Search

Your search keyword '"Neklason D."' showing total 11 results
Start Over Author "Neklason D."
11 results on '"Neklason D."'

3. Determining the requirements for cooperative DNA binding by Swi5p and Pho2p (Grf10p/Bas2p) at the HO promoter.

Author

Brazas, R M, Bhoite, L T, Murphy, M D, Yu, Y, Chen, Y, Neklason, D W, and Stillman, D J

Abstract

SW15 encodes a zinc finger DNA binding protein required for the transcription of the Saccharomyces cerevisiae HO gene, and PHO2 encodes a homeodomain DNA binding protein. In vitro biochemical studies using purified Swi5p and Pho2p proteins have demonstrated that Swi5p and Pho2p bind cooperatively to the HO promoter. In this report we investigate the regions of the Swi5p and Pho2p proteins required for cooperative DNA binding. The analysis of each protein gives a similar result: the zinc finger or homeodomain DNA binding domains are each sufficient for in vitro DNA binding, but additional regions of each protein are required for cooperative DNA binding. In vitro and in vivo experiments were conducted with promoters with altered spacing between the Pho2p and Swi5p binding sites. Mutations that increased the distance between the two binding sites had minimal effects on either in vitro cooperative DNA binding or in vivo upstream activating sequence activity. These observations suggest that the interaction domains of Swi5p and Pho2p are flexible and can tolerate an increase in distance between the two binding sites. The mechanism of the cooperative DNA binding by Swi5p and Pho2p is discussed.

Published
1995

4. Role of multidrug resistance P-glycoproteins in cholesterol esterification.

Author

Debry, P, Nash, E A, Neklason, D W, and Metherall, J E

Abstract

Cholesterol esterification, catalyzed by acyl-CoA:cholesterol acyltransferase (ACAT), plays a central role in cellular cholesterol homeostasis and in physiologic processes that lead to coronary heart disease. Although ACAT resides in the endoplasmic reticulum (ER), the cholesterol substrate for esterification originates in the plasma membrane and must be transported to the ER for esterification. Progesterone inhibits esterification, possibly by blocking the transport of cholesterol to the ER. Recent studies suggest that progesterone acts by inhibiting the activity of one or more of the multidrug-resistant (MDR) P-glycoproteins. In the current manuscript, we demonstrate that progesterone's ability to inhibit esterification is not mediated through the progesterone receptor. We evaluate a series of steroid hormones and find a strong correlation between a steroid hormone's hydrophobicity and its ability to inhibit both cholesterol esterification and MDR-catalyzed drug efflux. We also find that cholesterol esterification is inhibited by nonsteroidal MDR inhibitors, and that this inhibition specifically affects the esterification of cholesterol derived from the plasma membrane. MDR inhibitors also inhibit cholesterol esterification in a wide range of cultured human cell lines. These observations suggest that MDR activity normally functions in a general process of intracellular cholesterol transport.

