. J., Chan, D. W., Shih, I.-M.
(2003). Increased Plasma DNA Integrity in Cancer Patients. Cancer Res
63: 3966-3968
[Abstract]
[Full Text]
 |
|