Prostate cancer (PCa) is the most common solid tumor malignancy in men. Activation of ETS transcription factors (TFs), ERG, ETV1, ETV4, and ETV5, are present in approximately 60% of PCa, underscoring their importance in prostate oncogenesis (Nelson et al., 2003). In human PCa, ETS TFs are most commonly activated through gene rearrangements that fuse the androgen responsive gene, TMPRSS2, to either ERG, ETV1, ETV4, or ETV5 (Sizemore et al., 2017). Beyond ETS TF fusions, little is known about the underlying molecular mechanisms that lead to increased expression of wildtype (WT) ETS factors, which confer aggressive malignant phenotypes and associate with poor clinical outcomes in fusion negative PCa patients (Baena et al., 2013).

Capicua (CIC) is a High-mobility group (HMG) box TF that silences ETV1, ETV4, and ETV5 through direct target gene repression (Kim et al., 2021; Simón-Carrasco et al., 2018). CIC is frequently altered in human cancer, where it functionally suppresses tumor growth and metastasis (Ahmad et al., 2019; Bettegowda et al., 2011; Choi et al., 2015; Dissanayake et al., 2011; Kim et al., 2018; Okimoto et al., 2017; Seim et al., 2017; Yoshiya et al., 2021). Notably, in PCa, CIC is commonly altered through genomic loss (homozygous and heterozygous deletion) in ~10% of PCa patients (Abida et al., 2019; Grasso et al., 2012; Hieronymus et al., 2014; Huang et al., 2017; Robinson et al., 2015; Cancer Genome Atlas Research Network, 2015) and inactivation of CIC de-represses ETV1, ETV4, and ETV5 transcription to promote tumor progression (Bettegowda et al., 2011; Choi et al., 2015; Kim et al., 2018; Okimoto et al., 2017). Leveraging mutational profiling data from multiple PCa cohorts, we previously observed concurrent loss of the ETS2 repressor factor (ERF) in CIC-deficient prostate tumors (Huang et al., 2017). Combinatorial loss is most commonly the result of focal deletions (homozygous and heterozygous) at the 19q13.2 locus, where CIC and ERF are physically adjacent (long and short isoforms of CIC are separated from ERF by approximately 15 and 30 kb, respectively) to one another in the genome. Since ERF is a transcriptional repressor that binds ETS DNA motifs (Bose et al., 2017), we hypothesized that in a fusion independent manner, CIC and ERF cooperate to mutually suppress ETS target genes in PCa.

Through an integrative genomic and functional analysis, we mechanistically show that CIC and ERF directly bind and co-repress a proximal ETV1 regulatory element limiting PCa progression. Concomitant loss of CIC and ERF de-represses ETV1-mediated transcriptional programs and confer ETV1 dependence in multiple PCa model systems. Thus, we reveal a fusion-independent mechanism to de-repress ETS-mediated PCa progression and potentially uncover a therapeutic approach to target CIC-ERF co-deleted PCa.

CIC is a TF that directly suppresses ETV1, ETV4, and ETV5 TF family members (Futran et al., 2015; Jiménez et al., 2012; Kim et al., 2021; Okimoto et al., 2017). CIC silences target genes through direct binding of a highly conserved DNA-binding motif (T[G/C]AAT[G/A]AA; Figure 1A; Ajuria et al., 2011; Futran et al., 2015; Jiménez et al., 2012). CIC is commonly altered in multiple human cancer subtypes where it suppresses tumor growth and metastasis (Kim et al., 2021). CIC is located on chromosome 19q13.2, directly adjacent to another transcriptional repressor, namely the ERF (Figure 1B). ERF binds and competes for ETS TF-binding sites (GGAA-motifs) and is frequently altered in human PCa, predominantly through focal deletions (Bose et al., 2017; Hou et al., 2020). We thus hypothesized that concurrent loss of CIC and ERF may de-repress an ETS-driven transcriptional program that drives PCa progression in a fusion-independent manner. To explore this, we first queried 15 PCa datasets curated on cBioPortal (Cerami et al., 2012; Gao et al., 2013) and identified a high cooccurrence rate (p<0.001, two-sided Fisher’s exact test [FET]) for CIC (10%) and ERF (12%) homozygous and heterozygous deletions (Figure 1C), suggesting that concurrent loss occurs through focal copy number change at the 19q13.2 locus. Through analysis of these clinically annotated specimens, we observed that the CIC-ERF co-deletion was present at an increased frequency in PCa with higher Gleason scores and later tumor stages when compared to CIC-ERF replete tumors (Figure 1D). In order to understand the association between CIC and/or ERF alterations in specific PCa cohorts, we stratified published datasets to identify patients that represent primary PCa (Fraser et al., 2017; Hieronymus et al., 2014; ‘ Cancer Genome Atlas Research Network, 2015) (PNAS 2014, n=272; Cell 2015, n=333; Nature 2017, n=477 primary PCas) and metastatic castrate resistant prostate cancer (mCRPC) (Abida et al., 2019; Grasso et al., 2012; Robinson et al., 2015) (Nature 2012, n=50; Cell 2015, n=150; PNAS 2019, n=429 mCRPCs). This analysis revealed enrichment of CIC and ERF alterations including the CIC-ERF co-deletion in mCRPC samples (Figure 1E, Figure 1—source data 1, Figure 1—figure supplement 1). Importantly, CIC-ERF co-deleted tumors clustered as a subgroup when compared to the more well-characterized molecular subsets including ERG, ETV1, ETV4, SPOP, and FOXA1 altered PCas, suggesting a distinct molecular subtype of PCa (Figure 1F). In order to explore clinical outcomes of patients harboring CIC-ERF co-deleted tumors, we performed a survival analysis using the aforementioned PCa datasets and observed significantly worse outcomes in patients who harbored the CIC-ERF co-deletion (p=0.001, disease-free survival [DFS] [ERF-CIC co-deletion 25 events/90 total; no ERF-CIC co-deletion 153 events/910 total] and p=0.01, progression-free survival [PFS] [ERF-CIC co-deletion 16 events/52 total; no ERF-CIC co-deletion 77 events/442 total]; Figure 1G). One limitation of this analysis is that individual studies included overlapping tumors from the same patient (i.e. TCGA PanCancer and Firehose Legacy cohorts). Despite this overlap, we utilized this insight to formulate a hypothesis that CIC and ERF are co-deleted with increasing frequency in mCRPC and that the CIC-ERF co-deletion is associated with worse clinical outcomes in PCa patients.

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Figure 1—source data 1

Prostate cancer studies identified in cBioPortal demonstrating the total number of patients, number of patients with shallow or deep deletions in Capicua (CIC)-ETS2 repressor factor (ERF), and the frequency of CIC-ERF alterations in each cohort.

Studies that analyzed predominantly primary prostate cancers (green) and metastatic castrate resistant prostate cancer (mCRPC; yellow) are highlighted.

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Our initial findings provided rationale to explore the genetic and functional relationship between CIC and ERF. Independently, CIC and ERF have previously been reported to promote malignant phenotypes, including tumor growth and metastasis in multiple human cancer subsets (Bettegowda et al., 2011; Bose et al., 2017; Choi et al., 2015; Huang et al., 2017; Kawamura-Saito et al., 2006; Kim et al., 2018; Bunda et al., 2019; Okimoto et al., 2019; Okimoto et al., 2017; Simón-Carrasco et al., 2017; Wong et al., 2019; Yang et al., 2017). Since our clinical data indicated that combinatorial loss of CIC and ERF was associated with worse patient outcomes, we hypothesized that CIC and ERF loss may cooperate to enhance PCa progression. To investigate this, we engineered ERF, CIC, or both CIC and ERF-deficient immortalized prostate epithelial cells (PNT2) and performed a series of in vitro and in vivo experiments to test the combinatorial effect of the CIC-ERF co-deletion. Compared to single gene loss of CIC or ERF, genetic inactivation of both CIC and ERF increased colony formation (Figure 2A–B, Figure 2—figure supplement 1A) and spheroid formation (Figure 2C–D) in PNT2 cells. CIC-ERF co-deletion also enhanced malignant phenotypes including cellular viability, invasiveness, and migratory capacity in PNT2 (Figure 2E–G). Additionally, genetic silencing of both CIC and ERF increased the frequency of subcutaneous tumor xenograft formation in severe-combined immunodeficient (SCID) mice compared to control (Figure 2H, Figure 2—figure supplement 1B). Thus, our findings demonstrate that the combination of CIC and ERF loss augments the transformation of PNT2 and promotes malignant phenotypes.

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To assess the functional role of CIC and ERF in the context of human PCa progression, we leveraged two genetically annotated, androgen-insensitive PCa cell lines, DU-145 (moderate metastatic potential) and PC-3 (high-metastatic potential). DU-145 cells harbor a loss-of-function ERF mutation (ERF^A132S) (Huang et al., 2017) and express functional WT CIC, (Figure 3—figure supplement 1A). By comparison, PC-3 cells are deficient in CIC (homozygous deletion) and retain functional ERF (Figure 3—figure supplement 1B; Cerami et al., 2012; Gao et al., 2013; Seim et al., 2017). Thus, these cell line models provided isogenic systems to functionally interrogate the role of CIC and ERF in human PCa. Specifically, genetic reconstitution of ERF into ERF-deficient DU-145 cells decreased colony formation in both CIC proficient (parental cells) and CIC knockout (KO) conditions (Figure 3A–B, Figure 3—figure supplement 1C, D). While CIC loss did not enhance colony formation in ERF-deficient DU-145 cells, it significantly increased tumor cell viability, invasion, and migratory capacity compared to control (Figure 3C–D, Figure 3—figure supplement 1E). Importantly, we observed that ERF expression in CIC KO DU-145 cells rescued the CIC-mediated effects on viability and migration/invasion (Figure 3C–D, Figure 3—figure supplement 1E). These findings indicate that rescuing ERF can partially restore the functional effects of CIC loss in DU-145 cells. To further understand if ERF could suppress tumor growth in vivo, we reconstituted WT ERF into CIC proficient and deficient (CIC KO) DU-145 cells and generated subcutaneous xenografts in immunodeficient mice (NU/J). Consistent with our in vitro data, CIC KO increased the tumor growth rate in vivo and genetic reconstitution of WT ERF partially suppressed tumor growth compared to DU-145 CIC KO cells (Figure 3E). Moreover, genetic reconstitution of ERF into CIC proficient DU-145 cells suppressed the tumor growth rate in vivo (Figure 3E). We next used PC-3 cells, to further test how ERF and CIC functionally interact in the context of human PCa. We first noted that ERF overexpression (OE) or reconstitution of CIC alone decreased PC-3 colony formation, with combinatorial ERF OE and CIC rescue having the most significant reduction compared to parental PC-3 cells (Figure 3F–G, Figure 3—figure supplement 1F, G). Moreover, ERF and CIC expression had a similar impact on decreasing PC-3 viability, invasion, and migratory capacity (Figure 3H–I, Figure 3—figure supplement 1H). Similarly, genetic suppression of ERF resulted in a significant increase of colony formation, viability, and invasion compared to parental PC3 cells (Figure 3F–I, Figure 3—figure supplement 1I). Interestingly, OE of ERF in mice bearing CIC deficient PC-3 tumor xenografts decreased tumor growth compared to PC-3 parental and PC-3 cells expressing WT CIC (genetic rescue of CIC; Figure 3J). Since we consistently observed that ERF expression could partially rescue the effects of CIC loss in PCa, we hypothesized that WT CIC and ERF potentially cooperate to limit PCa progression.

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In order to mechanistically define how CIC and ERF (two TFs with known repressor function) were interacting to functionally regulate PCa, we performed chromatin immunoprecipitation followed by sequencing (ChIP-Seq) using a validated CIC antibody (Lin et al., 2020; Okimoto et al., 2019; Okimoto et al., 2017) in PNT2, and compared this to a publicly available ERF ChIP-Seq dataset in VCaP PCa cells (Bose et al., 2017), we were unsuccessful at pulling down ERF in PNT2 cells. This analysis identified 178 high-confidence (False-discovery rate (FDR) ≤0.05) CIC peaks that mapped to 130 annotated genes including known targets, ETV1, ETV4, and ETV5. Globally, CIC peaks were localized to distinct genomic regions including promoters (38.6%), untranslated regions (UTRs) (1.14%), introns (19.9%), and distal intergenic regions (38.64%). Interestingly, the distribution of ERF peaks was similar to CIC, with 32.8% in promoters, 1.2% in UTRs, 29.2% intronic, and 33.8% in distal intergenic regions (Figure 4A). Next, through a comparative ChIP-Seq analysis (Figure 4B), we identified 91 shared CIC and ERF target genes. Importantly, we focused on genes with shared CIC- and ERF-binding sites to potentially explain the functional cooperativity that we observed in our prior studies. In order to narrow down potential candidates, we performed Functional Clustering Analyses through the DAVID bioinformatics database (https://david.ncifcrf.gov) (Huang et al., 2009; Sherman et al., 2022) using the 91 shared CIC and ERF target genes (Supplementary file 1). Among these putative CIC and ERF targets, the PEA3 (ETV1, ETV4, and ETV5) TFs (known oncogenic drivers in PCa; Baena et al., 2013; Kim et al., 2016; Oh et al., 2012) were found to be the most highly enriched family. These findings suggested that CIC and ERF may co-regulate PEA3 family members through direct transcriptional control.

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Figure 4—source data 1

Full-length PCR gel images of ETV1 after Capicua (CIC) pull down in prostate epithelial cells (PNT2).

Cropped images and description shown in Figure 4E.

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Figure 4—source data 2

Full-length PCR gel images of ETV1 after ETS2 repressor factor (ERF) pull down in prostate epithelial cells (PNT2).

Cropped images and description shown in Figure 4F.

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Figure 4—source data 3

Full-length PCR gel images of ETV1 after ETS2 repressor factor (ERF) pull down in DU-145 cells.

Cropped images and description shown in Figure 4G.

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In order to further identify how CIC and/or ERF impact PEA3 TF expression, we performed quantitative real time polymerase chain reaction (qRT-PCR) in PNT2 cells, assessing ETV1, ETV4, or ETV5 mRNA levels in response to genetic silencing of CIC and/or ERF. As expected, CIC KO and/or combinatorial CIC and ERF loss in PNT2 cells (ERF and CIC WT) consistently increased ETV1, ETV4, and ETV5 levels compared to control (Figure 4—figure supplement 1A-F). In contrast, genetic silencing of ERF consistently increased ETV1 mRNA expression, but not ETV4 or ETV5 (Figure 4C, Figure 4—figure supplement 1G-J). These findings indicated that ETV1 may be a shared transcriptional target of CIC and ERF in prostate cells. In order to test a potential proteomic interaction between CIC and ERF, we performed co-immunoprecipitation (Co-IP) experiments but did not observe binding when either ERF or CIC was pulled down in HEK293T cells (Figure 4—figure supplement 1K-L). This led us to hypothesize that CIC and ERF may potentially bind (but not interact) to distinct regions along the ETV1 regulatory element. To explore this, we first localized CIC (TGAATGGA) and ERF (GGAA) DNA binding motifs within the proximal upstream regulatory element of ETV1 and independently confirmed CIC and ERF occupancy of the ETV1 promoter through ChIP-PCR (Figure 4D–G, Figure 4—figure supplement 1M, P). To extend these findings into the context of PCa, we reconstituted ERF in ERF deficient DU-145 cells and this consistently decreased ETV1 expression (not ETV4 or ETV5) in both CIC proficient and CIC deficient settings (Figure 4H, Figure 4—figure supplement 1Q-T). Moreover, ERF Knockdown (KD) or ERF OE in CIC deficient PC-3 cells increased and decreased ETV1 mRNA expression, respectively (Figure 4I–J). Since ETV1 is a known target of CIC (Dissanayake et al., 2011; Jiménez et al., 2012), we focused on further validating ETV1 as a molecular target of ERF. To this end, we engineered a ETV1 luciferase based promoter assays and observed a decrease in luciferase activity following ERF expression in 293T cells (Figure 4K). These genetic tools further validate that ERF can suppress ETV1 expression through direct transcriptional silencing of the ETV1 promoter and identifies ETV1 as an ERF target.

Consistent with a repressor function, ERF loss was previously shown to transcriptionally associate with ETV1-regulated gene set signatures (Huang et al., 2017). Yet it remains unclear if ERF can directly regulate ETV1 and how combinatorial loss of CIC and ERF controls ETV1-mediated (or other ETS family members) transcriptional programs. To explore this, we generated a signature gene set of upregulated genes from our dual CIC and ERF deficient PNT2 cells (ERF KD +CIC KO) and projected the Cancer Genome Atlas PCa (TCGA-PRAD) dataset onto the transcriptional space of these signature gene sets using the ssGSEA module (Version 10.0.9) on GenePattern (Reich et al., 2006). We found that CIC and ERF loss were significantly associated with the ETV1-regulated gene set (Information coefficient (IC)=0.619, p=0.0009), but was anti-correlated with the TMPRSS2-ERG fusion signature gene set (Setlur et al., 2008; Figure 4L, IC = –0.45, p=0.0009). Thus, the enrichment of the ETV1-regulated gene set signature was shared between ERF loss alone (Huang et al., 2017) and CIC-ERF dual suppression (Figure 4L). In contrast, combinatorial CIC and ERF loss negatively correlated with the TMPRSS2-ERG fusion signature gene set, which was not consistent with our prior studies using ERF KD alone (Huang et al., 2017). These findings led us to hypothesize that the dual suppression of CIC and ERF may increase ETV1-mediated transcriptional programs in PCa. This was supported by two major lines of experimental and conceptual evidence including: (1) dual suppression of ETV1 expression and ETV1 mediated transcriptional output by CIC and ERF; and (2) the majority of tumors derived from PCa patients that harbor ERF deletions also contain deletions in CIC.

In order to demonstrate enhanced survival dependence on ETV1 in PCa cells, we genetically silenced CIC in ERF-deficient DU-145 cells and assessed drug sensitivity to an ETV1 inhibitor (BRD32048) (Pop et al., 2014). We validated the pharmacologic effect of ETV1 inhibition (BRD32048) through suppression of known downstream target genes (ATAD2 and ID2) using qPCR in LNCaP cells (Figure 5—figure supplement 1A-C). Since BRD32048 was previously shown to decrease invasiveness in ETV1-fusion positive PCa cells (LNCaP), but not significantly impact tumor cell viability, we unexpectedly observed that silencing CIC in DU-145 cells mildly enhanced sensitivity to BRD32048 (Figure 5A). To further confirm these findings and to mitigate potential off-target effects, we silenced ETV1 using siRNA in PC3 and DU-145 cells expressing Crispr-based sgRNA targeting CIC (Figure 5—figure supplement 1D-F). Consistent with our pharmacologic studies, the viability of DU-145 CIC KO cells was decreased upon genetic ETV1 inhibition (Figure 5B). Similarly, pharmacologic and genetic ETV1 inhibition decreased invasiveness of CIC deficient DU-145 cells (Figure 5C–D). These findings indicate that loss of CIC in ERF deficient PCa cells can potentially modulate the sensitivity to ETV1-directed therapies. To expand these findings, we also consistently observed a decrease in viability and invasiveness upon ETV1 inhibition (BRD32048) in PNT2 cells with dual ERF and CIC suppression and in PC-3 cells with ERF KD (Figure 5—figure supplement 2A-J). These in vitro findings indicate that ETV1 inhibition in CIC and ERF deficient prostate cells can suppress invasion and potentially limit viability. Further studies targeting ETV1 in patient derived specimens that harbor endogenous CIC-ERF co-deletions is warranted. Collectively, our data indicate that CIC and ERF may cooperate to silence ETV1 transcriptional programs, limiting ETV1-mediated PCa progression.

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Molecular and functional subclassification of human PCa has revealed a dependence on ETS family TFs including ERG, ETV1, ETV4, and ETV5 (Feng et al., 2014; Oh et al., 2012). The predominant mode of ETS activation in PCa is through chromosomal rearrangements that fuse ERG, ETV1, ETV4, and ETV5 to the androgen-regulated TMPRSS2 gene, leading to fusion oncoproteins that drive oncogenesis (Clark and Cooper, 2009; Feng et al., 2014; Helgeson et al., 2008; Tomlins et al., 2006; Tomlins et al., 2005). Interestingly, recent data indicate that ETV1, ETV4, and ETV5 are upregulated in a fusion-independent manner and are associated with poor clinical outcomes in PCa patients (Baena et al., 2013; Hermans et al., 2008). Our study focused on understanding the molecular mechanisms that drive fusion-independent upregulation of ETS family members and we reveal a new molecular subclass of PCa defined by a co-deletion of two TFs, CIC and ERF.

CIC is a TF that directly silences ETV1, ETV4, and ETV5 transcription through direct repression at proximal regulatory sites (Jiménez et al., 2012). We observed that in ~10–12% of human PCa, CIC and ERF are co-deleted through focal homozygous or heterozygous deletions. It has been recently shown that ERF competes for ETS DNA binding motifs and our studies identify cooperative regulation of key target genes between CIC and ERF. Specifically, through ChIP-Seq analysis coupled with a series of in vitro and in vivo studies, we identify a coordinated binding of CIC and ERF to the proximal ETV1 regulatory element that physically and functionally regulates ETV1 expression. Therefore, we reveal ETV1 as a novel ERF target gene. Rescuing ERF in CIC deficient PCa cells decreases ETV1 expression and limits malignant phenotypes including viability, migration and invasion.

The 19q13.2 locus contains CIC and ERF, which are physically adjacent and oriented in opposing directions. The long and short isoforms of CIC are separated from ERF by ~15 and 30 kb, respectively. Thus, future studies directed at defining the genome topology and epigenetic states, both within and around this highly conserved region are warranted. In particular, studies aimed at mapping topology associated domains and key histone marks can potentially reveal shared upstream regulatory elements including enhancers or superenhancers that may co-regulate CIC and ERF in concert. These findings could reveal non-genetic mechanisms to functionally regulate CIC and ERF expression in a coordinated fashion.

Beyond PCa, we and others have observed that CIC and ERF are co-deleted in a subset of stomach adenocarcinoma (LeBlanc et al., 2017; Okimoto et al., 2017). Thus, combined CIC and ERF loss are not entirely specific for PCa. We speculate that since prostate (Baena et al., 2013) and potentially stomach adenocarcinoma (Keld et al., 2011) are highly dependent on PEA3 transcriptional dysregulation to enhance tumor progression, the dual loss of CIC and ERF may, in part, represent an alternative mode to de-repress ETS mediated transcriptional programs in these cancer subsets.

The use of ETV1 inhibitors has been limited to preclinical studies (Pop et al., 2014). These studies have largely focused on direct targeting of ETV1 fusion oncoproteins in PCa (Pop et al., 2014). Our findings indicate that patients with CIC-ERF deficient PCa may have a survival dependence on ETV1 and that these patients may potentially benefit from ETV1 directed therapies. A limitation of this targeted approach in PCa patients is that we did not find a statistically significant difference in ETV1 transcript levels in CIC-ERF co-deleted tumors compared to CIC-ERF replete tumors in the TCGA-PRAD (n=455) dataset. One potential explanation is that ETV1 is commonly upregulated in human PCas through mechanisms beyond CIC-ERF loss. Thus, while our data support the upregulation and potential induced dependence on ETV1 in our CIC-ERF deficient systems, it remains unclear if this will translate beyond our cell-line based models into PCa patients that harbor CIC-ERF co-deletions. Thus, larger studies that aim to evaluate: (1) ETV1 mRNA and protein expression levels; (2) the biological significance of ETV1 function; and (3) the clinical application of ETV1 inhibitors in patients with endogenous CIC-ERF co-deleted tumors (compared to CIC-ERF WT tumors) is warranted in this subset of PCa. Collectively, we have uncovered a molecular subset of PCa defined by a co-deletion of CIC and ERF and further demonstrate a mechanism-based strategy to potentially limit tumor progression through ETV1 inhibition in this subset of human PCa.

All sequencing data including RNASeq and ChIP seq have been deposited in GEO under accession codes GSE216732 and GSE216318, respectively.

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Author details

1. Nehal Gupta

   Department of Medicine, University of California, San Francisco, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8931-5759

2. Hanbing Song

   Department of Medicine, University of California, San Francisco, United States

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

3. Wei Wu

   Department of Medicine, University of California, San Francisco, United States

   Contribution

   Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

4. Rovingaile K Ponce

   Department of Medicine, University of California, San Francisco, United States

   Contribution

   Data curation, Writing – review and editing

   Competing interests

   No competing interests declared

5. Yone K Lin

   Department of Medicine, University of California, San Francisco, United States

   Contribution

   Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

6. Ji Won Kim

   Department of Medicine, University of California, San Francisco, United States

   Contribution

   Data curation, Writing – review and editing

   Competing interests

   No competing interests declared

7. Eric J Small

   1. Department of Medicine, University of California, San Francisco, United States
   2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, United States

   Contribution

   Supervision, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

8. Felix Y Feng

   1. Department of Medicine, University of California, San Francisco, United States
   2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, United States
   3. Department of Radiation Oncology, University of California, San Francisco, United States

   Contribution

   Supervision, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

9. Franklin W Huang

   1. Department of Medicine, University of California, San Francisco, United States
   2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, United States

   Contribution

   Data curation, Supervision, Writing – original draft, Writing – review and editing

   For correspondence

   franklin.huang@ucsf.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5447-0436

10. Ross A Okimoto

    1. Department of Medicine, University of California, San Francisco, United States
    2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, United States

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Writing – original draft, Writing – review and editing

    For correspondence

    ross.okimoto@ucsf.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-4467-8476

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