18 results on '"Goodfellow, Paul J."'
Search Results
2. DICER1 Mutations in Familial Pleuropulmonary Blastoma
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Hill, D. Ashley, Ivanovich, Jennifer, Priest, John R., Gurnett, Christina A., Dehner, Louis P., Desruisseau, David, Jarzembowski, Jason A., Wikenheiser-Brokamp, Kathryn A., Suarez, Brian K., Whelan, Alison J., Williams, Gretchen, Bracamontes, Dawn, Messinger, Yoav, and Goodfellow, Paul J.
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- 2009
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3. Single Missense Mutation in the Tyrosine Kinase Catalytic Domain of the RET Protooncogene is Associated with Multiple Endocrine Neoplasia Type 2B
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Carlson, Katrin M., Dou, Shenshen, Chi, David, Scavarda, Nancy, Toshima, Koji, Jackson, Charles E., Wells,, Samuel A., Goodfellow, Paul J., and Donis-Keller, Helen
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- 1994
4. Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative.
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Pearlman, Rachel, Frankel, Wendy L., Swanson, Benjamin J., Jones, Dan, Zhao, Weiqiang, Yilmaz, Ahmet, Miller, Kristin, Bacher, Jason, Bigley, Christopher, Nelsen, Lori, Goodfellow, Paul J., Goldberg, Richard M., Paskett, Electra, Shields, Peter G., Freudenheim, Jo L., Stanich, Peter P., Lattimer, Ilene, Arnold, Mark, Prior, Thomas W., and Haut, Mitchell
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HEREDITARY nonpolyposis colorectal cancer ,COLORECTAL cancer ,CANCER prevention ,HEREDITARY cancer syndromes ,GENETIC mutation ,DRUG target ,FECAL occult blood tests - Abstract
PURPOSE: Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement. METHODS: Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016. Universal Tumor screening (UTS) for mismatch repair (MMR) deficiency was performed for all, and pathogenic germline variants (PGVs) were identified using multigene panel testing (MGPT) in those who met at least one inclusion criterion: MMR deficiency, diagnosed < 50 years, multiple primary tumors (CRC or endometrial cancer), or with a first-degree relative with CRC or endometrial cancer. RESULTS: Five hundred twenty-five patients (15.9%) had MMR deficiency. Two hundred thirty-four of 3,310 (7.1%; 16% of the 1,462 who received MGPT) had 248 PGVs in cancer susceptibility genes. One hundred forty-two (4.3%) had a PGV in an MMR gene, and 101 (3.1%) had a PGV in a non-MMR gene. Ten with Lynch syndrome (LS) also had a non-MMR PGV and were included in both groups. Two (0.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (76 of 86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene PGVs (7.3% of total PGVs identified). Had UTS been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) would have been missed, including 6.3% (9 of 144) of those with LS. These results have treatment implications as 5.3% (175 of 3,310) had PGVs in genes with therapeutic targets. CONCLUSION: UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. At a minimum, 7.1% of individuals with CRC have a PGV and pan-cancer MGPT should be considered for all patients with CRC. [ABSTRACT FROM AUTHOR]
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- 2021
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5. MAX Mutations in Endometrial Cancer: Clinicopathologic Associations and Recurrent MAX p.His28Arg Functional Characterization.