Published
1997

5. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

Author

Seçil Aksoy, Michael O. Woods, Heinric Williams, Bruno Buecher, Finlay A. Macrae, Lotte N. Krogh, Jay Qiu, Wan K.W. Juhari, Jan T. Lowery, Anne-Marie Gerdes, Magnus von Knebel Doeberitz, Luigi Ricciardiello, Karsten Schulmann, Jose Luis Soto, Kristina Lagerstedt-Robinson, Kiwamu Akagi, Raj Ramesar, Uffe Birk Jensen, Angel Alonso, Robert Hüneburg, Olivier Caron, Michel Longy, Jan Lubinski, Kate Green, Annabel Goodwin, D. Gareth Evans, Julie Wods, Leigha Senter, Matthew F. Kalady, Mark Clendenning, Barbara A. Leggett, Ravindran Ankathil, Swati G. Patel, Julian Barwell, Katherine M. Tucker, Grant Lee, Pascaline Berthet, Dawn M. Nixon, Sonia S. Kupfer, Naohiro Tomita, Susan Parry, Trinidad Caldés, Robert W. Haile, Edenir Inêz Palmero, Karin Alvarez, Cassandra B. Nichols, Mark A. Jenkins, N. Jewel Samadder, Loic LeMarchand, John Burn, Francisco Lopez, Rodney J. Scott, Pierre Laurent-Puig, Julie Arnold, Christina Therkildsen, Hans K. Schackert, Pilar Garre, Reinhard Buettner, Adriana Della Valle, Patricia Esperon, Wolff Schmiegel, Karl Heinimann, Inge Bernstein, Matthias Kloor, Nicoline Hoogerbrugge, Rui Manuel Reis, Fränzel J.B. Van Duijnhoven, Christoph Engel, Mohd Nizam Zahary, Sylviane Olschwang, Sapna Syngal, Valérie Bonadona, Nicholas Pachter, Matilde Navarro, Albert de la Chapelle, Beate Betz, Jukka-Pekka Mecklin, Catherine Noguès, Elena M. Stoffel, Toni T. Seppälä, Chrystelle Colas, Anneke Lucassen, Allan D. Spigelman, Youenn Drouet, Elisa J. Cops, Uri Ladabaum, Steve Thibodeau, Jeffrey N. Weitzel, Fiona Lalloo, Patrick J. Morrison, Maurizio Genuardi, Kohji Tanakaya, Patrick M. Lynch, Frederik J. Hes, William D. Foulkes, Carmen Guillén-Ponce, Jenny von Salomé, Emilia Rogoża-Janiszewska, Andrew Latchford, John L. Hopper, Carrie Snyder, Verónica Barca-Tierno, Gabriela Möslein, Lauren M. Gima, Melissa C. Southey, Paul A. James, Marion Dhooge, Claudia Perne, Steven Gallinger, Heather Hampel, Amanda B. Spurdle, Ingrid Winship, Emmanuelle Fourme, Rish K. Pai, Daniela Turchetti, Marta Pineda, Jürgen Weitz, James Hill, Daniel D. Buchanan, Carlos A. Vaccaro, Noralane M. Lindor, Rachel Pearlman, Pål Møller, Christian P. Strassburg, Jane C. Figueiredo, Aída Falcón de Vargas, Silke Zachariae, Karolin Bucksch, Joanne Ngeow, Silke Redler, Henrik Okkels, Maija R.J. Kohonen-Corish, Hans F. A. Vasen, Verena Steinke-Lange, Roselyne Guimbaud, Deepak Vangala, Isabelle Coupier, Nils Rahner, Berrin Tunca, Sanne W. Bajwa-ten Broeke, Niels de Wind, Sophie Lejeune, José Gaston Guillem, Karin Wadt, Polly A. Newcomb, Elke Holinski-Feder, Florencia Neffa, Rodrigo Santa Cruz Guindalini, Paul E. Wise, Julian R. Sampson, Graham Casey, Lene Juel Rasmussen, Rolf H. Sijmons, Tadeusz Dębniak, Ann-Sofie Backman, Joji Utsunomiya, Melyssa Aronson, Aung Ko Win, Yves-Jean Bignon, Judy W. C. Ho, Robyn L. Ward, Mev Dominguez-Valentin, Karolina Malińska, Elizabeth E. Half, John-Paul Plazzer, Marjolijn J. L. Ligtenberg, Rachel Austin, Nicola K. Poplawski, Marcia Cruz-Correa, Nagahide Matsubara, Charlotte Kvist Lautrup, Thomas Hansen, Tatsuro Yamaguchi, Thomas John, David J. Amor, Ilana Solomon, Yun-Hee Choi, Meghan J. van Wanzeele, Rakefet Shtoyerman, Vanessa Huntley, Maartje Nielsen, Deborah Neklason, Kevin J. Monahan, Gülçin Tezcan, Stefan Aretz, Talya Boisjoli, Sophie Giraud, Thierry