Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Pik-Fang Kho^{1

2}, Frederic Amant³, Daniela Annibali³, Katie Ashton^{4

5

6}, John Attia^{4

7}, Paul L Auer^{8

9}, Matthias W Beckmann¹⁰, Amanda Black¹¹, Louise Brinton¹¹, Daniel D Buchanan^{12

13

14

15}, Stephen J Chanock¹⁶, Chu Chen¹⁷, Maxine M Chen¹⁸, Timothy H T Cheng¹⁹, Linda S Cook^{20

21}, Marta Crous-Bous^{18

22}, Kamila Czene²³, Immaculata De Vivo^{18

22}, Joe Dennis²⁴, Thilo Dörk²⁵, Sean C Dowdy²⁶, Alison M Dunning²⁷, Matthias Dürst²⁸, Douglas F Easton^{24

27}, Arif B Ekici²⁹, Peter A Fasching^{10

30}, Brooke L Fridley³¹, Christine M Friedenreich²¹, Montserrat García-Closas¹⁶, Mia M Gaudet³², Graham G Giles^{13

33

34}, Ellen L Goode³⁵, Maggie Gorman¹⁹, Christopher A Haiman³⁶, Per Hall^{23

37}, Susan E Hankinson^{22

38}, Alexander Hein¹⁰, Peter Hillemanns²⁵, Shirley Hodgson³⁹, Erling A Hoivik^{40

41}, Elizabeth G Holliday^{4

7}, David J Hunter^{18

42

43}, Angela Jones¹⁹, Peter Kraft^{18

42}, Camilla Krakstad^{40

41}, Diether Lambrechts^{44

45}, Loic Le Marchand⁴⁶, Xiaolin Liang⁴⁷, Annika Lindblom^{48

49}, Jolanta Lissowska⁵⁰, Jirong Long⁵¹, Lingeng Lu⁵², Anthony M Magliocco⁵³, Lynn Martin⁵⁴, Mark McEvoy⁷, Roger L Milne^{13

33

34}, Miriam Mints⁵⁵, Rami Nassir⁵⁶, Geoffrey Otton⁵⁷, Claire Palles¹⁹, Loreall Pooler³⁶, Tony Proietto⁵⁷, Timothy R Rebbeck^{58

59}, Stefan P Renner⁶⁰, Harvey A Risch⁵², Matthias Rübner⁶⁰, Ingo Runnebaum²⁸, Carlotta Sacerdote^{61

62}, Gloria E Sarto⁶³, Fredrick Schumacher⁶⁴, Rodney J Scott^{4

6

65}, V Wendy Setiawan³⁶, Mitul Shah²⁷, Xin Sheng³⁶, Xiao-Ou Shu⁵¹, Melissa C Southey^{12

33

34}, Emma Tham^{48

66}, Ian Tomlinson^{19

54}, Jone Trovik^{40

41}, Constance Turman¹⁸, Jonathan P Tyrer²⁷, David Van Den Berg³⁶, Zhaoming Wang¹¹, Nicolas Wentzensen¹¹, Lucy Xia³⁶, Yong-Bing Xiang⁶⁷, Hannah P Yang¹¹, Herbert Yu⁴⁶, Wei Zheng⁵¹, Penelope M Webb⁶⁸, Deborah J Thompson²⁴, Amanda B Spurdle¹, Dylan M Glubb¹, Tracy A O'Mara¹

Affiliations

¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
² School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia.
³ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals KU Leuven, University of Leuven, Leuven, Belgium.
⁴ Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁵ Centre for Information Based Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
⁶ Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia.
⁷ Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
⁸ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁹ Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
¹⁰ Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
¹¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
¹² Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹³ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁴ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia.
¹⁵ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
¹⁶ Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁷ Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹⁹ Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
²⁰ University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
²¹ Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Alberta, Canada.
²² Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
²³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁵ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²⁶ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, Minnesota, USA.
²⁷ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
²⁸ Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany.
²⁹ Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
³⁰ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, USA.
³¹ Department of Biostatistics, Kansas University Medical Center, Kansas City, Kansas, USA.
³² Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.
³³ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
³⁴ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
³⁵ Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
³⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
³⁷ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
³⁸ Department of Biostatistics & Epidemiology, University of Massachusetts, Amherst, Amherst, Massachusetts, USA.
³⁹ Department of Clinical Genetics, St George's, University of London, London, UK.
⁴⁰ Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁴¹ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
⁴² Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴³ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴⁴ VIB Center for Cancer Biology, Leuven, Belgium.
⁴⁵ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁴⁶ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
⁴⁷ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
⁴⁸ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁴⁹ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁵⁰ Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Oncology Institute, Warsaw, Poland.
⁵¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁵² Chronic Disease Epidemiology, Yale School of Medicine, New Haven, Connecticut, USA.
⁵³ Department of Anatomic Pathology, Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
⁵⁴ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁵⁵ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
⁵⁶ Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, USA.
⁵⁷ School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
⁵⁸ Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁵⁹ Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁶⁰ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁶¹ Center for Cancer Prevention (CPO-Peimonte), Turin, Italy.
⁶² Human Genetics Foundation (HuGeF), Turin, Italy.
⁶³ Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
⁶⁴ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
⁶⁵ Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁶⁶ Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
⁶⁷ State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁶⁸ Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