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Walker, Christopher J., Rush, Craig M., Dama, Paola, O'Hern, Matthew J., Cosgrove, Casey M., Gillespie, Jessica L., Zingarelli, Roman A., Smith, Blair, Stein, Maggie E., Mutch, David G., Shakya, Reena, Chia-Wen Chang, Selvendiran, Karuppaiyah, Song, Jonathan W., Cohn, David E., Goodfellow, Paul J., and Chang, Chia-Wen
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ENDOMETRIAL cancer ,CANCER genetics ,GENETIC mutation ,TRANSCRIPTION factors ,IMMUNOPRECIPITATION ,GENETICS ,AMINO acids ,ANIMAL populations ,ANIMALS ,ARGININE ,CANCER invasiveness ,CELL culture ,DISEASE susceptibility ,EPITHELIAL cells ,GENETIC techniques ,MICE ,PROTEINS ,RESEARCH funding ,ENDOMETRIAL tumors ,HISTIDINE ,PATHOLOGIC neovascularization - Abstract
Background: Genomic studies have revealed that multiple genes are mutated at varying frequency in endometrial cancer (EC); however, the relevance of many of these mutations is poorly understood. An EC-specific recurrent mutation in the MAX transcription factor p.His28Arg was recently discovered. We sought to assess the functional consequences of this hotspot mutation and determine its association with cancer-relevant phenotypes.Methods: MAX was sequenced in 509 endometrioid ECs, and associations between mutation status and clinicopathologic features were assessed. EC cell lines stably expressing MAXH28R were established and used for functional experiments. DNA binding was examined using electrophoretic mobility shift assays and chromatin immunoprecipitation. Transcriptional profiling was performed with microarrays. Murine flank (six to 11 mice per group) and intraperitoneal tumor models were used for in vivo studies. Vascularity of xenografts was assessed by MECA-32 immunohistochemistry. The paracrine pro-angiogenic nature of MAXH28R-expressing EC cells was tested using microfluidic HUVEC sprouting assays and VEGFA enzyme-linked immunosorbent assays. All statistical tests were two-sided.Results: Twenty-two of 509 tumors harbored mutations in MAX, including 12 tumors with the p.His28Arg mutation. Patients with a MAX mutation had statistically significantly reduced recurrence-free survival (hazard ratio = 4.00, 95% confidence interval = 1.15 to 13.91, P = .03). MAXH28R increased affinity for canonical E-box sequences, and MAXH28R-expressing EC cells dramatically altered transcriptional profiles. MAXH28R-derived xenografts statistically significantly increased vascular area compared with MAXWT and empty vector tumors (P = .003 and P = .008, respectively). MAXH28R-expressing EC cells secreted nearly double the levels of VEGFA compared with MAXWT cells (P = .03, .005, and .005 at 24, 48, and 72 hours, respectively), and conditioned media from MAXH28R cells increased sprouting when applied to HUVECs.Conclusion: These data highlight the importance of MAX mutations in EC and point to increased vascularity as one mechanism contributing to clinical aggressiveness of EC. [ABSTRACT FROM AUTHOR]- Published
- 2018
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6. Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing.
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Le Gallo, Matthieu, Rudd, Meghan L., Urick, Mary Ellen, Hansen, Nancy F., Zhang, Suiyuan, Lozy, Fred, Sgroi, Dennis C., Vidal Bel, August, Matias‐Guiu, Xavier, Broaddus, Russell R., Lu, Karen H., Levine, Douglas A., Mutch, David G., Goodfellow, Paul J., Salvesen, Helga B., Mullikin, James C., Bell, Daphne W., NISC Comparative Sequencing Program, and Matias-Guiu, Xavier
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SOMATIC mutation ,RENAL cell carcinoma ,ENDOMETRIAL tumors ,ENDOMETRIAL cancer ,EXOMES ,NUCLEOTIDE sequencing ,GENOTYPES ,NUCLEOTIDES ,ADENOCARCINOMA ,COMPARATIVE studies ,DEGENERATION (Pathology) ,DOCUMENTATION ,GENES ,GENOMES ,IMMUNOBLOTTING ,LONGITUDINAL method ,RESEARCH methodology ,MEDICAL cooperation ,GENETIC mutation ,PROGNOSIS ,PROTEINS ,RESEARCH ,RESEARCH funding ,TRANSFERASES ,EVALUATION research ,SEQUENCE analysis - Abstract
Background: The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome-wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases.Methods: We conducted whole exome sequencing of paired tumor-normal DNAs from 16 cases of CCEC (12 CCECs and the CCEC components of 4 mixed histology tumors). Twenty-two genes-of-interest were Sanger-sequenced from another 47 cases of CCEC. Microsatellite instability (MSI) and microsatellite stability (MSS) were determined by genotyping 5 mononucleotide repeats.Results: Two tumor exomes had relatively high mutational loads and MSI. The other 14 tumor exomes were MSS and had 236 validated nonsynonymous or splice junction somatic mutations among 222 protein-encoding genes. Among the 63 cases of CCEC in this study, we identified frequent somatic mutations in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%), and TAF1 (9.5%), as well as MSI (11.3%). Five of 8 mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase domain and included 2 recurrently mutated residues. Based on patterns of MSI and mutations in 7 genes, CCEC subsets molecularly resembled serous endometrial cancer (SEC) or endometrioid endometrial cancer (EEC).Conclusion: Our findings demonstrate molecular similarities between CCEC and SEC and EEC and implicate TAF1 as a novel candidate CCEC driver gene. Cancer 2017;123:3261-8. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]- Published
- 2017
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7. Identification of endometrial cancer methylation features using combined methylation analysis methods.
