The Cooperative Human Tissue Network of the National Cancer Institute: Supporting Cancer Research for 35 Years

After being made aware of an unmet need of many investigators operating outside of large medical centers for well-annotated normal and malignant human tissues for study, the NCI issued a Request for Application (RFA) for the Cooperative Agreement (CA) Grant and funded the Cooperative Human Tissue Network (CHTN) in 1987, “to stimulate, for the good of the public, cooperative efforts to collect and distribute human tumor tissues for cancer research (1).” The acquisition of normal and malignant tissues from human patients with cancer is complex, necessitating compliance with legal and ethical requirements to protect patients’ interests (patient diagnosis and assessment of prognostic factors take precedence). Obtaining human samples involves adherence to best technical practices to ensure the biospecimens are well-annotated and fit to support reproducible research. At the same time, large store-house biorepositories may struggle for sustainability (2–4). The CHTN was designed to provide technical best practices for tissue procurement and distribution in a cost-efficient manner. Its unique feature is that it is predominantly a prospective sample procurement network across a wide network of academic institutions (departments of pathology). Focusing operations prospectively in response to investigator requests improves biospecimen utilization rates and also allows investigators to specify/control some preanalytic variables. CHTN investigators may also be able to access archival biospecimens previously collected if they are available (retrospective sample procurement). Archival sample availability is critical to allow research comparing primary solid tumor samples to metastatic tumor samples which may be separated in time by many years.

CHTN has intentionally remained a specimen procurement bioresource, predominantly focused on delivering high-quality normal, diseased and malignant human tissue samples with associated data and blood. By comparison, in the years since 1987, several very large and well-recognized bioresources have been developed including the UK Biobank and the “All of Us” Research Program in the United States. The UK Biobank was established in 2006 to collect baseline assessments and follow-up health data on 500,000 consented United Kingdom residents between 40 and 69 years of age. Associated biospecimens are serial collections of blood, urine, and saliva (5). Similarly, the “All of Us” Research Program opened in 2018 in the United States with the goal of enrolling more than 1,000,000 adult participants from diverse backgrounds to share their electronic health records and provide additional health data, urine and blood samples to include germline whole-genome sequencing (WGS; ref. 6). Both of these resources are population-level biobanks designed to facilitate investigations into links between genetics, lifestyle factors, and disease development. Importantly, neither the UK Biobank nor the “All of Us” Research Program collect, store, or distribute tissue samples. This highlights an important distinction, as bioresources dedicated to curating and making solid tissue specimens from the population of patients with cancer will necessarily be smaller and will require the dedicated effort of medical professionals trained in assessing the quality of individual tissue specimens. Although large residual biospecimen collections from federally funded clinical trials do exist, we are not aware of another federally funded cooperative resource that supports unique, bespoke biospecimen procurements designed to meet the experimental needs of individual investigators to include specific human tissue specimens with specialized media, handling, and analysis.

When it began in 1987, the CHTN included three institutions: The University of Alabama at Birmingham (Birmingham, AL), the National Disease Research Interchange in conjunction with the Hospital of the University of Pennsylvania (Philadelphia, PA), and The Ohio State University (Columbus, OH), which housed a cooperative agreement with the Children's Cancer Study Group to provide pediatric tumor samples (7). This group was expanded in 1991 to include Case Western Reserve University and the Children's Hospital of Columbus (now Nationwide Children's Hospital; ref. 8). By 2001, the CHTN was comprised of six divisions, which included the Pediatric Division at Nationwide Children's Hospital plus five divisions designed to serve as the primary points of contact for investigators geographically located in different regions shown and described in Fig. 1. The divisions have remained largely unchanged since 2001 except the Southern Division which was moved from the University of Alabama at Birmingham to Duke University (Durham, NC) in 2019. Each division primarily serves investigators in its assigned geographical region; however, when needed, specific requests may be filled through the combined efforts of multiple divisions (called “networking a request”). The network is overseen by a Coordinating Committee composed of representatives from the six CHTN divisions and the NCI.

CHTN divisions are led by academic, diagnostic pathologists with extensive experience in tissue procurement, processing, and utilization in translational research. This is by design – the request for application (RFA) specifies that the principal investigator, “must be a board-certified anatomical and/or surgical pathologist, who is actively involved in the operation of a pathology laboratory that has demonstrated access to human cancer tissues.” Further, the funding opportunity announcement (FOA) defines the mission of the CHTN in four parts – only one of which is the provision of biospecimens. Other mission objectives include consultative assistance to researchers about the specific biospecimen needs of their project(s), development and dissemination of high-quality biospecimens, and education of the community regarding the critical nature of having available, high-quality tissue specimens for use in biomedical research.

