Abstract
Context
Seizure-related 6 homolog (SEZ6) is a cDNA that is strongly associated with neuroendocrine differentiation. Recently, SEZ6 expression was found in a subset of small cell lung carcinoma (SCLC). Furthermore, ABBV-011, a novel antibody-drug conjugate targeting SEZ6 has been developed and is currently in a clinical trial for the treatment of SCLC and neuroendocrine neoplasms, including medullary thyroid carcinoma (MTC).
Objective
We herein present the first evidence that SEZ6 is highly expressed in MTC.
Methods
SEZ6 immuno-expression was studied in 78 MTCs and correlated with clinicopathologic characteristics, outcome, and molecular profile.
Results
SEZ6 was highly expressed in primary tumors, regional recurrence, and distant metastasis. Using 2 different SEZ6 antibody clones, SC17.14 and 14E5, SEZ6 immunopositivity was seen in 91% to 93% of primary MTCs, 100% of regional recurrence, and 75% to 83% of distant metastasis. High level of SEZ6 immuno-expression determined using H score was associated with male sex, advanced stage, and extrathyroidal thyroidal extension. There was no correlation between SEZ6 expression and outcome or RET/RAS mutation status in MTC. The frequency of SEZ6 positivity in MTC without RET/RAS mutations was 83%.
Conclusion
SEZ6 may serve as a novel biomarker for MTCs. Although SEZ6 lacks any prognostic values in MTC, its positivity in 91% to 93% of MTCs, including MTCs without RET and RAS mutations, renders SEZ6-targeted antibody-drug conjugate therapy a promising targeted therapy for MTCs.
Keywords: SEZ6, medullary thyroid carcinoma, grade, stage, prognosis
Seizure-related 6 homolog (SEZ6) was first discovered as a brain-specific and seizure-related cDNA in the 1990s (1). It encodes a membrane protein that is normally expressed in the central nervous system (1). Recently, SEZ6 has been found to be one of the top 25 genes most strongly associated with neuroendocrine differentiation and SEZ6 protein is overexpressed in neuroendocrine cell lines (2). It is postulated that SEZ6 may play a role in neurosecretory functions, membrane signaling of neurons, and cell-cell recognition. Using 10% cytoplasmic and nuclear staining as a cutoff for SEZ6 positivity, Kudoh et al (3) reported SEZ6 immunopositivity in 70% of small cell lung carcinoma (SCLC) and 10% (1/10) of pulmonary adenocarcinoma and squamous cell carcinoma. Similarly, Wiedemeyer et al have shown that SEZ6 is expressed in a subset of SCLC and is minimally expressed in normal non-neural tissue (4). Furthermore, SEZ6 RNA expression correlates with advanced stage and shortened overall survival in patients with SCLC (4).
In recent years, 2 novel antibody-drug conjugates targeting SEZ6, ABBV-011 (clinical trial identification: NCT03639194), and ABBV-706 (clinical trial identification: NCT05599984), have been developed and are currently in phase 1 clinical trials for treatment of refractory or relapsed SCLC (4), high grade central nervous system tumors, and high grade neuroendocrine neoplasms, including medullary thyroid carcinoma (MTC) (5). Upon binding to the SEZ6 on the cell membrane, these SEZ6-drug conjugates are rapidly internalized, driving potential tumor regression in vitro and in vivo (4, 5).
A pilot study in our laboratory has discovered strong immuno-expression of SEZ6 in a significant proportion of MTC, a neuroendocrine carcinoma derived from C cells of the thyroid gland. Such high expression level of SEZ6 in MTC raises the possibility of treating these tumors with SEZ6-specific targeted therapy. We herein present the first study investigating the expression of SEZ6 in primary and metastatic MTCs and its correlation with molecular profile, clinicopathologic features, and outcomes.
Material and Methods
Study Cohort
The study was approved by the institutional review board (IRB protocol 17-103). The study cohort was composed of 78 cases of MTC, including 56 resected primary MTCs, 10 regional recurrences, and 12 distant metastases. The RET germline mutation status was known in all cases. Additionally, somatic RET and RAS mutation status was known in 71 cases, including 50 primary MTCs and all regional/distant recurrences. The tumors were genotyped using MSK-IMPACT targeted next-generation sequencing platform (n = 72) (6) and the commercially available ThyGenNext® platform (n = 1). All resected primary MTCs with available materials to perform immunohistochemistry (IHC) studies and molecular genotyping were collected and described in detail in previous studies (7, 8). Among them, 49 tumors were successfully sequenced, and their molecular profile was reported previously (8). The recurrent and metastatic MTCs were randomly chosen from cases with genomic profile and available materials to perform IHC.
Additionally, 7 cases of incidental C cell hyperplasia (CCH) were included. The presence of CCH was confirmed by calcitonin or synaptophysin IHC.