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Trimarchi, Michael P., Yan, Pearlly, Groden, Joanna, Bundschuh, Ralf, and Goodfellow, Paul J.
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DNA methylation ,ENDOMETRIAL cancer ,CANCER genetics ,PHENOTYPES ,GENETIC mutation - Abstract
Background: DNA methylation is a stable epigenetic mark that is frequently altered in tumors. DNA methylation features are attractive biomarkers for disease states given the stability of DNA methylation in living cells and in biologic specimens typically available for analysis. Widespread accumulation of methylation in regulatory elements in some cancers (specifically the CpG island methylator phenotype, CIMP) can play an important role in tumorigenesis. High resolution assessment of CIMP for the entire genome, however, remains cost prohibitive and requires quantities of DNA not available for many tissue samples of interest. Genome-wide scans of methylation have been undertaken for large numbers of tumors, and higher resolution analyses for a limited number of cancer specimens. Methods for analyzing such large datasets and integrating findings from different studies continue to evolve. An approach for comparison of findings from a genome-wide assessment of the methylated component of tumor DNA and more widely applied methylation scans was developed. Methods: Methylomes for 76 primary endometrial cancer and 12 normal endometrial samples were generated using methylated fragment capture and second generation sequencing, MethylCap-seq. Publically available Infinium HumanMethylation 450 data from The Cancer Genome Atlas (TCGA) were compared to MethylCap-seq data. Results: Analysis of methylation in promoter CpG islands (CGIs) identified a subset of tumors with a methylator phenotype. We used a two-stage approach to develop a 13-region methylation signature associated with a “hypermethylator state.” High level methylation for the 13-region methylation signatures was associated with mismatch repair deficiency, high mutation rate, and low somatic copy number alteration in the TCGA test set. In addition, the signature devised showed good agreement with previously described methylation clusters devised by TCGA. Conclusion: We identified a methylation signature for a “hypermethylator phenotype” in endometrial cancer and developed methods that may prove useful for identifying extreme methylation phenotypes in other cancers. [ABSTRACT FROM AUTHOR]
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- 2017
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8. Patterns of CTCF and ZFHX3 Mutation and Associated Outcomes in Endometrial Cancer.
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Walker, Christopher J., Miranda, Mario A., O'Hern, Matthew J., McElroy, Joseph P., Coombes, Kevin R., Bundschuh, Ralf, Cohn, David E., Mutch, David G., and Goodfellow, Paul J.
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ENDOMETRIAL cancer ,CANCER genetics ,CANCER genes ,DNA copy number variations ,BAYESIAN analysis ,DEGENERATION (Pathology) ,GENETIC polymorphisms ,GENETICS ,GENETIC mutation ,PROBABILITY theory ,PROGNOSIS ,PROTEINS ,RESEARCH funding ,ENDOMETRIAL tumors ,ODDS ratio - Abstract
Background: The genetic events responsible for tumor aggressiveness in endometrioid endometrial cancer (EEC) remain poorly understood. The chromosome 16q22 tumor suppressor genes CTCF and ZFHX3 are both frequently mutated in EEC, but their respective roles in outcome have not been determined.Methods: Targeted deep sequencing of CTCF and ZFHX3 was performed for 542 EEC samples. Copy number loss (CNL) was determined using microsatellite typing of paired tumor and normal DNA and a novel Bayesian method based on variant allele frequencies of germline polymorphisms. All statistical tests were two-sided.Results: Mutation rates for CTCF and ZFHX3 were 25.3% and 20.4%, respectively, and there was a statistically significant excess of tumors with mutation in both genes (P = .003). CNL rates were 17.4% for CTCF and 17.2% for ZFHX3, and the majority of CNLs included both CTCF and ZFHX3. Mutations were more frequent in tumors with microsatellite instability, and CNLs were more common in microsatellite-stable tumors (P < .001). Patients with ZFHX3 mutation and/or CNL had higher-grade tumors (P = .001), were older (P < .001), and tended to have more frequent lymphovascular space invasion (P = .07). These patients had reduced recurrence-free and overall survival (RFS: hazard ratio [HR] = 2.35, 95% confidence interval [CI] = 1.38 to 3.99, P = .007; OS: HR = 1.51, 95% CI = 1.11 to 2.07, P = .04).Conclusions: Our data demonstrate there is strong selection for inactivation of both CTCF and ZFHX3 in EEC. Mutation occurs at high frequency in microsatellite-unstable tumors, whereas CNLs are common in microsatellite-stable cancers. Loss of these two tumor suppressors is a frequent event in endometrial tumorigenesis, and ZFHX3 defects are associated with poor outcome. [ABSTRACT FROM AUTHOR]- Published
- 2015
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9. Polymerase ɛ ( POLE) mutations in endometrial cancer: Clinical outcomes and implications for Lynch syndrome testing.