The CHTN has been continuously funded for more than 35 years since 1987, with the most recent reissue of the request for applications as RFA-CA-18–025: UM1 Research Project with Complex Structure Cooperative Agreement (9). Prior publications containing CHTN updates occurred in 1989 (1), 1993 (7), 1998 (8), 2002 (10), 2004 (11), 2008 (12), 2010 (13), and most recently, in 2018 (14). This most recent publication thoughtfully described “lessons learned” through three decades of operation from the perspective of a subset of network leaders. In this review, we will provide an updated operational summary through the end of 2021, an assessment of CHTN's biospecimen disbursements over time, and discuss technological changes in biomedical research that have altered the types of requests fielded by CHTN, especially over the last fifteen years. We will illustrate operational changes observed as CHTN adapted to meet investigators’ evolving needs, and discuss new technologies and strategies being incorporated for the future.

CHTN specimen distribution began in June 1987, starting slowly (160 specimens distributed in the first month of operation) and accumulating momentum, exceeding 60,000 samples per year four times in the first 20 years of operation (2000, 2001, 2005, and 2006; Fig. 2). Since 2007, however, the total number of specimens distributed annually has been lower, with the network distributing more than 50,000 samples per year only twice (2008 and 2012). Although there are likely internal/divisional operational issues and funding shifts that contributed to this change, advances in biomedical research technology and the increasing utilization of molecular biomarkers to drive clinical care have also played a major role; these will be further discussed.

The health care system since 2007 has seen seismic shifts in clinical practice that have adversely impacted biospecimen availability for research. The emergence of neoadjuvant treatments for many solid tumors dramatically reduced the availability of aliquots of these tumors for research at the time of resection due to complete pathologic response (15–19). Molecular biomarker testing shifted from individual genes examined by Sanger sequencing (i.e., KRAS testing to direct EGFR-based therapy in colorectal cancer; refs. 20, 21) to panels of hundreds of genes, simultaneously interrogated using NGS to inform the choice of therapy (e.g., Foundation CDx assay; ref. 22).

Today, sequencing technology is maturing to the point that whole-exome sequencing (WES) and WGS are being used with increasing frequency in the clinic. Expanded panel-based testing now includes RNA sequencing/expression analysis, the ability to detect copy-number alterations and biomarker calculations such as tumor mutational burden and microsatellite instability (23). As these large panels were being increasingly performed on tissue samples, an improved appreciation for both tumor heterogeneity (24) and tumor genotype evolution throughout the disease course (25) necessitated a move away from research based on larger samples of the primary tumor (obtained at surgical resection in early-stage patients), with a corresponding shift toward research on the basis small biopsy samples of metastatic lesions. Requests for biospecimens from metastatic lesions became more common, as well as requests for biospecimens obtained at specific points in the treatment arc (such as after exposure to immune checkpoint inhibitors or targeted agents). In addition, the emergence of assays to identify cell-free, circulating DNA, and the most recent evolution of using such assays to detect subclinical minimal residual disease (26, 27) has rekindled research focus on blood-based biospecimens.

Technological advances over the last fifteen years have also shifted the types of biospecimens needed as substrates for assays that remain, for the moment, in the research realm. For example, the optimal substrate for single-cell sequencing is disaggregated, viable cells obtained from freshly procured tissue samples (28, 29). Investigating therapeutic options in vivo can now be performed on viable patient-derived models (cell cultures, organoid cultures, or patient-derived xenografts) rather than commercially available immortalized cell lines (30–32). The creation of these patient-derived models (often called avatars) requires the use of freshly-procured or specially cryopreserved tissue samples.

The expertise of current principal investigators and coordinators is offered to new CHTN investigators at the time of application, especially if requests are unusual and/or unlikely to be accommodated. Suggestions for modifying analytical techniques (thus using smaller tissue aliquots) may be recommended. Special services such as macrodissection of tissue samples to increase percentages of tumor cells in some specimens can also be provided by the CHTN.