Frebourg, Christophe Rosty, Heike Görgens, Lone Sunde, Allyson Templeton, Jacob Nattermann, Mala Pande, Joan Brunet, Nancy Uhrhammer, James M. Church, Florencia Spirandelli, Laurent Briollais, James G. Dowty, Jeanette C. Reece, Rachel Susman, Fay Kastrinos, Kirsi Pylvänäinen, Gabriel Capellá, Helène Schuster, Min H. Chew, Markus Loeffler, Christine Lasset, Michael J. Hall, Capuccine Delnatte, Floor A. Duijkers, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Digital Precision Cancer Medicine (iCAN), ATG - Applied Tumor Genomics, HUS Abdominal Center, Clinical sciences, Medical Genetics, Win A.K., Dowty J.G., Reece J.C., Lee G., Templeton A.S., Plazzer J.-P., Buchanan D.D., Akagi K., Aksoy S., Alonso A., Alvarez K., Amor D.J., Ankathil R., Aretz S., Arnold J.L., Aronson M., Austin R., Backman A.-S., Bajwa-ten Broeke S.W., Barca-Tierno V., Barwell J., Bernstein I., Berthet P., Betz B., Bignon Y.-J., Boisjoli T., Bonadona V., Briollais L., Brunet J., Bucksch K., Buecher B., Buettner R., Burn J., Caldes T., Capella G., Caron O., Casey G., Chew M.H., Choi Y.-H., Church J., Clendenning M., Colas C., Cops E.J., Coupier I., Cruz-Correa M., de la Chapelle A., de Wind N., Debniak T., Della Valle A., Delnatte C., Dhooge M., Dominguez-Valentin M., Drouet Y., Duijkers F.A., Engel C., Esperon P., Evans D.G., Falcon de Vargas A., Figueiredo J.C., Foulkes W., Fourme E., Frebourg T., Gallinger S., Garre P., Genuardi M., Gerdes A.-M., Gima L.M., Giraud S., Goodwin A., Gorgens H., Green K., Guillem J., Guillen-Ponce C., Guimbaud R., Guindalini R.S.C., Half E.E., Hall M.J., Hampel H., Hansen T.V.O., Heinimann K., Hes F.J., Hill J., Ho J.W.C., Holinski-Feder E., Hoogerbrugge N., Huneburg R., Huntley V., James P.A., Jensen U.B., John T., Juhari W.K.W., Kalady M., Kastrinos F., Kloor M., Kohonen-Corish M.R., Krogh L.N., Kupfer S.S., Ladabaum U., Lagerstedt-Robinson K., Lalloo F., Lasset C., Latchford A., Laurent-Puig P., Lautrup C.K., Leggett B.A., Lejeune S., LeMarchand L., Ligtenberg M., Lindor N., Loeffler M., Longy M., Lopez F., Lowery J., Lubinski J., Lucassen A.M., Lynch P.M., Malinska K., Matsubara N., Mecklin J.-P., Moller P., Monahan K., Morrison P.J., Nattermann J., Navarro M., Neffa F., Neklason D., Newcomb P.A., Ngeow J., Nichols C., Nielsen M., Nixon D.M., Nogues C., Okkels H., Olschwang S., Pachter N., Pai R.K., Palmero E.I., Pande M., Parry S., Patel S.G., Pearlman R., Perne C., Pineda M., Poplawski N.K., Pylvanainen K., Qiu J., Rahner N., Ramesar R., Rasmussen L.J., Redler S., Reis R.M., Ricciardiello L., Rogoza-Janiszewska E., Rosty C., Samadder N.J., Sampson J.R., Schackert H.K., Schmiegel W., Schulmann K., Schuster H., Scott R., Senter L., Seppala T.T., Shtoyerman R., Sijmons R.H., Snyder C., Solomon I.B., Soto J.L., Southey M.C., Spigelman A., Spirandelli F., Spurdle A.B., Steinke-Lange V., Stoffel E.M., Strassburg C.P., Sunde L., Susman R., Syngal S., Tanakaya K., Tezcan G., Therkildsen C., Thibodeau S., Tomita N., Tucker K.M., Tunca B., Turchetti D., Uhrhammer N., Utsunomiya J., Vaccaro C., van Duijnhoven F.J.B., van Wanzeele M.J., Vangala D.B., Vasen H.F.A., von Knebel Doeberitz M., von Salome J., Wadt K.A.W., Ward R.L., Weitz J., Weitzel J.N., Williams H., Winship I., Wise P.E., Wods J., Woods M.O., Yamaguchi T., Zachariae S., Zahary M.N., Hopper J.L., Haile R.W., Macrae F.A., Moslein G., and Jenkins M.A.

Subjects
0301 basic medicine, Proband, Oncology, Male, Heredity, DNA mismatch repair, [SDV]Life Sciences [q-bio], SUSCEPTIBILITY, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Residence Characteristics, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PMS2, ComputingMilieux_MISCELLANEOUS, MLH1, Age Factors, Middle Aged, Penetrance, Lynch syndrome, 3. Good health, Pedigree, Phenotype, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, Adult, medicine.medical_specialty, PENETRANCE, congenital, hereditary, and neonatal diseases and abnormalities, GENES, 3122 Cancers, colorectal cancer, BREAST, Risk Assessment, 03 medical and health sciences, Sex Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Retrospective Studies, business.industry, MUTATIONS, Cancer, medicine.disease, digestive system diseases, MSH2, MSH6, MODEL, INDIVIDUALS, 030104 developmental biology, Lynch Syndrome, Gene-Environment Interaction, business
Abstract

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Published
2021
Full Text
View/download PDF

6. Mapping genetic susceptibility to spontaneous preterm birth: Analysis of Utah pedigrees to find inherited genetic factors.

Author

Workalemahu T, Clark EAS, Madsen MJ, Yu Z, Dalton SE, Esplin MS, Manuck T, Neklason D, Wilfred Wu CH, Jorde LB, Camp NJ, Silver RM, and Varner MW

Abstract

Background: Spontaneous preterm birth (SPTB) is the leading cause of neonatal morbidity and mortality. It is a final common pathway for multiple etiologies, some of which are well known while others likely remain to be identified. Despite recent advancements in identifying genetic risk factors, the mechanisms of many SPTBs remain poorly understood due to the phenotypic heterogeneity and complexity. Large family-based studies decrease heterogeneity and improve power to identify genetic causes of SPTB., Objective: To identify inherited genetic factors in SPTB etiology using large families., Study Design: Using the Utah Population Database, which links a 4.5 million-person genealogy to state birth certificate and fetal death records, we identified large pedigrees containing multiple women with early SPTB (<34 weeks' gestation) and any SPTB (<37 weeks' gestation). We reviewed birth certificate data to exclude those with maternal and fetal diagnoses associated with iatrogenic preterm birth, resulting in 74 large multiplex pedigrees for early SPTB. Enrolled women with SPTB underwent comprehensive clinical phenotyping with review of primary medical records. Seven pedigrees, each containing at least 3 sampled women with SPTB, were the focus of this genetic study. High-density single-nucleotide polymorphism genotyping was conducted in maternal peripheral blood samples from women in the seven pedigrees. Shared genomic segments analysis was performed to identify genome-wide significant chromosomal regions shared in excess by women with SPTB., Results: We identified two genome-wide significant chromosomal regions. In single-pedigree SGS analysis, a 1.75 Mega base region in chromosome 8 (8q24.23) was shared by 5 out of 6 women with SPTB in a single large pedigree (false positive rate=0.028). In duo-pedigree analysis, a 1.05 Mega base region in the same 8q24.23 locus was identified in a second pedigree (false-positive rate [duo]= 0.0019). The intersecting region at the 8q24.23 locus contains FAM135B (family with sequence similarity 135 member B) and KHDRBS3 (KH RNA binding domain containing, signal transduction associated 3) genes, which have previously been implicated in oncogenesis and ovarian cancer, respectively. Duo-pedigree SPTB analysis also identified a second genome-wide significant 67 kilo base locus in chromosome 12 (12q21.1-q21.2) that was shared by all women with SPTB in two independent pedigrees (false-positive rate [duo] =0.01). The intersecting region at the 12q21.1-q21.2 locus contains CAPS2 (calcyphosine 2) and KCNC2 (potassium voltage-gated channel subfamily C member 2) genes, both implicated in vascular-related complications of pregnancy and preterm labor., Conclusion: Using large SPTB families, we identified shared chromosomal regions (8q24.23 and 12q21.1-q21.2), providing evidence for inherited (segregating) risk loci in SPTB etiology. Further investigation into genes in SPTB etiology, including functional validation may provide avenues for novel therapeutic development and guide efforts for SPTB prevention to prolong pregnancy and improve outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Published
2024
Full Text
View/download PDF

7. Colonoscopy and Upper Endoscopy Surveillance in Lynch Syndrome: A Longitudinal Study From a Large Tertiary Healthcare System.