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Billingsley, Caroline C., Cohn, David E., Mutch, David G., Stephens, Julie A., Suarez, Adrian A., and Goodfellow, Paul J.
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POLYMERASE genetics ,GENETIC mutation ,ENDOMETRIAL cancer ,DIAGNOSIS of hereditary nonpolyposis colorectal cancer ,PROGRESSION-free survival ,MICROSATELLITE repeats ,POLYMERASE chain reaction ,GENETICS - Abstract
BACKGROUND DNA polymerase ɛ ( POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with a markedly increased somatic mutational burden. POLE-mutant tumors were described as a molecular subtype with improved progression-free survival by The Cancer Genome Atlas. In this study, the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations were investigated in patients with endometrioid EC. METHODS Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 544 tumors. Correlations between demographic, survival, clinicopathologic, and molecular features were investigated. Statistical tests were 2-sided. RESULTS Thirty POLE mutations (5.6%) were identified. Mutations were associated with younger age (<60 years; P=.001). POLE mutations were detected in tumors with microsatellite stability (MSS) and microsatellite instability (MSI) at similar frequencies (5.9% and 5.2%, respectively) and were most common in tumors with MSI that lacked mutL homolog 1 ( MLH1) methylation ( P<.001). There was no association with progression-free survival (hazard ratio, 0.22; P=.127). CONCLUSIONS The discovery that mutations occur with equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking MLH1 methylation has implications for Lynch syndrome screening and mutation testing. The current results indicate that POLE mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of an association between POLE mutation and progression-free survival indicates that POLE mutation status is unlikely to be a clinically useful prognostic marker. However, POLE testing in MSI ECs could serve as a marker of somatic disease origin. Therefore, POLE tumor testing may be a valuable exclusionary criterion for Lynch syndrome gene testing. Cancer 2015;121:386-394. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]
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- 2015
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10. A Drosophila Model of Multiple Endocrine Neoplasia Type 2.
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Read, Renee D., Goodfellow, Paul J., Mardis, Elaine R., Novak, Nancy, Armstrong, Jon R., and Cagan, Ross L.
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DROSOPHILA , *PROTEIN-tyrosine kinases , *CELLULAR signal transduction , *CELL proliferation , *GENE expression , *GENETIC mutation - Abstract
Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that RetMEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which RetMEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for RetMEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRetMMEN2 isoforms targeted to the developing retina led to aberrant cell proliferation inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRetMEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRetMEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRetMEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis. [ABSTRACT FROM AUTHOR]
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- 2005
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11. RAS/RAF mutation and defective DNA mismatch repair in endometrial cancers.
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Mutch, David G., Powell, Matthew A., Mallon, Mary Ann, and Goodfellow, Paul J.