These clinical and research shifts have resulted in increases in requests that are considered more difficult to fulfill (fresh rather than frozen or fixed tissue, brief ischemic times, rare diagnoses, deeper clinical annotation, high tumor content, matched blood, and tissue). Specifically, requests for fresh tissue aliquots rose from 15% in 2007–2011 to 25% in 2017–2021. Requests for blood and blood-based biospecimens with or without matched tissue specimens rose from 10% in 2007–2011 to 27% in 2017–2021, and requests for the upon-demand service of “chart reviews” (to provide deeper biospecimen annotation or pinpoint a biospecimen aliquot to a specific point in time on a patient's treatment journey) rose three-fold between 2007–2011 and 2017–2021. These trends across the last three five-year cycles are shown in Fig. 3. A “chart review” allows a requesting investigator to effectively design their own case report form (CRF) for their experiments where additional background information (smoking history, surgical history, family history, etc.) can be obtained to accompany the biospecimen. When resources are limited, this “just-in-time” annotation has been the optimal approach to clinical data abstraction and distribution.

CHTN divisions are successfully evolving to meet these changing demands, even though they are more labor-intensive to fulfill. For example, CHTN policies, designed to meet or exceed federal requirements for the protection of human subjects, require informed consent of biospecimen donors when their CHTN samples will be used in a viable expansion protocol (such as PDX or organoid culture creation) or for WES/WGS. Informed consent is also required for the drawing of blood. In contrast, the distribution of deidentified biospecimens left over from routine clinical care (such as archival formalin-fixed, paraffin-embedded tissues) may occur under a waiver of informed consent if sufficient privacy protections for the patient are in place (as determined by the local Institutional Review Board). Thus, increased demand for biospecimens requiring informed consent of donors is inherent within the increased requests for fresh tissue and blood. Some CHTN divisions are responding by increasing the allocation of their direct support toward patient consent and regulatory affairs. In another example, meeting requests for viable tissue biospecimens is more labor-intensive than meeting requests for frozen or fixed biospecimens. Viable tissue specimens, rapidly acquired and transferred into specialized media (often provided in advance by the investigator), must be documented, processed, and shipped out on the same day they are procured to facilitate overnight delivery. In comparison, frozen or fixed biospecimens can often be batch-handled and do not require specialized media or overnight shipping. The expansion of requests for blood biospecimens has included investigator intent to perform specialized assays including the isolation of cell-free, circulating tumor DNA or circulating tumor cells; such downstream assays may require CHTN to utilize and distribute nonstandard consumables for biospecimen stabilization, and/or perform more intensive processing protocols such as double-centrifugation of plasma under refrigeration.

During fixed or decreasing funding for the CHTN program, an increase in required work per distributed biospecimen likely contributes substantially to the recent reduction in samples shipped yearly during these five-year periods (Fig. 2). Interestingly, there has been a slight increase in the proportion of commercial investigators over the last ten years, which could also reflect relative changes in funding to research occurring in the public and private sectors (Fig. 4). In addition, the quantity of biospecimens requested by any individual investigator has decreased. A deeper review of operational data shows that the 26.4% decrease in mean number of annual biospecimens distributed between 2012–2016 and 2017–2021 was accompanied by only a 14.4% decrease in the mean number of investigators served. Anecdotally, we note investigators who previously requested 50 fixed colorectal cancer specimens may now be requesting 10 viable, unique fresh aliquots of colorectal cancer.

There has also been a relative leveling off in the quantity of samples distributed over the last four years (Fig. 2). Excluding the dip in 2020, which was likely due to the COVID-19 pandemic and the transition of Southern Division from the University of Alabama at Birmingham to Duke University that occurred in mid-2019, the mean number of samples shipped per year in 2018, 2019, and 2021 was 35,958 with a standard deviation of only 900.

The ability of CHTN to provide specialized prospective biospecimen collections and retrospective sample procurement has been highly effective, resulting in the cumulative distribution of 1,375,041 biospecimens through the end of 2021. These CHTN specimens supported at least 341 publications between 2017 and 2021 with an average impact factor of 6.8. It is important to note that some of the CHTN division institutions (and their pathologists) also supported The Cancer Genome Atlas (TCGA) program as tissue source sites, expert pathology reviewers and with biospecimen processing infrastructure. The TCGA produced 73 publications between 2008 and February, 2021, many of them high impact and widely-cited (33). Representative recent high-impact publications are presented in Table 1. Note that publications may not be included in CHTN's records if formal acknowledgement of CHTN was omitted by the authors. The network served 889 active investigators in 2021 and 63 new investigators were approved between January 1, 2022 and October 14, 2022.