PMID: 32851660
PMCID: PMC7757859
DOI: 10.1002/ijc.33206

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Pik-Fang Kho et al. Int J Cancer. 2021.

. 2021 Jan 15;148(2):307-319.

doi: 10.1002/ijc.33206. Epub 2020 Aug 7.

Authors

Affiliations

¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
² School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia.
³ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals KU Leuven, University of Leuven, Leuven, Belgium.
⁴ Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁵ Centre for Information Based Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
⁶ Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia.
⁷ Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
⁸ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁹ Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
¹⁰ Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
¹¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
¹² Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹³ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁴ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia.
¹⁵ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
¹⁶ Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁷ Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹⁹ Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
²⁰ University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
²¹ Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Alberta, Canada.
²² Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
²³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁵ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²⁶ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, Minnesota, USA.
²⁷ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
²⁸ Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany.
²⁹ Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
³⁰ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, USA.
³¹ Department of Biostatistics, Kansas University Medical Center, Kansas City, Kansas, USA.
³² Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.
³³ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
³⁴ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
³⁵ Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
³⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
³⁷ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
³⁸ Department of Biostatistics & Epidemiology, University of Massachusetts, Amherst, Amherst, Massachusetts, USA.
³⁹ Department of Clinical Genetics, St George's, University of London, London, UK.
⁴⁰ Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁴¹ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
⁴² Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴³ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴⁴ VIB Center for Cancer Biology, Leuven, Belgium.
⁴⁵ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁴⁶ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
⁴⁷ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
⁴⁸ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁴⁹ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁵⁰ Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Oncology Institute, Warsaw, Poland.
⁵¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁵² Chronic Disease Epidemiology, Yale School of Medicine, New Haven, Connecticut, USA.
⁵³ Department of Anatomic Pathology, Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
⁵⁴ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁵⁵ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
⁵⁶ Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, USA.
⁵⁷ School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
⁵⁸ Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁵⁹ Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁶⁰ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁶¹ Center for Cancer Prevention (CPO-Peimonte), Turin, Italy.
⁶² Human Genetics Foundation (HuGeF), Turin, Italy.
⁶³ Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
⁶⁴ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
⁶⁵ Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁶⁶ Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
⁶⁷ State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁶⁸ Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

PMID: 32851660
PMCID: PMC7757859
DOI: 10.1002/ijc.33206

Abstract

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10^-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Keywords: HDL cholesterol; LDL cholesterol; Mendelian randomization; endometrial cancer risk; triglycerides.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST

Peter A. Fasching reports personal fees from Novartis, grants from Biontech, personal fees from Roche, personal fees from Pfizer, personal fees from Daiichi-Sankyo, personal fees from Astra Zeneca, personal fees from Eisai, personal fees from Merck Sharp & Dohme, grants from Cepheid, personal fees from Lilly, personal fees from Pierre Fabre, personal fees from Seattle Genetics, during the conduct of the study. Deborah J. Thompson is an employee of Genomics plc. The research described in this article was completed before her employment at Genomics plc. All other authors declare no potential conflicts of interest.

Figures

**FIGURE 2**
Relationships between low-density lipoprotein (LDL) cholesterol, body mass index (BMI) and endometrioid endometrial cancer identified by previous^, and current Mendelian randomization analysis. Red lines represent adverse effects, and green lines represent protective effects

See this image and copyright information in PMC

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. - PubMed
1. Johnatty SE, Tan YY, Buchanan DD, et al. Family history of cancer predicts endometrial cancer risk independently of lynch syndrome: implications for genetic counselling. Gynecol Oncol. 2017;147:381–387. - PubMed
1. Webb PM. Environmental (nongenetic) factors in gynecological cancers: update and future perspectives. Future Oncol. 2015;11:295–307. - PubMed
1. Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet. 2016;387:1094–1108. - PubMed
1. Nead KT, Sharp SJ, Thompson DJ, et al. Evidence of a causal association between insulinemia and endometrial cancer: a Mendelian randomization analysis. J Natl Cancer Inst. 2015;107(9):djv178 10.1093/jnci/djv178. - DOI - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Affiliations

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical