The Biology and Disease Human Proteome Project (B/D-HPP) Annual Report 2017-2018

The Biology and Disease Human Proteome Project (B/D-HPP) Annual report 2017-2018

Submitted by Fernando Corrales and Ileana Cristea on behalf of all members and liaisons of the B/D-HPP Executive committee

1 The Biology and Disease Human Proteome Project (B/D-HPP) Annual report 2017-2018

1. Overview and expansion The Biology and Disease-driven Human Proteome Project (B/D-HPP) is focused to support the use of state-of- the-art proteomic methods to characterize and quantify proteins for in-depth understanding of the molecular mechanisms of biological processes and human disease across life sciences. The B/D-HPP is truly a grass root initiative where groups of individual come together globally to address key issues. One goal of the B/D-HPP is to broaden the impact of proteomics to the broader community based on organ and disease areas. A second goal is to develop popular proteins within the B/D-HPP in order to prioritize protein targets that are highly relevant to each particular field to deliver relevant assays for the measurement of these selected targets and to disseminate and make publicly accessible the information and tools generated. At the last International HUPO in Dublin, there were 19 B/D-HPP initiatives with 3 closely related HPP resource pillars. It is from these initiatives that the chairs and the B/D-HPP create 6 main sessions for the international HUPO meeting 2017. These and other groups also have a chance to present and catch up with each other on Sunday and Thursday workshops hosted HPP. An additional effort of the B/D-HPP is to encourage and support the scientific career development of the early career researchers among the HUPO community. In this sense the initiative is strongly contributing to the activities of the early career researchers helping them to create opportunities to present their work at international HUPO congresses (e.g. the ECR manuscript competition) or to interact with more senior HUPO scientists (e.g. the ECR mentoring day). The organization is Fernando Corrales, chair and Ileana Cristea (co-chair) with the most amazing executive committee consisting of Jennifer Van Eyk (past-chair), Gil Omenn (Ex officio), Hui Zhang, Eric Deutsch, Pengyuan Yang, Tadashi Yamamoto, Sanjeeva Srivastava, Paola Roncada and Michelle Hill, Ferdinando Cerciello (ECR representative) and Mark Baker (HPP Chair).

1.a. B/D HPP initiatives activity this year. According to the procedure established last year, we sent out a questionnaire to determine the viability and work being carried out by the various initiatives. The aims were:

1. To update the information about the initiatives on the B/D-HPP initiative page of the HUPO website. We would like to have an updated and attractive picture of the B/D group aims, activity and achievements to facilitate cross interactions with other HPP groups and to attract additional partners from the scientific community. 2. To compile the collected information in a B/D-HPP annual report. That will provide a global view of the B/D-HPP as a whole and will highlight our strengths. 3. To explore the willingness to participate in the HUPO Congress. This is the main HUPO activity and the participation of the B/D groups is highly encouraged by submitting abstracts to the HPP session topics, active inputs in the Sunday and Thursday programs on popular/priority proteins, PTMs, etc. 5. To explore the willingness to prepare manuscripts for the JPR Special Issue. To find new ways of interaction across B/D and C-HPP groups.

Results from the questionnaire

2018 Questionnaire B/D HPP

An international collaborative project that deals with mapping, annotating and characterizing the proteome using proteomics technologies in its relation to human biology and/or diseases. B/D-HPP provides a framework for the coordination of 19 initiatives that integrate about 50 multi-national research groups.

B/D HPP Questionnaire items 1-4 B/D HPP Questionnaire item 6

1. Please state the name of your initiative, name and email of chair and co-chairs, starting date of your B/D initiative and any additional information: 6. Are you currently doing research on popular/priority proteins? 2. What are your main aims? 2.a. Brief statement: Yes: 2.b. Some of the current lines of work include (fill in for your initiative): 80 If not, would you be willing to? 10 2.c. Main achievements in 2017: 70 3. Any related documents you’d like to link? 9 3.a Websites and links (fill in for your initiative): 60 Yes No In the future 8 HBPP Cancer FAN 3.b Papers (fill in for your initiative) 7 3.b.1 Papers published in collaboration within the initiative 50

* CVD HIPP

* 6 3.b.2 List Top 5 papers for 2017

40 * HKUPP *

3.c Congresses in 2017? (Committees, lectures… )(fill in for your initiative) * EyeOme 5 30 * 3.c.1 Participation in proteomics meetings in 2017? Liver 4 3.c.2 Participation in congresses organized by other biomedical or clinical associations 20 Mitochondria 3 3.d Other documents 4. Educational and dissemination activity (Courses, workshops, summer schools, etc) in 2017 10 PediOme 2

Plasma 1

s s

s RAD

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e 0

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r Yes No In the future

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Updated information for each initiative: leadership, participatin c

h • Protein lists available from peptide atlas (https://db.systemsbiology.net/sbeams/cgi/

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laboratories, main aims, plans and activity. Valuable information to b

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i PeptideAtlas/proteinList?protein_list_id=45 ).

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keep updated the B/D HPP web page. e

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s Five papers already published (EyeOme, Liver and RAD).

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• In addition to the 72 papers (top 5 published by initiatives’ labs) / l

a • Two published tools for selecting popular proteins from the literature

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reported by the 13 initiatives answering the questionnaire, 17 were i t

a Data-Driven Approach To Determine Popular Proteins for Targeted Proteomics Translation of Six Organ Systems. c

collaborative efforts of the participating laboratories. u d Lam MP, Venkatraman V1, Xing Y, Lau E, Cao Q2, Ng DC, Su AI3, Ge J2, Van Eyk JE1, Ping P. • Participation in 44 international congressess, 20 on proteomics and E J Proteome Res. 2016 Nov 4;15(11):4126-4134. Epub 2016 Jul 19. 24on other biomedical, clinical disciplines. *Collaborative publications Systematic Protein Prioritization for Targeted Proteomics Studies through Literature Mining. • Organisation of 30 educational and dissemination related activities. **Proteomics Yu KH, Lee TM, Wang CS, Chen YJ, Ré C, Kou SC, Chiang JH, Kohane IS, Snyder M. ***Biomediacal/clinical J Proteome Res. 2018 Apr 6;17(4):1383-1396. doi: 10.1021/acs.jproteome.7b00772. Epub 2018 Mar 15.

B/D HPP Questionnaire item 7 B/D HPP Questionnaire item 8 8. During the analysis of your specific and perhaps unique samples that might be of great value to identify missing proteins. 7. Activities and meetings planned for 2018 • Would you be willing to share raw MS data sets for reanalysis in collaboration with other HPP initiatives? Meeting participation/organization • Would you be willing to share samples? Like what? Initiative HUPO/HPP Others 11 Cancer 1 10 • Would you be willing to run samples from other teams? CVD 1 9 EyeOme 8 Initiative Data Samples Run samples 14 FAN 5 7 Cancer 1 1 1 HBPP 1 3 CVD 1 1 1 12 6 HIPP 1 EyeOme 1 0 0 5 Liver 2 FAN 1 1 1 10 4 HBPP 1 0 0 Mitochondria 1 1 8 3 HIPP IMOP Liver 1 0 1 2 PediOme 1 Mitochondria 1 0 1 6 Plasma 1 1 1 IMOP 1 0 1 4 RAD 1 1 0 PediOme 1 1 1 HUPO/HPP Others Plasma 1 0 1 2 RAD 1 1 1 KUHPP 1 0 1 0 12 5 10 • Some initiatives (HBPP, CVD, Liver, RAD) report activities including setting up Data Samples Run samples analytical methods (for popular proteins in some cases) and preparation of • Data sharing if published or under collaboration publications (new data and reviews). • Type of sample not indicated but in the case of RAD (serum). Difficulties due to • All initiatives attending the HUPO meeting in Orlando were planning to present their regulatory issues work but this has not being included in the agenda. • Availability to run limited number of samples according to capacity.

B/D HPP Questionnaire item 10

10. Would your initiative be willing to prepare a data-driven manuscript based around your initiative for the HPP special issue in Journal of Proteome Research? Manuscripts are due by 31 May 2018

Initiative HPP 6 session track Sunday HPP Pis Thursday HPP Early morning Cancer 1 1* 1 1* CVD 1 1 1 1 EyeOme 1 1 1 1 FAN 1 1 1 1 HBPP 1 1 1 1 HIPP 1 0 1 0 Liver 1 1 1 1 Mitochondria 0 0 0 0 IMOP 0 0 0 0 PediOme 1 1 1 1 Plasma 1 1 1 1 RAD 1 1 0 1 KUHPP 1 1 1 1 11 9 10 9

2. Contributions to HUPO Orlando 2018. This year the initiative is involved at International HUPO Sunday: HPP Investigators Meeting Sunday-Wednesday Bioinformatics Hub Monday – Wednesday: B/D-HPP Scientific Track comprising 6 sessions ECR manuscript competition Clinical Fellow Travel Award Thursday: HPP Strategic Workshop

3. Outreach by B/D-HPP to the proteomics and broader scientific community

3.a. B/D-HPP played a role in other proteomics and educational meetings or manuscripts this year: Some examples are listed below. 1. Clinical Proteomics Course at the University Hospital A Coruña, October 23-27, 2017 (HUPO endorsed activity). 2. C-HPP meeting Santiago de Compostela (2018). Links between C-HPP and B/D-HP.

3 3. HPP session in the “Technological Platforms and Precision Medicine” Summer School. University Complutense of Madrid, El Escorial, July 23-27, 2018. 4. HIPP Summer School, Madrid, September 10-13, 2018 (http://www.hipp- summerschool.com/modules.php?name=webstructure&idwebstructure=1) 5. 28th HBPP Workshop, May 8-9 2018, Adelaide, Australia

3.b. B/D-HPP newsletter and contribution of HUPOST At HUPO 2017, it was decided that instead of running a sperate B/D-HPP newsletter, B/D-HPP will contribute articles to HUPOST, which will also move to a new format. The modern look and feel of HUPOST is expected to be more user-friendly and engaging.

Since Oct 2017, ten HUPOST articles have been contributed from B/D-HPP. Most articles have been written by Michelle Hill, with the topics in consultation with B/D-HPP EC. A few initiatives were specifically invited to contribute articles, and recently, a general call was made to all B/D initiatives.

2018 August - Sample menu for BD-HPP at Orlando 2018 (Michelle Hill) July - This summer, be HIPP in Madrid…. (Etienne Caron) June - 1st HUPO Glycoproteomics Initiative Study (Nicki Packer) May - Getting down to details: disease-associated PTMs and proteoforms (Michelle Hill) April - New HPP initiative on Rheumatic and autoimmune diseases (RAD) (Michelle Hill) March - EyeOme (Michelle Hill) Jan - Proteomics goes clinical (Michelle Hill) and I Clinical Proteomics Course (Fernando Corrales)

2017 December - Round table with clinical scientist travel grant winners at HUPO2017 (Michelle Hill) November – The sweet life - On the large scale – Calling for HGI Study Participants (Michelle Hill and Nicki Packer)

The contributed articles aimed to disseminate information including achievements, up-coming events, as well as cross-laboratory studies. For example, the Human Glycoproteomics Initiative (HGI) is running a community glycoproteomics software study, under the leadership of new chair, Nicki Packer. Compared to the PDF file version of B/D-HPP newsletter, we are not communicating a list of upcoming events, or hot papers via this media. Instead, papers of note are highlighted within some of the articles, but this means the frequency and number of papers highlighted would be less than before. Upcoming events could still be included with every HUPOST issue as a listing