CHTN divisions facilitate prospective and retrospective biospecimen procurement and distribution under practices that meet or exceed federal requirements for the protection of donor participants. All divisions must also meet or exceed widely-accepted best practices for biorepository operations (34, 35). The Pediatric and Southern Divisions maintain accreditation under the College of American Pathologists’ Biorepository Accreditation Program (36) which is an optional accreditation program that provides biobanks an opportunity to formally demonstrate their compliance with best practices. All tissue biospecimens distributed to investigators by CHTN divisions undergo histologic quality assessment to confirm diagnosis and assess percentage of necrosis and percentage of tumor nuclei; these data are provided to the receiving investigators. Each division of CHTN also contributes in unique ways to the overall cooperative network; these will be briefly discussed.

The Eastern Division of the CHTN (ED) has been housed at the University of Pennsylvania since the creation of CHTN in 1987. In addition to sample procurement and distribution, ED excels in the educational mission of the CHTN – that is, assisting in developing and disseminating knowledge on best practices for successfully operating a biorepository, and educating the community about the importance of available, high-quality tissue specimens for medical research.

Over the past 5 years, the ED has contributed to three peer-reviewed publications specifically around biospecimen infrastructure and science, and informatics. The ED team has independently presented 10 abstracts as either poster or platform presentations, facilitated three round table conversations and 14 educational workshops for the cancer research and biobanking communities.

As part of the ED community education program, the ED partnered with a regional school to implement an educational program for middle school children interested in STEM. The goal of this initiative was to expand the students’ perception of pathology and research laboratories and to begin to shape their understanding of the role of biorepositories in the medical field. In other actions, the ED Coordinator cohosted a Tweetchat with Salud America! at UT Health San Antonio to discuss Biospecimen Donation, and how donating can improve health for all people, especially those who suffer health disparities.

The ED Coordinator continues to advance the educational mission of the CHTN as a Director-at Large of the Americas in the International Society of Biological and Environmental Repositories (ISBER). She is an active member of multiple committees for this society and is currently an advisor to the ISBER Education and Training Committee. She developed the ISBER Biobanking 101 Workshop series and continues to cochair this interactive series now in its 5th year. Many of her initiatives focus on training future generations of biobankers, including building awareness of the new Qualification in Biorepository Science (QBRS^cm). This credential, which she achieved in its inaugural year, is administered by the American Society of Clinical Pathology and identifies a proficiency level for biobanking professionals.

The Midwestern Division of CHTN (MWD) has been housed at The Ohio State University since 1987. It supports high-quality, high-volume sample distribution and contributes significantly to the educational missions of the CHTN by annually presenting multiple abstracts at biobanking and scientific conferences locally, nationally and internationally. During the last five years, MWD personnel have published three peer-reviewed biospecimen science journal articles (37–39) and have made 34 CHTN-related conference podium/poster presentations independently and four cooperatively with staff from other CHTN Divisions. Also, during this time period, the MWD principal investigator was an invited speaker (2019) and workshop moderator (2021) for the International Society for Biological and Environmental Repositories (ISBER) regional and annual meetings.

The Midwestern Division created a CHTN tissue procurement manual and published Version 1.0 in August 2020 on the OSU Knowledge Bank website (40). This original medical art project captures the teaching essentials of surgical specimen malignant tumor patterns and research tissue procurement. Mr. Steven Moon completed all original artwork for the manual.

The MWD principal investigator serves on the Executive and Program Committees for the Digital Pathology Association and the Education Committee, Best Practices for the American Society for Clinical Pathology. The MWD principal investigator is also Editor in Chief of the Journal of Pathology Informatics and Diagnostic Pathology journals. The MWD Coordinator serves on the International Society of Biological and Environmental Repositories (ISBER) Education and Training Subcommittee.

In 2022, MWD has established an image repository using PathPresenter (PathPresenter) that allows investigators to review and select digitized slide images and request them for use in artificial intelligence algorithm development, etc.

The Pediatric Division of CHTN (pCHTN) is unique, as it was established to be the primary provider of pediatric tumor and normal biospecimens to investigators across the entire network, regardless of geography. This vital resource has been a part of CHTN since 1987 when it initially contributed samples to CHTN under a cooperative agreement through The Ohio State University. For over three decades the pCHTN has used both its institutional resources and its longstanding partnership (since 1989) with the Children's Oncology Group (COG) to provide pediatric biospecimens to CHTN researchers. The pCHTN also houses and administrates a collection of 34 TMAs, many of which were customized to address specific COG research projects. These COG TMAs are available to CHTN investigators via a separate application process. The pCHTN can also facilitate specialized creation of new TMAs from COG-approved cases on a fee-for-service basis. Other special services also available through pCHTN on a fee-for-service basis include laser capture microdissection, nucleic acid extractions, flow cytometry, cell line creation, and clinical genetic/genomic testing. The pCHTN director is a former chair of the College of American Pathologists’ Biorepository Accreditation Program committee and continues to lead the U.S. working group contributing to the International Standards Organization Standard “General requirements for biobanking” (ISO 20387:2018; ref. 41).

In 2001, the CHTN was expanded to six divisions with the addition of the University of Virginia (UVA) being added as the Mid-Atlantic Division. The Mid-Atlantic division initially served only two states (Virginia, Maryland, and the District of Columbia and was also assigned to provide samples for the internal research programs on the campuses of the NIH.) This smaller footprint of service coverage was due to the fact that UVA was brought into the network in part for its demonstrated facility with the then relatively new technology of tissue microarray (TMA) construction. The Mid-Atlantic Division was charged with creating TMAs to be distributed by the CHTN in addition to providing TMA construction for other programs coordinated through the Cancer Diagnosis program of the NCI, such as the Cooperative Breast Cancer Tissue Resource (CBCTR). Over the years, the Mid-Atlantic Division has created 18 different TMA designs specifically for the CHTN and four discrete TMA sets for the CBCTR that encompassed 28 separate TMA blocks to cover the breast cancer tissue cohorts. The CHTN TMA designs included representations of normal tissue (normal tissue surveys, normal endometrium cycle, normal nervous system) as well as cancer cohorts (breast, colorectal, lung, ovarian, pancreas, prostate).

In 2018, the requirement for the open competition of the CHTN parent grant required that submitting applications include at least two subsites outside of the state of the submitting institution, to ensure diversity not only in terms of geographic distribution, but also in race and ethnicity. The University of Virginia successfully renewed its membership in the CHTN in this grant cycle by joining with two additional tissue procurement sites: the Medical University of South Carolina (MUSC) and the University of New Mexico (UNM, Albuquerque, NM). These sites provide an expanded diversity of race and ethnicity to the patient cohort available at UVA with MUSC having 22% African Americans in its patient cohort and UNM having 49% Hispanics in its patient cohort, compared with 11% and 3%, respectively, for the UVA patient cohort.

The Western Division of CHTN (WD) was part of the 2001 expansion of CHTN and has been housed at Vanderbilt University since that time. It is unique in the network because it serves as the CHTN Central IT Coordinating site and provides network-wide informatics infrastructure for the CHTN. In addition, WD has created for its internal use a suite of applications that align their workflow and optimize their capabilities that connect with a deidentified Investigator Donor Portal. The Donor Portal was created as a “marketplace” experience for the CHTN Investigators to access frozen and FFPE inventory, donor case selection tools for fresh tissue collection, digital slide images, deidentified pathology reports and chart reviews, as well as access to their CHTN investigator application and requests. Resource planning and analytics modules are based on previous collections to assist investigators with grant submissions.

As an example of the Western Division's commitment to the quality and training missions of the CHTN, the WD coordinator was the first person to obtain a Black Belt in Lean Six Sigma and the second CHTN Coordinator to obtain the professional certification “Qualification in Biorepository Sciences (QBRS)” from the American Society of Clinical Pathology and ISBER (42).

The Southern Division of CHTN (SD) was housed at the University of Alabama at Birmingham from 1987 through 2019, with the principal investigator providing international, longstanding leadership in biospecimen availability and quality (43–46). In 2019, the Southern Division was moved to Duke University where it continues to support the distributive, educational, and quality missions of CHTN, as well as the evolution of the resource through novel pathology informatics strategies. SD is home to the Frameshift Molecular Registry of Tumors software which aggregates and normalizes granular somatic sequencing data from commercial vendors and internal laboratories (47). This allows cohorts of retrospective biospecimens to be aggregated via specific somatic variants. For example, investigators can request retrospective pancreatic adenocarcinoma samples known to contain MTOR missense mutation p.A519T. Early experience suggests that, while organ-of-origin requests for tumors are still common, many requests include requirements for biospecimens to contain at least one relevant biomarker (such as HER2 overexpression in the case of breast adenocarcinoma). More recently, occasional requests arrive for organ-agnostic, variant-specific biospecimens, (such as requests for “all solid tumors with CHEK2 mutations”), mirroring changes that are anecdotally seen in inclusion criteria for interventional clinical trials over the same time period SD is also optimizing blood sample distribution through its partnership with Duke University's Clinical Laboratories. In this model, residual blood and fluid samples from specific cohorts of patients are recovered using a just-in-time bioinformatics approach that alerts SD staff to the presence of appropriate samples on the basis of clinical criteria. SD also offers whole-slide imaging, nucleic acid extraction, multiplexed IHC stains for standard immune markers, and digital spatial profiling/transcriptomics via the NanoString GeoMx platform (48).

The SD director previously served on and now chairs the College of American Pathologists’ Biorepository Accreditation Program committee. The SD director serves on the ISBER Standards Committee and was also a contributor to the fourth edition of the ISBER Best Practices (34). Since becoming the SD for CHTN, the SD director spoke at the ISBER annual meeting in 2019 on the CAP biobanking standard. The SD director then copresented a workshop on new models for bioresources to reduce scientific irreproducibility at the ISBER North American Regional Meeting in 2019. The larger SD group presented a total of five abstracts at ISBER annual meetings in 2019 and 2021.

The critical need for biospecimens distributed through CHTN to be representative of all communities the United States was emphasized in the most recent RFA. CHTN divisions are responding, with each division establishing subsites for procurement of additional biospecimens. Also, divisions whose staff routinely obtain informed consent of donors, such SD, are working with their institutional community engagement organizations to improve diversity of participants through staff implicit bias training and the formation of community panels to optimize broad consent form wording and consent practices.

Beginning in March 2020, every CHTN division and subsite was adversely affected by the pandemic. The most common occurrence that year was a complete shut-down of nonessential medical operations (clinical operations and interventional, treatment-related clinical research). Elective surgical procedures were cancelled. Staff considered nonessential were not permitted to be present on the hospital campus. It would take about two years for clinical and research operations to fully resume prior levels. As research activities resumed during later 2020, some divisional infrastructures began procuring biospecimens from COVID-19 patients or decedents at the time of autopsy to support research with guidance from their local occupational safety offices. The Coordinating Committee for the network elected to not ship COVID-19–positive fresh or frozen biospecimens to CHTN investigators due to biosafety concerns during transport. Fixed specimens and tissue blocks were able to be shipped.

In keeping with the educational mission of CHTN, the Midwestern division of CHTN published their experiences as a result of the COVID-19 pandemic (37). The Southern division director coauthored a two-part series “Biobanking in the COVID-19 Era and Beyond” which was published in the ISBER journal (49, 50).

In May 2019, the Southern Division of CHTN moved from University of Alabama at Birmingham to Duke University; this was the first change to the CHTN divisional structure made since 2001. The on-boarding process was carefully documented by the NCI and Duke University CHTN leaders; an immediate requirement included updating CHTN documents to reflect the new location of SD – this included updating the investigator agreements; since these are signed by institutional officials, these revisions had to be reviewed and approved by the contract review offices of all divisions’ parent institutions. New CHTN staff benefitted from the existence of prior operational documentation, and during the first two years the CHTN Coordinating Committee worked to fill in gaps in documentation when they were discovered. On-boarding was greatly facilitated by the goodwill of existing principal investigators and coordinators, who assisted as new staff gained familiarity with the multiple software platforms including TissueQuest (investigator request platform), ShipLog, and JasperReports. The new division also had to operationalize a substantial ramp-up in space and personnel. Finally, investigator copayment fees are received into the divisions as program income; this is an uncommon mechanism for SD's parent institution; policies surrounding the utilization of this income took substantial effort to clarify. These observations may help with future divisional on-boarding necessitated through transition or network expansion.

Currently, the network's Strategic Planning Committee (comprised of the principal investigators of all divisions plus NCI representation) is undertaking a series of projects to ensure the network continues to evolve optimally to meet researchers’ needs. Website information is ensured to be current and website design is updated as needed with links to social media channels. The network has a presence at large scientific meetings to increase awareness of the resource, and a current effort is focused on developing a new digital marketing strategy also aimed at increasing awareness. The Strategic Planning Committee is also planning a larger roll-out of several ancillary research services centered on tissue. For example, because of the increased focus on machine learning in recent years, there is an interest in providing whole-slide imaging services - all CHTN divisions have the capability to digitize glass slides. Nucleic acid extraction, IHC, in situ hybridization, and image analytic services are available through several divisions, and two of the six CHTN divisions also offer digital spatial profiling/spatial transcriptomics. At the inception of the cooperative network, it was clear that optimizing tissue quality for biomedical research was a critical goal. In the same way, the expanded use of multiplexed profiling and sequencing, as well as image analytics will be optimized for research through the involvement of pathologists, such as CHTN pathologists, to maximize reproducibility. CHTN pathologists have always identified the best representative slides and tissue sections for investigators to study—in the case of image analytics and spatial profiling, CHTN pathologists can extend their involvement to identify the optimal regions of interest on tissue sections for molecular and digital quantification.

Overall, the vision for the future of CHTN includes enhanced availability of more labor-intensive biospecimen types such as matched blood specimens to accompany fresh tissue, newer analytic services such as whole-slide imaging and spatial profiling, and broadened community representation through expanded subsites and targeted recruitment. From a data perspective, the future of CHTN also includes leveraging new data types (e.g., whole-slide images), advances in data ontologies, and new data analytic strategies including machine learning and artificial intelligence to provide more thorough biospecimen annotations. This will facilitate distribution of more social element, molecular phenotype, and clinical outcome data.

Investigators wishing to engage with CHTN can visit the network's central website at https://chtn.org where they can access information and an application. It is important to emphasize that CHTN is a prospective procurement resource catering to specific investigator experimental requests rather than a true “biobank” of stored samples ready to release. As such, investigators are routed through an application/consultation approach rather than a search page. Researchers wishing to identify previously stored samples that may be readily available for use can access the NCI's separate Specimen Resource Locator, at https://specimens.cancer.gov – this link is also available on the CHTN homepage. CHTN Applications will be processed by the CHTN division assigned to the investigator's geography as shown in Fig. 1.

S.J. McCall reports grants from NCI during the conduct of the study; personal fees from Astra-Zeneca and personal fees from Takeda Pharmaceuticals outside the submitted work; and co-creator of Frameshift Molecular Registry of Tumors Software, licensed by Duke University. C.A. Moskaluk reports grants from NCI during the conduct of the study. N.C. Ramirez reports grants from National Cancer Institute/NCI paid to Nationwide Children's Hospital during the conduct of the study. No disclosures were reported by the other authors.

This work was supported by grants UM1CA239755, NCI Cooperative Human Tissue Network Southern Division, P20CA251657, Core 1 Biospecimen/Pathology, P30CA014236 BioRepository & Precision Pathology Center (to S.J. McCall); UM1CA239752, NCI Cooperative Human Tissue Network Mid-Atlantic Division; Henry Jackson Foundation: Subject recruitment and biospecimen procurement for the Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) consortium; Philips Corporation: Pivotal study for validation of Philips DX (to C. Moskaluk); and UM1CA239749, NCI Cooperative Human Tissue Network, Midwestern Division (to A. Parwani). UM1CA239754, NCI Cooperative Human Tissue Network Pediatric Division; U24CA196173, COG Relapse Tumor – Supplement; U24CA196175, SWOG Biospecimen Bank to support NCI NCTN; P50CA272170, Core B Biospecimen Core; U24CA196173, COG Biospecimen Bank to support NCI NCTN; U24CA254445, EET Biobank, NCI Early-Phase and Experimental Clinical Trials Biospecimen Bank; U24CA196067, NRG Oncology Biospecimen Bank (to N. Ramirez); UM1CA183727, NCI Cooperative Human Tissue Network Western Division; P50CA236733, Core 1 Tissue Pathology and Cellular Analysis; P30DK058404, Translational Analysis Core (to M.K. Washington);UM1CA239745, NCI Cooperative Human Tissue Network Eastern Division; University of Maryland A Phase II Biomarker Study of Parathyroid Tumor Clonal Status in Primary Hyperparathyroidism (V.A. Livolsi). The authors would like to acknowledge previous principal investigators of CHTN divisions; for Ohio State University: Kathryn P. Clausen, Leona W. Ayers; for Nationwide Children's Hospital: William A. Newton, Jr; for the University of Alabama at Birmingham: William E. Grizzle; for Case Western Reserve University: Thomas G. Pretlow, II. The authors would also like to acknowledge the current and previous program officers for CHTN through the NCI: Rodrigo Chuaqui and Roger Aammodt.