Author

Gibson E, Li H, Staub J, Neklason D, Keener M, and Kanth P

Abstract

Background and Aims: Lynch syndrome (LS) is caused by pathogenic mutations in mismatch repair (MMR) genes. There are limited data on differences in colorectal cancer (CRC) surveillance by MMR genes, and an international consensus on surveillance based on genes is not established. We aimed to evaluate colonoscopy and esophagogastroduodenoscopy (EGD) surveillance outcomes and compare CRC surveillance findings by the mutated gene., Methods: One hundred one patients with LS were included and colonoscopy results were compared by MMR mutation. Primary outcomes included the development and recurrence of adenoma, CRC, high-grade dysplasia, advanced adenoma, and sessile serrated lesions. Logistic regressions evaluated the relationship between genes and the development or recurrence of primary outcomes. Survival analysis evaluated primary outcomes in patients with ≥ 2 colonoscopies. EGD results were summarized., Results: Three hundred twenty seven colonoscopies were reviewed. Compared to PMS2 , MLH1 was associated with a higher risk of advanced adenoma/high-grade dysplasia/CRC development (odds ratio [OR] 9.85, 95% confidence interval [CI]: 1.97-77.24) and MSH2 was associated with a higher risk of adenoma development (OR 4.17, 95% CI: 1.11-17.61). Among those with > 2 colonoscopies, MLH1 (hazard ratio 18.98, 95% CI: 1.31-274.51) and MSH6 (hazard ratio 15.03, 95% CI: 1.16-194.65) had a higher risk of sessile serrated lesions compared to MSH2 . Among patients who had adenoma detected once, MLH1 had a higher risk of adenoma recurrence compared to MSH6 (OR 14.59, 95% CI: 1.53-244.30) and PMS2 (OR 47.15, 95% CI: 4.26-984.28). MSH2 had a higher risk of adenoma recurrence compared to PMS2 (OR 11.89, 95% CI: 1.38-164.78). Of 170 EGDs, an actionable finding was identified in 16% of patients during their first 3 EGDs., Conclusion: Surveillance colonoscopy outcomes differed in patients with LS and suggest the need to guide surveillance based on MMR gene mutation., (© 2024 The Authors.)

Published
2024
Full Text
View/download PDF

8. Surgical Interventions, Malignancies, and Causes of Death in a FAP Patient Registry.

Author

Cannon AR, Keener M, Neklason D, and Pickron TB

Subjects
Anastomosis, Surgical, Cause of Death, Female, Humans, Quality of Life, Registries, Adenomatous Polyposis Coli surgery, Proctocolectomy, Restorative
Abstract

Background: Familial adenomatous polyposis (FAP) patients are at risk for numerous malignancies. Multiple surgeries exist to mitigate the risk of colorectal cancer. Surgeons must weigh future quality of life versus the risk of dysplasia. As FAP patient longevity increases, there remains a risk of other malignancies. This study examines surgical interventions, development of cancers, and causes of mortality in a FAP registry., Methods: Patients with FAP or attenuated FAP (aFAP) were identified by linking the Hereditary Gastrointestinal Cancer Registry with University of Utah's medical records. Patients without sufficient information were excluded. Patient demographics, surgical histories, cancer diagnoses, and causes of death were extracted. Logrank and Fisher's exact tests were employed to detect significant differences between groups., Results: After exclusion criteria, 140 patients were analyzed. Sixty patients (42.9%) underwent total proctocolectomy with ileal pouch-anal anastomosis (IPAA) followed by 50 (35.7%) having total colectomy with ileorectal anastomosis (IRA). IPAA patients were more likely female (p = 0.01) and have FAP (p < 0.01) versus IRA patients. Nineteen patients (15.0%) required additional colorectal surgeries; however, no differences were based on initial surgery. Colorectal cancer was diagnosed in 22 patients (15.7%), while 7 (5.0%) developed gastric cancer. Of the 15 deceased patients, 6 (40%) died due to gastric adenocarcinoma., Discussion: This study suggests that aFAP and FAP patients are undergoing appropriate colorectal interventions to reduce colorectal cancer mortality; however, repeat interventions are frequent. Gastric malignancy is common and represents the leading cause of death. Further studies are needed to determine appropriate surveillance protocols to reduce this risk of malignancy.

Published
2021
Full Text
View/download PDF

9. Clinical and Molecular Features of Post-Colonoscopy Colorectal Cancers.

Author

Samadder NJ, Neklason D, Snow A, Samowitz W, Cessna MH, Rowe K, Sandhu I, Boucher K, Pappas L, Smith KR, Wong J, Curtin K, Provenzale D, and Burt RW

Subjects
Aged, Aged, 80 and over, Carcinogenesis, Carcinoma diagnosis, Carcinoma pathology, Cohort Studies, Colon, Ascending pathology, Colon, Descending pathology, Colon, Transverse pathology, Colonic Neoplasms diagnosis, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Colorectal Neoplasms diagnosis, Colorectal Neoplasms pathology, CpG Islands, Female, Humans, Male, Middle Aged, Rectal Neoplasms diagnosis, Rectal Neoplasms genetics, Rectal Neoplasms pathology, Retrospective Studies, Sigmoid Neoplasms diagnosis, Sigmoid Neoplasms genetics, Sigmoid Neoplasms pathology, Carcinoma genetics, Colonoscopy, Colorectal Neoplasms genetics, DNA Methylation, Microsatellite Instability, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras) genetics
Abstract