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ENDOMETRIAL cancer ,GENETIC mutation ,CANCER ,GENES ,COLON cancer ,GENETICS - Abstract
Objective: Defective DNA mismatch repair is a common genetic abnormality in both colon cancers and endometrial cancers. Cancers with defective DNA mismatch repair have the so-called mutator phenotype and accumulate genetic errors at an increased rate. An early mutational target in cells with defect DNA mismatch repair may be the RAS/RAF pathway. Colon cancers often have KRAS2 mutations and, if not KRAS2 mutations, may have BRAF mutations. This study investigated the spectrum and frequency of mutations in BRAF and KRAS2 in endometrial carcinomas on the basis of mismatch repair status.Study Design: Four hundred forty-one patients with endometrial cancer were staged properly and graded and evaluated for mismatch repair status. These patients were then stratified to groups by the degree of microsatellite instability that was observed in their tumors. One hundred forty-six of the selected tumors were then evaluated for KRAS2 and BRAF mutations on the basis of their microsatellite instability.Results: One hundred forty-six endometrioid endometrial cancers were evaluated for KRAS2 and BRAF mutations. Thirty-five cancers (24%) had activating KRAS2 mutations, but only a single BRAF mutation was identified in an microsatellite instability-positive cancer. Twenty-four of 81 microsatellite instability high cancers (29.6%) in which the MLH1 repair gene was methylated had KRAS2 mutations. When compared with the other groups, this finding approached statistical significance (P=.06). KRAS2 mutation status was associated with increasing age at diagnosis (P=.02).Conclusion: Despite many similarities between colon and endometrial cancers, the mechanism of the development of endometrial cancers appears to be different from colon cancers in that BRAF is not affected by a mismatch repair problem, because only KRAS2 mutations were seen. In addition, increasing age appears to lead to an increased likelihood that such a mutation will occur. [ABSTRACT FROM AUTHOR]- Published
- 2004
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12. Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC.
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Kitamura, Yutaka, Goodfellow, Paul J., Shimizu, Kazuo, Nagahama, Mistuji, Ito, Kunihiko, Kitagawa, Wataru, Akasu, Hiroki, Takami, Hiroshi, Tanaka, Shigeo, and Wells, Jr., Samuel A.
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ONCOGENES , *GENETIC mutation , *THYROID cancer - Abstract
Germ-like and somatic mutations in the RET proto-oncogene are associated with inherited and sporadic medullary thyroid carcinoma (MTC). The majority of patients with multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) carry germ-line point mutations that result in the substitution of one of five cysteine residues. We investigated exons 10, 11, 13, 14 and 16 of the RET proto-oncogene in 33 unrelated Japanese patients with MTC. Eleven of the 33 cases (33%) were found to have germ-line mutations. Three previously unreported mutations in exon 10 and 11 were identified: one in codon 620, (TGC→GGC), resulting in a cysteine to glycine substitution, and two in codon 630, (TGC→TCC) and (TGC→TAC), resulting in cysteine to serine and cysteine to tyrosine changes, respectively. The new mutations were present in the germ-line DNA of four unrelated patients for whom a family history of MTC had not been documented. Because the new RET alleles described here involve cysteine residues in a region of protein previously associated with FMTC and MEN2A, it is very likely that they represent mutations that predispose to the development of MTC. [ABSTRACT FROM AUTHOR]
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- 1997
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13. Estrogen receptor-alpha as a predictive biomarker in endometrioid endometrial cancer.
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Backes, Floor J., Walker, Christopher J., Goodfellow, Paul J., Hade, Erinn M., Agarwal, Garima, Mutch, David, Cohn, David E., and Suarez, Adrian A.
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ESTROGEN receptors , *TREATMENT of endometrial cancer , *BIOMARKERS , *GENE expression , *GENETIC mutation , *HEALTH outcome assessment - Abstract
Background We sought to validate the prognostic significance of estrogen receptor alpha (ERα) expression and to investigate the relationship between ESR1 mutation status and outcomes in a large cohort of patients with endometrial cancer. We also investigated the predictive value of ERα for lymph node involvement in a large surgically staged cohort. Methods A tumor microarray (TMA) was constructed including only pure endometrioid adenocarcinomas, stained with ER50 monoclonal antibody, and assessed using digital image analysis. For mutation analysis, somatic DNA was extracted and sequenced for ESR1 gene hotspot regions. Differences in patient and tumor characteristics, recurrence and survival between ERα positive and negative, mutated and wild-type tumors were evaluated. Results Sixty (18.6%) tumors were negative for ERα. Absence of ERα was significantly associated with stage and grade, but not with disease-free or overall survival. ERα was a strong predictor of lymph node involvement (RR: 2.37, 95% CI: 1.12–5.02). Nineteen of 1034 tumors (1.8%) had an ESR1 hotspot mutation; twelve in hotspot 537Y, four in 538D and three in 536 L. Patients with an ESR1 mutation had a significantly lower BMI, but were comparable in age, stage and grade, and progression-free survival. Conclusion Patients with ERα negative endometrioid endometrial cancer are more often diagnosed with higher grade and advanced stage disease. Lymph node involvement is more common with lack of ERα expression, and may be able to help triage which patients should undergo lymphadenectomy. Mutations in ESR1 might explain why some low risk women with low BMI develop endometrial cancer. [ABSTRACT FROM AUTHOR]
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- 2016
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14. FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.
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Jeske, Yvette W., Ali, Shamshad, Byron, Sara A, Gao, Feng, Mannel, Robert S, Ghebre, Rahel G, DiSilvestro, Paul A, Lele, Shashikant B, Pearl, Michael L, Schmidt, Amy P, Lankes, Heather A, Ramirez, Nilsa C, Rasty, Golnar, Powell, Matthew, Goodfellow, Paul J, and Pollock, Pamela M
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TREATMENT of endometrial cancer , *FIBROBLAST growth factor receptors , *GENETIC mutation , *PROGRESSION-free survival , *CLINICAL trials - Abstract
Purpose Activating FGFR2 mutations have been identified in ~ 10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort. Methods Tumors were collected as part of the GOG 210 clinical trial “Molecular Staging of Endometrial Cancer” where samples underwent rigorous pathological review and had more than three years of detailed clinical follow-up. DNA was extracted and four exons encompassing the FGFR2 mutation hotspots were amplified and sequenced. Results Mutations were identified in 144 of the 973 endometrioid ECs, of which 125 were classified as known activating mutations and were included in the statistical analyses. Consistent with FGFR2 having an association with more aggressive disease, FGFR2 mutations were more common in patients initially diagnosed with stage III/IV EC (29/170;17%) versus stage I/II EC (96/803; 12%; p = 0.07, Chi-square test). Additionally, incidence of progression (progressed, recurred or died from disease) was significantly more prevalent (32/125, 26%) among patients with FGFR2 mutation versus wild type (120/848, 14%; p < 0.001, Chi-square test). Using Cox regression analysis adjusting for known prognostic factors, patients with FGFR2 mutation had significantly ( p < 0.025) shorter progression-free survival (PFS; HR 1.903; 95% CI 1.177–3.076) and endometrial cancer specific survival (ECS; HR 2.013; 95% CI 1.096–3.696). Conclusion In summary, our findings suggest that clinical trials testing the efficacy of FGFR inhibitors in the adjuvant setting to prevent recurrence and death are warranted. [ABSTRACT FROM AUTHOR]
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- 2017
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15. Frequent mutations in the RPL22 gene and its clinical and functional implications
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Novetsky, Akiva P., Zighelboim, Israel, Thompson, Dominic M., Powell, Matthew A., Mutch, David G., and Goodfellow, Paul J.
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RIBOSOMAL proteins , *GENETIC mutation , *CANCER genetics , *CLINICAL pathology , *ENDOMETRIAL cancer , *ANTISENSE DNA , *GENETIC code , *MICROSATELLITE repeats - Abstract
Abstract: Objective: To determine the frequency and spectrum of mutations in RPL22 a gene identified by The Cancer Genome Atlas (TCGA) as mutated in endometrioid endometrial cancer, and determine the relationship between RPL22 defects and clinicopathologic features. Methods: Direct sequencing of the entire coding region of the RPL22 cDNA and exons 2/4 was performed in tumors with/without microsatellite instability (MSI). RPL22 expression was assessed by immunofluorescence microscopy in the KLE, RL952 and AN3CA cell lines, wildtype, heterozygous and homozygous mutants, respectively. Relationships between RPL22 mutation and clinicopathological features were assessed using Chi-squared analysis and Student''s t test. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of recurrence. Results: A single nucleotide deletion in an A8 coding repeat was identified in exon 2 of the RPL22 gene in 116/226 (52%) of MSI-high tumors. No mutations were identified in MSI-stable tumors. Only 2% of the tumors expressed a homozygous A deletion. RPL22 mutation was not associated with stage, grade, race and lymphovascular space invasion. Women whose tumors harbored RPL22 mutations were significantly older (67 vs. 63years, p =0.005). There was no difference in PFS between patients with the wildtype and mutant genotypes. Conclusions: RPL22 is frequently mutated in MSI-high endometrioid endometrial cancers. The A8 mutation identified was not reported in the whole exome sequences analyzed by the TCGA. The demonstration of frequent mutation in RPL22 may point to a limitation of the exome capture and next generation sequencing analysis methods for some mononucleotide string mutations. Functional assessment of the RPL22 knockdown may be warranted. [Copyright &y& Elsevier]
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- 2013
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16. FGFR2 mutations are rare across histologic subtypes of ovarian cancer
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Byron, Sara A., Gartside, Michael G., Wellens, Candice L., Goodfellow, Paul J., Birrer, Michael J., Campbell, Ian G., and Pollock, Pamela M.