3.c. Papers One of the main goals of the Biology and Disease Human Proteome Project (B/D-HPP) is to unveil the molecular basis of physiological/pathological processes by the identification of the driver proteins involved. To guide studies in this direction, B/D HPP initiatives have been encouraged to configure lists of popular proteins in their specific areas (highly cited proteins in association with the topic of interest) to generate functional hypothesis and to pave the way for new clinical developments. Two web tools have been recently developed to perform systematic bibliographic searches to rank the most cited proteins under the selected specific topic (Lam et al JPR 2017; Yu KS et al 2018). The usefulness of the popular protein approach has been proved in two studies demonstrating the principal role of the reconfiguration of one carbon metabolism in the liver during hepatocarcinogenesis (Mora MI JPR 2017) and the development of a targeted method to monitor B-type natriuretic peptidoforms that might prove useful for the diagnosis and monitorization of heart failure (Shenyan Zhang et al JPR 2017). Characterization of proteoforms and PTMs is yet an unmet need to understand the dynamics of pathogenic processes. A novel mass spectrometry-based whole protein assay enabled to quantitate the percentage of mutant 4 KRAS4b present in colorectal cancer tissue, and the differences on C-terminal carboxymethylation, which is critical for KRAS function (Ioanna Ntai et al PNAS 2108). Understanding PTM status of drug targets and the functional effects is key to next generation therapies. Jenny Van Eyk and co-workers have beautifully shown that S-nitrosylation of GSK3B at specific residues send the protein to the nucleus, away from its cytoplasmic location resulting in a different repertoire of phosphorylated substrates, suggesting different drug responses (Shengbing Wang et al Circulation Research 2018) The detailed description of the collection of peptides associated to human HLA is of paramount importance to understand the immune system and to guide the development of next-generation vaccines and immunotherapies against autoimmunity, infectious diseases and cancers. Mass spectrometry (MS) is the only available technology to interrogate the immunopeptidome in an accurate, systematic and unbiased manner. The Human Immunopeptidome Proteome Project (HIPP) (Caron E et al Immunity 2017) has developed the first public database of quality-controlled immunipeptidomic data generated by mass spectrometry (Shao W et al Nucleic Ac Res 2018). Combination of MHC isolation, peptide analysis and exome sequencing, has allowed for identifying immunoglobulin neoantigens as targets for lymphoma immunotherapy (Khodadoust MS et al Nature 2017) and ovarian cancer (Shuster H ert al PNAS 2018) and open new avenues for the development of individualized immunotherapies. One of the principal aims of the B/D-HPP is to contribute to the better understanding of human organ physiology and pathology by providing comprehensive proteome insights. To this end, eye and plasma proteomes have been recently updated. A total of 9,782 non-redundant proteins are now in the human eye proteome database. Proteomes of 11 tissues and biofluids are included, with the highest number (6538 proteins) from vitreous humor and the lowest number (827) from aqueous humor (Ahmad MT et al Proteomics, 2018). More than 122000 peptide sequences belonging to 3509 protein identifications compliant with the HPP guidelines are described in the last Plasma Peptide Atlas (Schwenk JM et al JPR 2017). Besides database facilitating the access of the scientific community to proteome wide information and resources, the B/D HPP community has paid much attention to the identification of protein biomarkers in different fields. The state of the art of biomarker discovery in paediatrics research has been recently reviewed, noting a significant increase of publications and clinical trials in the field but still at a lower pace compare to studies in adult subjects (Shores DR et al J Pediatrics 2017). Collaborations within the RAD-HPP have already resulted in several publications in 2017, including circulating biomarkers for knee radiographic osteoarthritis (L Lourido et al Scient Rep, 2017), use of mass spectrometry (Fernández-Puente P et al JOP 2017) or protein array to discover and validate biomarkers for Osteoarticular Pathologies (Geraldino-Pardilla L et al Rheumatology 2017) (Sierra- Sánchez A et al JPR 2017), and anti-citrullinated protein antibodies in rheumatoid arthritis. The in depth analysis of the synaptosomal proteome allowed the association of specific protein expression patterns with social behaviour in patients with schizophrenia. This is an excellent example illustrating the advantages of establishing joint C- (chromosome 15) and B/D HPP (Brazilian Brain initiative) ventures. A similar cooperation lead to a comprehensive description of the human mitochondrial proteome under standardized protocols (Alberio T et al JPR 2017), which are currently being used to assess the pharmacological interest of targeting specific mitochondrial proteins to kill selectively cancer cells (Leanza L et al Cancer Cell 2017). Cancer biomarker discovery has experienced significant progress, as shown by the recent studies published by members of the Cancer B/D-HPP initiative. Novel DIA MS-based and proteogenomic approaches have proved their efficiency to discover new protein species and splice variants that can be used to improve colorectal cancer screening (Bosch LJW et al Annals of Internal Medicine 2017; Komor MA MCP 2017) and point to promising therapeutic targets in breast cancer (Huang K et al Nat Commun 2017). Finally, realising that food allergy is a global health concern, the pros and cons of current analytical methods for allergenic risk assessment have been reviewed (Mazzucchelli G et al, Mol Nutr Food Res 2017) by members of the Food and Nutrition B/D-HPP initiative. Moreover, this group has also critically evaluated the state of the art proteomic and metaproteomic approaches to study the host-microbiome interaction (Starr AE et al Anal Chem 2018). As illustrated by the above-mentioned achievements, the productive interaction between HPP groups is shedding light to many relevant aspects of human biology. The cooperative efforts should then guide our next steps in the endeavor of generating a comprehensive human proteome map with all functional annotations needed to decipher the code of life and set the bases of the future molecular precision medicine. 5