Background & Aims: Post-colonoscopy colorectal cancers (PCCRCs) may arise from missed lesions or due to molecular features of tumors that allow them to grow rapidly. We aimed to compare clinical, pathology, and molecular features of PCCRCs (those detected within 6-60 months of colonoscopy) and detected CRCs (those detected within 6 months of a colonoscopy)., Methods: Within a population-based cross-sectional study of incident CRC cases in Utah (from 1995 through 2009), we identified PCCRCs (those cancers that developed within 5 years of a colonoscopy) and matched the patients by age, sex, and hospital site to patients with detected CRC. Archived specimens were retrieved and tested for microsatellite instability (MSI), CpG island methylation, and mutations in KRAS and BRAF. There were 2659 cases of CRC diagnosed within the study window; 6% of these (n = 159) were defined as PCCRCs; 84 of these cases had tissue available and were matched to 84 subjects with detected CRC., Results: Higher proportions of PCCRCs than detected CRCs formed in the proximal colon (64% vs 44%; P = .016) and were of an early stage (86% vs 69%; P = .040). MSI was observed in 32% of PCCRCs compared with 13% of detected CRCs (P = .005). The other molecular features were found in similar proportions of PCCRCs and detected CRCs. In a multivariable logistic regression, MSI (odds ratio, 4.20; 95% CI, 1.58-11.14) was associated with PCCRC. There was no difference in 5-year survival between patients with PCCRCs vs detected CRCs., Conclusion: In this population-based cross-sectional study of incident CRC cases in Utah, we found PCCRCs to be more likely to arise in the proximal colon and demonstrate MSI, so PCCRCs and detected CRC appear to have different features or processes of tumorigenesis. Additional studies are needed to determine if post-colonoscopy cancers arise through a specific genetic pathway., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Published
2019
Full Text
View/download PDF

10. Characterization of an APC Promoter 1B deletion in a Patient Diagnosed with Familial Adenomatous Polyposis via Whole Genome Shotgun Sequencing.

Author

Kalbfleisch T, Brock P, Snow A, Neklason D, Gowans G, and Klein J

Abstract

Recently, deletions have been identified and published as causal for Familial Adenomatous Polyposis in the 1B promoter region of the APC gene.  Those deletions were measured using multiplex ligation-dependent probe amplification.  Here, we present and characterize an ~11kb deletion identified by whole genome shotgun sequencing.  The deletion occurred in a patient diagnosed with Familial Adenomatous Polyposis, and was located on chr5, between bases 112,034,824 and 112,045,845, fully encompassing the 1B promoter region of the APC gene.   Results are presented here that include the sequence evidence supporting the presence of the deletion as well as base level characterization of the deletion site.  These results demonstrate the capacity of whole genome sequencing for the detection of large structural variants in single individuals.

Published
2015
Full Text
View/download PDF

11. Biochemical variants of Smith-Lemli-Opitz syndrome.

Author

Neklason DW, Andrews KM, Kelley RI, and Metherall JE

Subjects
Acetates blood, Cell Line, Cholesterol biosynthesis, Cholesterol blood, Humans, Kinetics, Lymphocytes metabolism, Lymphocytes pathology, Smith-Lemli-Opitz Syndrome classification, 3-Hydroxysteroid Dehydrogenases blood, Dehydrocholesterols blood, Smith-Lemli-Opitz Syndrome genetics, Smith-Lemli-Opitz Syndrome metabolism
Abstract

Smith-Lemli-Opitz (SLO or RSH) syndrome is characterized by multiple congenital anomalies, mental retardation, and defective growth; it results from an inherited defect in the biosynthesis of cholesterol. Patients have elevated plasma concentrations of 7-dehydrocholesterol, the immediate biosynthetic precursor of cholesterol and most also have low circulating levels of cholesterol. To understand better the biochemical basis of clinical variability, we evaluated cholesterol biosynthesis in lymphoblasts from 3 unrelated SLOS patients with distinct phenotypes. One patient has "type I SLOS", the second has the more severe "type II SLOS" and the third is classified as atypical and had been postulated to have a defect in sterol transport. The lymphoblasts of each patient show normal subcellular localization of cholesterol and 7-dehydrocholesterol by gradient fractionation. Biochemical differences in the ability of the lymphoblasts to convert 7-dehydrocholesterol to cholesterol are described and correspond to the severity of disease (type II > type I > atypical). Recently, the gene responsible for most SLOS cases (DHCR7) was mapped to chromosome 11 and mutations in DHCR7 were found in each of these patients. The biochemical differences described here likely result from the different mutations observed in DHCR7., (Copyright 1999 Wiley-Liss, Inc.)

Published
1999
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results