. 2023 Oct 24;7(20):6092-6107.

doi: 10.1182/bloodadvances.2023010045.

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41

Claire C Homan^{1

2}, Michael W Drazer³, Kai Yu⁴, David M Lawrence^{1

2

5}, Jinghua Feng^{2

5}, Luis Arriola-Martinez^{1

2}, Matthew J Pozsgai³, Kelsey E McNeely³, Thuong Ha^{1

2}, Parvathy Venugopal^{1

2}, Peer Arts^{1

2}, Sarah L King-Smith^{1

2}, Jesse Cheah^{1

2}, Mark Armstrong^{1

2}, Paul Wang^{2

5}, Csaba Bödör⁶, Alan B Cantor⁷, Mario Cazzola^{8

9}, Erin Degelman¹⁰, Courtney D DiNardo¹¹, Nicolas Duployez^{12

13}, Remi Favier¹⁴, Stefan Fröhling^{15

16}, Ana Rio-Machin¹⁷, Jeffery M Klco¹⁸, Alwin Krämer¹⁹, Mineo Kurokawa²⁰, Joanne Lee²¹, Luca Malcovati^{8

9}, Neil V Morgan²², Georges Natsoulis²³, Carolyn Owen²⁴, Keyur P Patel¹¹, Claude Preudhomme^{12

13}, Hana Raslova²⁵, Hugh Rienhoff²³, Tim Ripperger²⁶, Rachael Schulte²⁷, Kiran Tawana²⁸, Elvira Velloso^{29

30}, Benedict Yan²¹, Erika Kim³¹, Raman Sood⁴, Amy P Hsu³², Steven M Holland³², Kerry Phillips³³, Nicola K Poplawski^{33

34}, Milena Babic^{1

2}, Andrew H Wei³⁵, Cecily Forsyth³⁶, Helen Mar Fan³⁷, Ian D Lewis³⁸, Julian Cooney³⁹, Rachel Susman⁴⁰, Lucy C Fox⁴¹, Piers Blombery⁴¹, Deepak Singhal⁴², Devendra Hiwase^{34

42}, Belinda Phipson^{43

44}, Andreas W Schreiber^{2

5

45}, Christopher N Hahn^{1

2

34}, Hamish S Scott^{1

2

5

34}, Paul Liu⁴, Lucy A Godley³, Anna L Brown^{1

2

34}; NISC Comparative Sequencing Program

Affiliations

¹ Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.
² UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
³ Departments of Medicine and Human Genetics, Section of Hematology/Oncology, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL.
⁴ Division of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
⁵ ACRF Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, SA, Australia.
⁶ HCEMM-SE Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
⁷ Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
⁸ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
⁹ Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
¹⁰ Alberta Children's Hospital, Calgary, Alberta, Canada.
¹¹ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
¹² Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France.
¹³ Jean-Pierre Aubert Research Center, INSERM, Universitaire de Lille, Lille, France.
¹⁴ Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children's Hospital, Paris, France.
¹⁵ Department of Translational Medical Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ German Cancer Consortium (DKTK), Heidelberg, Germany.
¹⁷ Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
¹⁸ St Jude Children's Research Hospital, Memphis, TN.
¹⁹ Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
²⁰ Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²¹ Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.
²² Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
²³ Imago Biosciences, Inc, San Francisco, CA.
²⁴ Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB, Canada.
²⁵ Institut Gustave Roussy, Université Paris Sud, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France.
²⁶ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
²⁷ Division of Pediatric Hematology and Oncology, Riley Children's Hospital, Indiana University School of Medicine, Indianapolis, IN.
²⁸ Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom.
²⁹ Service of Hematology, Transfusion and Cell Therapy and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31) HCFMUSP, University of Sao Paulo Medical School, Sao Paulo, Brazil.
³⁰ Genetics Laboratory, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
³¹ National Cancer Institute, National Institutes of Health, Rockville, MD.
³² National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
³³ Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
³⁴ Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
³⁵ Department of Haematology, Peter McCallum Cancer Centre, Royal Melbourne Hospital, Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Melbourne, VIC, Australia.
³⁶ Central Coast Haematology, North Gosford, NSW, Australia.
³⁷ Department of Medicine, The University of Queensland, Brisbane, QLD, Australia.
³⁸ Adelaide Oncology & Haematology, North Adelaide, SA, Australia.
³⁹ Department of Haematology, Fiona Stanley Hospital, Murdoch, WA, Australia.
⁴⁰ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
⁴¹ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁴² Department of Haematology, SA Pathology, Adelaide, SA, Australia.
⁴³ Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
⁴⁴ Department of Paediatrics and Department of Molecular Biology, The University of Melbourne, Melbourne, VIC, Australia.
⁴⁵ School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia.

PMID: 37406166
PMCID: PMC10582382
DOI: 10.1182/bloodadvances.2023010045

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41

Claire C Homan et al. Blood Adv. 2023.

. 2023 Oct 24;7(20):6092-6107.

doi: 10.1182/bloodadvances.2023010045.

Authors

Affiliations

¹ Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia.
² UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
³ Departments of Medicine and Human Genetics, Section of Hematology/Oncology, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL.
⁴ Division of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
⁵ ACRF Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, SA, Australia.
⁶ HCEMM-SE Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
⁷ Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
⁸ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
⁹ Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
¹⁰ Alberta Children's Hospital, Calgary, Alberta, Canada.
¹¹ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
¹² Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France.
¹³ Jean-Pierre Aubert Research Center, INSERM, Universitaire de Lille, Lille, France.
¹⁴ Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children's Hospital, Paris, France.
¹⁵ Department of Translational Medical Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ German Cancer Consortium (DKTK), Heidelberg, Germany.
¹⁷ Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
¹⁸ St Jude Children's Research Hospital, Memphis, TN.
¹⁹ Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
²⁰ Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²¹ Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.
²² Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
²³ Imago Biosciences, Inc, San Francisco, CA.
²⁴ Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB, Canada.
²⁵ Institut Gustave Roussy, Université Paris Sud, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France.
²⁶ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
²⁷ Division of Pediatric Hematology and Oncology, Riley Children's Hospital, Indiana University School of Medicine, Indianapolis, IN.
²⁸ Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom.
²⁹ Service of Hematology, Transfusion and Cell Therapy and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31) HCFMUSP, University of Sao Paulo Medical School, Sao Paulo, Brazil.
³⁰ Genetics Laboratory, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
³¹ National Cancer Institute, National Institutes of Health, Rockville, MD.
³² National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
³³ Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
³⁴ Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
³⁵ Department of Haematology, Peter McCallum Cancer Centre, Royal Melbourne Hospital, Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Melbourne, VIC, Australia.
³⁶ Central Coast Haematology, North Gosford, NSW, Australia.
³⁷ Department of Medicine, The University of Queensland, Brisbane, QLD, Australia.
³⁸ Adelaide Oncology & Haematology, North Adelaide, SA, Australia.
³⁹ Department of Haematology, Fiona Stanley Hospital, Murdoch, WA, Australia.
⁴⁰ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
⁴¹ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁴² Department of Haematology, SA Pathology, Adelaide, SA, Australia.
⁴³ Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
⁴⁴ Department of Paediatrics and Department of Molecular Biology, The University of Melbourne, Melbourne, VIC, Australia.
⁴⁵ School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia.

PMID: 37406166
PMCID: PMC10582382
DOI: 10.1182/bloodadvances.2023010045

Abstract

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.

Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

A complete list of the members of the NIH Intramural Sequencing Center Comparative Sequencing Program appears in “Appendix.”

Figures

**Figure 1.**
**HHM genomics cohorts.** Germ line variants in the HHM cohorts were visualized using the ProteinPaint web application. Carriers-with HM cohorts (diagnosed with HM) are visualized above the protein. Carriers-without HM cohorts (no HM diagnosis) are below the protein. Variants (displayed as protein changes where possible) are color coded by variant type. The number of individuals with each variant is indicated within the circle when the number is greater than 1. (A) Germ line *RUNX1* (66 carriers-without HM and 52 carriers-with HM individuals); (B) Germ line *GATA2* (9 carriers-without HM and 13 carriers-with HM individuals); and (C) Germ line *DDX41* (22 carriers-without HM and 29 carriers-with HM individuals) cohorts.

**Figure 2.**
**Defining the spectrum of CH in germline *GATA2, RUNX1*, and *DDX41* carriers-without HM.** (A) Each individual in the carriers-without HM cohort was defined as having CH (yellow) or no identifiable CH (no-CH, green), based on the identification of somatic clinically relevant variants, driver somatic variants. The age of the individual at the time of sample collection is indicated. (B) Correlation of the ages of malignancy development (HM, red) observed in the germ line malignancy cohorts with the carriers-without HM cohort, with (yellow) and without CH (green). (C) Demographics of individuals with CH variants in the *RUNX1* germ line carriers-without HM cohorts. Column graph shows the number of somatic variants identified in individuals with CH. Error bars show the standard error of the mean. Line graphs show the prevalence of CH in the carriers-without HM germ line cohort in different age groups. ∗P < .05, logistic regression model. (D) Violin plots showing the distribution of VAFs of driver somatic variants (shown in panel A) in the germ line *RUNX1* carriers-without HM cohort in individuals under the age of 50 years or >50 years old. VAFs for X-chromosome genes were normalized in male individuals to compensate for ploidy, enabling comparison with autosomal genes. HM, hematologic malignancy.

**Figure 3.**
**Spectrum of CH in age-related CH compared with the germ line *RUNX1* carriers-without HM cohort.** (A) Prevalence of CH in the control population compared with the germ line *RUNX1* carriers-without HM cohort. The control population includes cohorts from Jaiswal et al³² and Genovese et al³³ (n = 27 783). The 0 to 18 age group is only available for the *RUNX1* cohort. (B) Mutational spectrum of CH in the control population compared with the germ line *RUNX1* carriers-without HM cohort. Graph shows the frequency of variants in individuals with CH in each cohort. The control population includes cohorts from Desai et al,³⁶ Abelson et al,³⁵ and Jaiswal et al.³² ∗P < .05, ∗∗P < .001, 2-proportions Z test, approximate to normal distribution, ±95% confidence interval.

**Figure 4.**
**Molecular monitoring of germ line *RUNX1* carriers with CH.** (A) Driver somatic variants identified in *RUNX1* carriers-without HM individuals across age. Circle size = increasing VAF, color = gene. Individuals with unknown age were given the value 0 (D01_2, D02_2, S_E_4, U02_3, U02_4). (B) Longitudinal case studies with the VAF of detected driver somatic variants plotted across years. Clinical diagnosis at the time of monitoring is indicated below the age of the individual at which the sample was collected. AML, acute myeloid leukemia; TCP, thrombocytopenia.

**Figure 5.**
**Clinically relevant somatic variants identified in the germ line carriers-with HM cohorts.** Distribution of the clinically relevant somatic variants, driver somatic variants, identified in the carriers-with HM cohorts. From outside to inside: 1. Gene with the somatic variant. The length of the black bar indicates the frequency of variant within the germ line carriers-with HM cohort. 2. The age and sex of the individual with the somatic variant. Triangle = female, circle = male. Age groups are indicated by colors (green = child [≤14 years], orange = AYA [15-39 years], adult = pink [≥40 years], black = the age of the individual is unknown). 3. The type of HM is indicated by the color of the bar. 4. VAF of the somatic variant in the sample as represented on a sliding scale (darker = high VAF, lighter = low VAF). 5. The inner ring depicts the association of different somatic variants in the sample. The colored ribbon depicts a unique sample and the associated somatic variants observed in the sample. (A) Germ line *RUNX1* carriers-with HM cohort. Only shown are the genes that are identified as somatically mutated in 2 or more individuals. (B) Germ line *GATA2* carriers-with HM cohort, showing all driver somatic variants and (C) Germ line *DDX41* carriers-with HM cohort showing all driver somatic variants. (D) Violin plot displaying the distribution of driver somatic variant VAFs observed in the germ line carriers-with HM cohorts. Boxes represent the 25th and 75th percentiles, with the horizontal line in the middle indicating the median, and the vertical lines representing the 95th percentile cohorts. ∗P < .05, 1-way analysis of variance of log-transformed values, with Tukey multiple comparison test. (E) TMB in germ line *RUNX1* and *DDX41* carriers-with HM cohorts. TMB is the number of SNV and INDELs divided by 38Mb coding region. Only malignancy samples where we had available a matched germ line control tissue were used for analysis. Boxes represent the 25th and 75th percentiles, with the horizontal line in the middle indicating the median, and the vertical lines representing the max and min values. ∗P < .05 nonparametric Mann-Whitney U test. AYA, adolescents and young adults; AML, acute myeloid leukemia; AL, acute leukemia; B-ALL, B-cell acute lymphoblastic leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; JMML, juvenile myelomonocytic leukemia; MPN, myeloproliferative neoplasms; T-ALL, T-cell acute lymphoblastic leukemia.

**Figure 6.**
**Somatic variants in *RUNX1* are the most common event in the germ line *RUNX1* carriers-with HM cohort.** (A) Plot of acquired somatic *RUNX1* variants and associated germ line *RUNX1* variants. Data points are colored according to the somatic and associated germ line variant observed in the patient. VAF of more than 60% indicates a copy neutral loss of heterozygosity (CNLOH) or Trisomy 21. (B) Somatic and germ line *RUNX1* variants are visualized using the ProteinPaint web application. Variants are colored according to the somatic and associated germ line variant observed in the patient. The number of probands for each variant is indicated within the circle where the number is greater than 1. All variants are annotated to RUNX1c; NM_001754.4; LRG_ 482. (C) The proportion of male and females harboring a somatic *RUNX1* variant is significantly different. ∗P < .05. (D) Sex and age distribution of individuals with a somatic *RUNX1* variant; adult ≥ 40 years, AYA = 15 to 39 years, children ≤14 years. Data points are colored according to the somatic and associated germ line variant observed in the patient. AYA, adolescents and young adults.

**Figure 7.**
**A somatic variant in *DDX41* is the most common event in the germ line *DDX41* carriers-with HM cohort.** (A) Plot of acquired somatic *DDX41* variants and associated germ line *DDX41* variants. Data points are colored according to the somatic and associated germ line variant observed in the patient. (B) Somatic and germ line DDX41 variants are visualized using the ProteinPaint web application. Variants are colored according to the somatic variant and associated germ line variant observed in the patient. The number of probands for each variant is indicated within the circle where the number is greater than 1. All variants are annotated to DDX41; NM_016222.4; LRG_ 1386. (C) The proportion of male and females harboring a somatic *DDX41* variant shows no significant difference. (D) Sex and age distribution of individuals with a somatic *DDX41*; adult ≥40 years, AYA = 15 to 39 years, children ≤14 years. AYA, adolescents and young adults.

See this image and copyright information in PMC

References

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Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41

Affiliations

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials