Transmembrane protein TMEM98 as a multifunctional regulator in cancer: from signaling pathways to translational implications.

Introduction
Transmembrane proteins (TMEMs) play crucial roles in many cellular processes, such as signal relaying, molecular transport, and structural cytoskeletal organization [1, 2]. With advances in high-throughput sequencing and functional genomics, our knowledge of TMEM family proteins, especially in tumorigenesis, has been greatly improved. These proteins steer hallmark behaviors such as unchecked proliferation, epithelial-to-mesenchymal transition, invasion, and distant spread [1].
TMEM98 is emerging as a versatile oncogenic regulator. Normally present in many tissues, it becomes dysregulated in several solid tumours. In gastric cancer, TMEM98 over-expression correlates with poor survival by stabilising its own mRNA and driving proliferation and invasion [3]. More broadly, it governs adhesion, growth, invasion and apoptosis [4]. and remodels the tumour micro-environment by strengthening endothelial adhesion while stimulating vascular-smooth-muscle migration and proliferation, thereby promoting angiogenesis [5]. Mechanistically, it is implicated in various oncogenic signaling pathways, most striking of which include Wnt/β-catenin, AKT/GSK3β, NF90-associated regulation of transcription, as well as MYRF self-cleavage, highlighting its multifactorial and intricate involvement in cancer development [3, 6–9]. Specifically, TMEM98 binds the RNA-binding protein NF90 to form a feed-forward loop that protects its transcript [3]. Elsewhere, TMEM98 tempers canonical Wnt signalling by targeting the GSK3 adaptor FRAT2 [8]; blocks MYRF self-cleavage and nuclear entry in the endoplasmic reticulum [6, 10]; and, when silenced, dampens the AKT/GSK3β cascade and cell-cycle drivers such as cyclin D1 and β-catenin [5]. In addition to its oncological implications, TMEM98 mutations also correlate with developmental eye abnormalities, such as nanophthalmos, indicating that it is also involved in relating developmental processes to neoplastic transformation [11, 12]. Although there is an accumulating literature, there remains no coherent review integrating its molecular mechanisms and cancer-specific signaling functions into current knowledge.
This paper fills that void by presenting an integrated overview of TMEM98 functional dynamics in cancer, revealing its mechanistic functions, signal transduction pathway involvement, tissue-specific expression patterns, and therapeutic or diagnostic utility potential. We also indicate directions for research and translational application of TMEM98 in cancer diagnosis and treatment.
In the pages that follow, we first position TMEM98 within the broader TMEM family, then outline its gene features and regulation, survey its cancer-specific roles, dissect the key signalling axes it modulates, and close with translational prospects and open questions.

TMEM protein family

Structural characteristics
TMEM proteins are = versatile membrane sentinels, including 272 members [13], which are ubiquitously expressed across tissues and organs [2, 14]. They lodge in plasma and organelle membranes via one or more hydrophobic helices [13, 15], and facilitate the assembly of monomeric, dimeric, or higher-order complexes [14, 16]. These configurations enable TMEMs to participate in processes such as signal transmission, ion exchange, cytoskeletal tethering, and intercellular recognition [2, 17, 18].
Recent advances in cryo-electron microscopy and structural prediction technologies have revealed the 3D structures of several TMEMs. TMEM175 looks like a potassium channel yet picks ions its way [13, 19–23], while TMEM16A unfurls a twin-pore scaffold that guides other TMEM channels [13, 24–32]. Additionally, N-/C-terminal orientation and partnering define function [33–36].
Topological diversity among TMEMs has been verified through both predictive and experimental methods. For example, TMEM30B [18, 35, 37–40], TMEM116 [18, 35, 41–43] and TMEM213 [18, 35, 36, 44, 45] have been localized to the endoplasmic reticulum or early endosomes, displaying diverse N-/C-terminal orientations and membrane integration patterns [35, 36], implying their involvement in specialized subcellular functions. Although TMEM98 lacks a direct genomic paralogue, two closely related single-pass neighbours, TMEM97 (σ−2 receptor) and TMEM10 (Opalin), share its overall topology and membrane locale and may functionally compensate when TMEM98 is inhibited. TMEM97 resides in the ER/Golgi, binds the Wnt co-receptor LRP6, and amplifies β-catenin signalling, counterbalancing TMEM98’s FRAT2-mediated repression of the same pathway; conversely, TMEM10, up-regulated during oligodendrocyte maturation, promotes MYRF-driven myelin gene expression, offsetting TMEM98’s brake on MYRF auto-cleavage [6, 46].

Biological functions
Despite their conserved architecture, TMEM proteins display wide-ranging biological functionalities. They choreograph ion flow, metabolism, mechanics, and immunity [13, 20]. Several TMEMs function as ion channels. TMEM175 [21, 22], TMEM206 [47–49], TMEM38 [13], and TMEM63 [50–53] are known to mediate the transport of potassium, protons, or calcium, thereby playing key roles in maintaining organelle pH balance and calcium homeostasis [13, 54–56]. Some TMEMs are mechanosensitive [57–60]. For instance, TMEM120A (TACAN) is critical in mechanical nociception [57, 58, 60, 61], and TMEM150C (Tentonin3) responds to mechanical cues in sensory neurons [13, 59, 62–66]. TMEM135, in contrast, TMEM135 balances mitochondrial fission and lipid crosstalk [17, 67–73]. On the proliferative stage, TMEM14A presses the G1/S gas pedal [74–76], while TMEM119 [77], TMEM48 [2, 78, 79], and TMEM45B [80–83] enhance proliferation and survival in multiple malignancies [18, 77, 78, 80, 84, 85]. In the immune context, TMEMs can function as platforms for immunomodulatory signaling. Their dimerization often acts as immune switches, shaping checkpoint and cytokine traffic [16].

TMEMs in cancer
Aberrant TMEM expression has been observed in various malignancies, often correlating with diagnostic, prognostic, and therapeutic parameters. TMEM201, for example, is overexpressed in hepatocellular carcinoma (HCC), where it drives cell proliferation and migration, and may serve as a biomarker of high-risk disease [86]. TMEM45A, TMEM48, and TMEM116 similarly promote tumor progression in lung, cervical, and head and neck cancers [45, 78, 80]. Additionally, TMEM expression patterns often reflect the immune status of the tumor microenvironment. Overexpression of certain TMEMs is associated with immune suppression, such as increased infiltration of regulatory T cells (Tregs) and elevated expression of checkpoint molecules like PD-L1 and CD276 [86, 87]. Recent studies have identified TMEM115 as a biomarker associated with immune infiltration in hepatocellular carcinoma (HCC). Notably, patients exhibiting low TMEM115 expression tend to show elevated levels of PD-L1 and reduced expression of LAG3 [88].

TMEMs in other disorders
TMEM proteins also play critical roles beyond cancer, particularly in neurological and metabolic disorders. TMEM175, a lysosomal potassium channel, mutates in Parkinson’s disease, upsetting pH and stalling α-synuclein clearance; some Chinese early-onset cases even carry combined TMEM175/TMEM163 variants [20–23]. TMEM43 [13] and TMEM63 [51, 56, 89, 90] are involved in synaptic regulation and may influence neurodevelopmental processes such as axon guidance [15]. In the context of inherited and metabolic diseases, TMEM38B fractures bone in osteogenesis imperfecta, TMEM43 enlarges hearts in arrhythmogenic cardiomyopathy [13], and TMEM150C blunts hearing in auditory-neuropathy spectra [13, 59, 62–66]. TMEM135 is implicated in age-related metabolic syndromes due to its central role in mitochondrial and lipid metabolism [17].

Molecular characteristics and functional mechanisms of TMEM98

Structure, localization, and expression profile
The human TMEM98 gene, mapped to chromosome 17q11.2, encodes a conserved type II single-pass transmembrane protein composed of 226 amino acids (Fig. 1). AlphaFold modelling (global pLDDT > 80) predicts three short α-helical bundles capped by a flexible ectoloop that forms solvent-exposed grooves suitable for antibody or small-molecule binding; although no crystal or cryo-EM structure is yet available, nanophthalmos topology studies corroborate this orientation. A single full-length transcript predominates and is broadly expressed, with highest levels in retinal pigment epithelium, neural tissue, vascular endothelium, and many solid tumours [10, 91].

Subcellular mapping places TMEM98 at the plasma membrane, Golgi, and recycling endosomes, with a fraction secreted in exosomes [8, 91], implying roles in cargo sorting and intercellular signalling. The immunogenic ectodomain is therefore tractable for therapeutic antibodies or antibody–drug conjugates, while the short cytosolic tail, harbouring FRAT2- and NF90-binding motifs, offers handles for stapled-peptide, PROTAC, or structure-guided campaigns once high-resolution data emerge. This simple topology, tumour-biased expression, and accessible extracellular loop collectively identify TMEM98 as a druggable entry point and set the stage for the cancer-focused analyses that follow.

Regulatory molecular mechanisms
TMEM98 exerts its biological effects not only through protein-level functions but also via its mRNA, which has been shown to participate in post-transcriptional regulation. In gastric cancer cells, TMEM98 mRNA harbors a specific 3′-UTR motif that binds to the NF90 protein, stabilizing NF90 and enhancing tumor cell proliferation and invasiveness [3]. This study introduced the novel concept of an “mRNA-protein mutual stabilization feedback loop,” providing a new perspective on the functional relevance of untranslated mRNA regions. Additionally, TMEM98 negatively regulates the FRAT2-dependent Wnt/β-catenin signaling pathway. By downregulating FRAT2 protein levels, TMEM98 suppresses β-catenin nuclear activation, potentially acting as a regulatory “brake” to maintain signaling equilibrium [8]. This mechanism highlights its role in fine-tuning oncogenic signal transduction.
Of particular interest, TMEM98 forms a complex with the transcription factor MYRF, inhibiting its self-cleavage activation process. MYRF is an endoplasmic reticulum-anchored membrane transcription factor whose function depends on autoproteolysis that releases its N-terminal domain for nuclear translocation. TMEM98 binding interferes with this process, thereby modulating MYRF activity and impacting retinal development and ocular stability [6, 10]. These findings suggest a broader implication of TMEM98 in controlling transcription factor processing and, potentially, cancer cell gene expression profiles.
Furthermore, TMEM98 is a central target within microRNA (miRNA) regulatory networks. For example, miR-29c-5p and miR-219-5p directly bind to the 3′-UTR of TMEM98, downregulating its expression and affecting cellular processes such as migration and wound healing in head and neck cancers and keratinocytes [92, 93]. These results underscore the significance of TMEM98 in cancer-related epigenetic regulation and miRNA-mediated signaling.

Functional roles of TMEM98 in cancer

Non-Small cell lung cancer (NSCLC)
In NSCLC, TMEM98 is significantly upregulated in tumor tissues. Silencing TMEM98 via siRNA markedly inhibits cell proliferation, invasion, and migration [94]. Additional clinicopathological analyses of 38 paired specimens showed an increase of TMEM98 at both the mRNA and protein levels compared with adjacent normal lung parenchyma; high staining intensity correlated with larger primary tumors and nodal involvement [94]. Mechanistically, TMEM98 knockdown in A549 and H460 cells results in the downregulation of key invasion-and migration-associated proteins, including MMP-2, MMP-9, RhoC, and MTA1 (Table 1; Fig. 2). These findings indicate that TMEM98 facilitates NSCLC progression by modulating pathways involved in extracellular matrix degradation and cytoskeletal remodeling, suggesting its potential as a therapeutic target [94].

Gastric cancer
In gastric cancer, TMEM98 exhibits an atypical regulatory pattern: its mRNA levels are significantly elevated and correlate with poor prognosis, while protein expression remains unchanged. Notably, TMEM98 mRNA directly binds to NF90, stabilizing its expression and enhancing tumor cell proliferation and invasion [3] (Fig. 2). This effect is dependent on an 8-nucleotide binding site in the 3′-UTR; mutations in this region abrogate the mRNA’s oncogenic function (Table 1). This interaction stabilizes NF90 protein levels, which subsequently promote both the expression and stability of TMEM98 mRNA. This study introduces the concept of “non-coding mRNA function” in cancer, paving the way for RNA-based therapeutic strategies.

Hepatocellular carcinoma (HCC)
TMEM98 has been implicated in chemoresistance in HCC. It is highly expressed in HCC tissues and is significantly associated with tumor stage, recurrence rate, overall survival, and response to transarterial chemoembolization (TACE) [7]. Its expression is markedly elevated in HCC tissues and shows a significant correlation with advanced tumor stage, early postoperative recurrence, shorter overall survival, and reduced disease-free survival. Notably, TMEM98 mRNA levels are significantly higher in HCC patients who underwent TACE compared to those who did not receive TACE treatment [7]. Silencing TMEM98 restores chemosensitivity in liver cancer cells. Mechanistically, TMEM98 may promote chemoresistance by activating the AKT pathway while suppressing p53 activity, thereby enhancing cellular adaptation to stress [95] (Table 1; Fig. 2). These findings highlight TMEM98 as both a biomarker for therapeutic response and a candidate for personalized treatment strategies.

Ovarian cancer
Contrary to its role in other cancers, TMEM98 expression is downregulated in ovarian cancer [96]. Both patient samples and cell lines show reduced TMEM98 levels compared to controls. Low TMEM98 expression promotes proliferation, migration, angiogenesis, and inhibits apoptosis, potentially through downregulation of Caspase-3 and upregulation of the anti-apoptotic protein Bcl-2 [96] (Fig. 2). Bioinformatics analysis suggests a negative correlation between TMEM98 and PARP activity, indicating a possible role in DNA damage response regulation [96] (Table 1). These findings underscore TMEM98’s context-dependent dual roles as either a tumor suppressor or promoter. Unlike NSCLC and HCC, ovarian cancer lacks TMEM98-dependent oncogenic circuits, such as the MMP-2/−9–RhoC invasion loop that drives lung cancer dissemination and the AKT-mediated p53 suppression pathway that contributes to chemoresistance in HCC; instead, TMEM98 downregulation tips the balance toward growth via reduced apoptosis. In addition, TMEM98 directly binds the GSK-3 adaptor FRAT2, triggers its proteasomal degradation, and, as a consequence, lowers nuclear β-catenin levels and TCF/LEF transcriptional output [8]. Because canonical Wnt activity, driven in part by FRAT-family proteins, is a recognized promoter of stemness, invasion, and chemoresistance in epithelial ovarian cancer [97, 98], this TMEM98-FRAT2 axis provides a plausible negative-feedback brake that can explain why TMEM98 behaves as a tumour-suppressor in the ovary yet acts pro-oncogenically in NSCLC and HCC. Notably, FRAT1 (a close FRAT2 paralogue) is frequently over-expressed in high-grade serous ovarian carcinoma and correlates with β-catenin accumulation [98], further supporting the idea that dampening FRAT-mediated Wnt signalling is tumour-restraining in this tissue. Currently, there are no direct experimental comparisons of FRAT2/Wnt activity across these cancers, representing a key gap for further study.

Head and neck tumors and breast cancer
In head and neck squamous cell carcinoma (HNSCC), miR-29c-5p targets TMEM98 to suppress tumor cell proliferation and migration; mechanistic studies show that miR-29c-5p overexpression decreases TMEM98-driven cyclin-D1 and vimentin levels, arrests cells in G2/M, and reduces xenograft growth [92]. Similarly, in HER2-positive breast cancer, TMEM98 has been identified as a subtype-specific marker and is associated with poor prognosis for patients [99], highlighting its potential utility in molecular classification and personalized therapy (Table 1; Fig. 2).

TMEM98-Associated signaling pathways in cancer
The diverse biological functions of TMEM98 in cancer are primarily mediated through its interaction with multiple critical signaling networks. Acting through protein-protein interactions, post-transcriptional mechanisms, and pathway modulation, TMEM98 serves as an integrative signaling hub. It plays regulatory roles in the Wnt/β-catenin and AKT/GSK3β pathways, influences MYRF activity, and participates in both NF90-mediated feedback loops and microRNA-driven regulatory circuits (Fig. 3).

Suppression of Wnt/β-Catenin signaling linked to stemness and metastasis
The Wnt/β-catenin axis not only drives bulk-tumor proliferation but is a linchpin for cancer-stem-cell (CSC) maintenance, epithelial-to-mesenchymal transition (EMT), and distant colonization. TMEM98 functions as a negative modulator of this cascade by targeting FRAT2, a protein that normally enhances β-catenin stability through GSK3β inhibition. By reducing FRAT2 levels, TMEM98 diminishes β-catenin accumulation and transcriptional activity in the nucleus, thereby introducing a negative feedback mechanism that curbs Wnt signaling overactivation [8]. This positions TMEM98 as a critical modulator maintaining the balance of this oncogenic pathway (Fig. 3b).
Sustained β-catenin signaling is a hallmark of self-renewing tumor-initiating cells in gastric, colorectal, and lung cancers; pharmacologic or genetic β-catenin blockade depletes tumorsphere formation and ALDHhi/CD44+ sub-fractions [100, 101]. TMEM98-dependent FRAT2 degradation, therefore, predicts a tangible drop in CSC frequency. Although direct sphere-formation assays with TMEM98 are still pending, van der Wal et al. showed that ectopic TMEM98 lowers TOPflash reporter output and downstream c-Myc expression by > 50%, a level of β-catenin suppression that in parallel studies was sufficient to exhaust CSC pools [8]. Conversely, miR-3648-driven de-repression of FRAT2 restores β-catenin tone and boosts invasion in gastric-cancer xenografts, underscoring how relief from TMEM98 control can rekindle stem-like traits [102]. Complementing these findings, siRNA-TMEM98 curbs MMP-2/−9, RhoC, and MTA1 expression and reduces Transwell invasion by ~ 40% in non-small-cell lung-cancer cells, indicating additional crosstalk with the AKT/GSK3β branch of the pathway [94]. Collectively, TMEM98 acts as a gatekeeper that restrains Wnt-driven CSC maintenance and metastatic dissemination, underscoring its potential as a dual anti-stemness/anti-metastatic target.

Activator of the AKT/GSK3β/Cyclin D1 pathway
TMEM98 contributes to cell proliferation by activating the AKT pathway. Its expression is upregulated in response to PDGF-BB stimulation in both tumor cells and vascular smooth muscle cells (VSMCs). This upregulation enhances Akt phosphorylation; phospho-Akt then inhibits GSK-3β via Ser9 phosphorylation, allowing Cyclin D1 to accumulate and accelerate cell-cycle progression. TMEM98 knockdown has been shown to significantly reduce proliferation and migration in both cell types [5, 95], indicating its role in both cancer advancement and vascular pathology, and suggesting its potential as a dual therapeutic target (Fig. 3c).

Post-Transcriptional feedback via NF90
In gastric cancer, TMEM98 engages in a non-coding RNA–protein feedback loop. Its mRNA binds directly to NF90 through a conserved sequence in its terminal exon. This interaction stabilizes NF90 protein levels, which in turn enhance the expression and stability of TMEM98 mRNA, forming a self-reinforcing feedback loop [3]. This regulatory mechanism underscores the significance of untranslated regions in mRNA biology and highlights a previously underappreciated mode of oncogenic regulation driven by RNA itself (Fig. 3a).

Regulation of MYRF cleavage
MYRF is a membrane-bound transcription factor whose activity depends on autoproteolytic cleavage in the endoplasmic reticulum (ER). The cleaved N-terminal fragment enters the nucleus to regulate gene transcription. TMEM98 interacts with the C-terminal region of MYRF, inhibiting its cleavage and nuclear translocation. Loss of TMEM98 results in uncontrolled MYRF activation, leading to ocular phenotypes such as axial elongation and nanophthalmos [6, 10]. This regulatory mechanism may also extend to neurodevelopment and cancer stemness, positioning TMEM98 as a key modulator in cell fate decisions and a potential pharmacological target for MYRF-associated pathways (Fig. 3d).

MicroRNA regulatory networks
TMEM98 is also embedded within extensive microRNA (miRNA) networks. For example, miR-219-5p is upregulated under hypoxic conditions and downregulates TMEM98 by binding to its 3′-UTR, thereby impairing keratinocyte wound healing [93].In head and neck squamous cell carcinoma, miR-29c-5p is downregulated, and its restoration directly targets TMEM98 to inhibit tumor proliferation and migration [92]. Additionally, a triplet of miRNAs—miR-103b, miR-877-5p, and miR-29c-5p—has been found to co-target TMEM98 in lung adenocarcinoma-derived exosomes, offering potential diagnostic value [103] (Fig. 3e).

Clinical applications and translational potential of TMEM98

Tumor diagnosis and molecular subtyping
TMEM98 is heterogeneously expressed across malignancies: it is up-regulated in NSCLC, gastric, liver, and head-and-neck cancers, yet down-regulated in ovarian tumors. Its expression levels are closely associated with tumor stage, lymph node metastasis, and overall survival, underscoring its prognostic value [3, 7, 94]. Moreover, TMEM98 serves as a subtype-specific gene in HER2-positive breast cancer and adenosquamous carcinoma of the cervix, suggesting its utility in molecular subtyping and stratified diagnosis [99, 104]. TMEM98-associated microRNAs, such as miR-29c-5p, miR-103b, and miR-877-5p, are markedly upregulated in plasma-derived exosomes. These miRNAs enable non-invasive detection of early-stage lung adenocarcinoma, with diagnostic performance reaching an AUC of 0.873, highlighting TMEM98’s significant potential for clinical implementation as a circulating biomarker [103], supporting liquid-biopsy use cases that could complement imaging and tissue histology.

Therapeutic target and broader clinical utility
TMEM98 has demonstrated substantial therapeutic potential due to its central role in key oncogenic pathways. Gene silencing via siRNA significantly suppresses tumor growth, invasiveness, and chemoresistance in various cancer models, including NSCLC, gastric, liver, and head and neck cancers [3, 7, 92, 94]. Because TMEM98 is upstream of critical regulators such as AKT, Wnt/β-catenin, and MYRF, it can also be indirectly targeted using combination therapies. Strategies include the use of AKT inhibitors in HCC, NF90 disruption in gastric cancer, and manipulation of MYRF activity through genome editing or small-molecule inhibitors [6, 10].
Clinically, TMEM98 expression serves as a prognostic biomarker. In HCC, its elevated expression is associated with reduced survival and resistance to transarterial chemoembolization (TACE) [7]. Conversely, in ovarian cancer, low TMEM98 levels correlate with heightened invasiveness and angiogenic activity [96]. These associations highlight TMEM98’s potential for guiding risk stratification and personalized treatment.
Beyond oncology, the clinical relevance extends to systemic disorders including nanophthalmos and developmental conditions mediated via MYRF interactions [10, 105]. Such cross-disease associations position TMEM98 as a versatile, translational biomarker with applications spanning oncology, developmental disorders, and neurological diseases, highlighting opportunities for innovative, biomarker-based therapies.

Summary and future directions
TMEM98 has revealed itself as a multifaceted transmembrane protein of great interest in tumorigenesis as well as in larger physiological regulation. TMEM98 is centrally involved in modulating various signaling pathways such as Wnt/β-catenin, AKT/GSK3β, NF90, and MYRF, influencing critical cellular behaviors like proliferation, migration, apoptosis, and treatment responsiveness. Interestingly, its regulation extends beyond protein to include mRNA interaction and microRNA-mediated control, which underlines its intricate and multi-tiered role in disease pathophysiology. Notably, current findings underscore TMEM98’s context-dependent dual roles as either a tumor suppressor or a tumor promoter.
Despite significant advances, many areas remain unexplored and deserve further exploration. There is still a long way to go before TMEM98 becomes a viable clinical target. Based on our thorough literature review, we found no ongoing clinical trials or direct therapeutic approaches currently targeting TMEM98. This underlines a clear gap between basic research and clinical translation. We believe it is crucial to explore more deeply how different isoforms of TMEM98 function, as well as how its untranslated regions might regulate its behavior. Extension of the TMEM98 investigation into other tumor varieties and non-cancerous diseases will be crucial to completely chart its pathophysiological significance. In particular, the determination of functional roles of TMEM98 isoforms and untranslated regions might uncover unforeseen levels of regulation. In addition, its possible role in the immune environment, particularly in modulating tumor–immune interactions, remains to be studied systematically. For therapeutic exploitation of TMEM98, the development of specific delivery systems, e.g., RNA interference platforms or CRISPR gene editing systems, will be mandated for clinical application. High-resolution structural studies, multi-omic CRISPR screens, and single-cell spatial profiling should be coupled with organoid and conditional in vivo models to capture tissue-restricted phenotypes. Translationally, the field must optimise tumour-targeted siRNA, antisense or base-editing platforms, incorporate TMEM98 isoforms into multiplex diagnostic assays, and evaluate combinatorial strategies that pair TMEM98 inhibition with pathway-targeted drugs and immune-checkpoint blockade.
In short, TMEM98 is an attractive intersection of cancer and systems biology, connecting basic molecular mechanisms to clinical implications. Its widening functional landscape places it as not only a disease-specific effector but also as an integrative biomarker for precision medicine.