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GENETIC mutation , *HISTOLOGY , *OVARIAN cancer , *GENITAL cancer , *FIBROBLAST growth factors , *MOLECULAR genetics , *CARCINOGENESIS , *CANCER-related mortality , *CANCER treatment - Abstract
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. [Copyright &y& Elsevier]
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- 2010
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17. Penetrance and Expressivity of MSH6 Germline Mutations in Seven Kindreds Not Ascertained by Family History.
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M. Buttin, Barbara, Powell, Matthew A., Mutch, David G., Babb, Sheri A., Huettner, Phyllis C., Edmonston, Tina Bocker, Herzog, Thomas J., Rader, Janet S., Gibb, Randall K., Whelan, Alison J., and Goodfellow, Paul J.
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COLON cancer , *GENETIC mutation , *DNA , *TUMORS , *IMMUNOHISTOCHEMISTRY techniques ,CANCER susceptibility - Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by inherited mutations in DNA mismatch-repair genes, most commonly MLH1 or MSH2. The role MSH6 plays in inherited cancer susceptibility is less well defined. The aim of this study was to investigate the penetrance and expressivity of MSH6 mutations in kindreds ascertained through endometrial cancer probands unselected for family history. Detailed pedigrees were constructed for six MSH6 mutation carriers. All reported cancers and precancers were confirmed, and tissues were obtained when available. Tumors were analyzed for microsatellite instability (MSI) and for expression of MSH2, MLH1, and MSH6. MSH6 mutation status was determined for 59 family members. Of these 59 individuals, 19 (32%) had confirmed cancers and precancers. There was an excess of mutation carriers among the 19 affected family members (11 [58%] of 19) compared with those among the 40 unaffecteds (8 [20%] of 40, P = .0065, odds ratio = 5.5, 95% CI = 1.66-18.19). In four of the seven tumors analyzed from mutation carriers other than the probands, MSI and/or MMR protein expression was consistent with the involvement of MSH6. Overall estimated penetrance of the MHS6 mutations was 5 7.7%. Of the tumors in mutation carriers, 78% were part of the extended HNPCC spectrum. This study demonstrates that MSH6 germline mutations are, indeed, associated with increased cancer risk and that the penetrance of mutations may be higher than appreciated elsewhere. A combination of MSI and immunohistochemistry analyses may be helpful in screening for MSH6 mutation carriers. [ABSTRACT FROM AUTHOR]
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- 2004
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18. A Familial Syndrome of Pancreatic Cancer and Melanoma with a Mutation in the CDKN2 Tumor-Suppressor Gene.
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Whelan, Alison J., Bartsch, Detlef, and Goodfellow, Paul J.
- Subjects
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DISEASE susceptibility , *CANCER genetics , *GENETIC polymorphisms , *PANCREATIC cancer genetics , *MELANOMA , *FAMILIAL diseases , *TUMORS , *GENETIC mutation , *PROTEIN kinases , *PROTEIN kinase CK2 , *CYCLIN-dependent kinases , *GENETICS - Abstract
This article presents the results of a study on the genetic predisposition towards cancer in a family. This study looked at a family where more than one type of cancer occurred in members at a young age and it sought to find a connection between an increased risk of pancreatic cancer, melanomas and other types of tumors. The study provides evidence linking the predisposition to cancer in this family to an inherited mutation in the cyclin-dependent kinease inhibitor 2 (CDKN2) tumor-suppressor gene. In the case of this family it appears that the disruption of the function of CDKN2 contributed to pancreatic tumorigenesis.
- Published
- 1995
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