SEZ6 IHC
SEZ6 IHC was performed using 2 primary antibodies: clone SC17.14 (Creative BioLabs Cat# HOM-19458, RRID:AB_3661831, dilution 1:500, Creative Biolabs, Shirley, NY, USA), and clone 14E5 (Abcam Cat# ab252863, RRID:AB_3661830, dilution 1:250, Abcam, Limited, Cambridge, UK) on the Leica Bond III automatic platform (Leica Biosystems, Wetzlar, Germany). For clone SC17.14, the secondary antibody utilized was a rabbit anti-mouse included in the BOND Polymer Refine Detection (Leica Biosystems, Wetzlar, Germany). For clone 14E5, the secondary antibody used was a rabbit anti-rat (dilution 1:800, cat AI-4001, Vector, Newark, CA, USA). The percentage of positive cells, the staining intensity, and the H score of SEZ6 were evaluated by 3 pathologists (R.G., B.X., or A.A.) in MTC and in background non-neoplastic non-oncocytic thyroid follicular cells.
Statistical Analysis and Interpretation of SEZ6 IHC
All statistical analyses were performed using SPSS software, version 29 (IBM, Armonk, NY, USA). The H scores of SEZ6 were compared between primary MTCs and background non-neoplastic non-oncocytic thyroid follicular cells for each SEZ6 clone using the paired Student t test, and among primary and recurrent MTCs, using a one-way analysis of variance (ANOVA) test.
The cut off for SEZ6 positivity was determined using a H score generating a specificity of > 95% in primary MTCs. The sensitivity of SEZ6 in detecting MTC in various settings, including primary tumors and regional and distant metastases, as well as the frequency of SEZ6 positivity according to RET or RAS mutation status, were calculated.
The clinicopathologic characteristics and outcome of all primary MTCs were collected. The association between H score and various clinicopathologic features was determined using a two-tailed Student t test or one-way ANOVA.
Outcome data were available in 54 patients with resected primary MTC. Receiver operating characteristic (ROC) analyses failed to identify an H score correlating with outcome. Therefore, the median H score was used to separate SEZ6 expression into high and low subgroups. Univariate survival analysis using the log rank test was performed to determine the prognostic value of SEZ6 using overall survival (OS), disease-specific survival (DSS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS).
Results
SEZ6 IHC in Primary MTCs Using 2 Different Primary Antibody Clones
The results of SEZ6 IHC in primary MTCs using 2 separate clones are shown in Table 1 and Fig. 1. For both clones, there was a significant difference between MTC and background non-neoplastic non-oncocytic follicular cells in terms of staining intensity (P < .001), percentage of cells with positive SEZ6 stain (any intensity) (P < .001), and H score (P < .001). The mean H score was 224 and 77 in MTC and non-neoplastic thyroid respectively for the SC17.14 clone, and 204 and 28 respectively for the 14E5 clone.
Table 1.
SEZ6 immunohistochemistry in primary medullary thyroid carcinomas and background follicular cells using 2 different primary antibody clones SC17.14 and 14E5
| SC17.14 clone | 14E5 clone | |
|---|---|---|
| Primary medullary thyroid carcinoma | ||
| Staining pattern | ||
| Cytoplasmic | 2 (4%) | 3 (5%) |
| Cytoplasmic & membranous | 54 (96%) | 53 (95%) |
| Strongest staining intensity | ||
| Weak | 2 (4%) | 0 (0%) |
| Moderate | 4 (7%) | 3 (5%) |
| Strong | 50 (89%) | 53 (95%) |
| Percentage of positive cells | 95 ± 2% | 92 ± 3% |
| H score | 224 ± 9 | 204 ± 10 |
| Non-neoplastic non-oncocytic follicular cells | ||
| Strongest staining intensity | ||
| Negative | 2 (4%) | 4 (8%) |
| Weak | 24 (47%) | 36 (71%) |
| Moderate | 23 (45%) | 9 (18%) |
| Strong | 2 (4%) | 2 (4%) |
| Percentage of positive cells | 67 ± 4% | 25 ± 4% |
| H score | 77 ± 5 | 28 ± 5 |
Values are n (column%) for categorical variables and mean ± standard error of mean for continuous variables.
Figure 1.
SEZ6 immuno-expression in medullary thyroid carcinoma (MTC). (A) The level of SEZ6 immuno-expression (14E5 clone) does not correlate with disease-specific survival (DSS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS). (B) Heatmap correlating the type of MTC, RET and RAS genotype, and SEZ6 immunopositivity using SC17.14 and 14E5 clones. SEZ6 expression in a primary MTC (C-E) and a regional recurrence (F-H). C and F, hematoxylin and eosin; D and G, 14E5 clone; E and H, SC17.14 clone. Inserts: membranous staining of SEZ6.
When comparing the performance of the 2 clones, the 14E5 clone showed significantly less nonspecific stain in the background follicular cells in terms of percentage of positive cells (means: 67% for the SC17.14 clone, 25% for the 14E5 clone, P < .001) and H score (means: 77 for the SC17.14 clone, 28 for the 14E5 clone, P < .001). We also noted nonspecific staining in the lymphocytes and oncocytic follicular cells when using the SC17.14 clone. Therefore, the assessment of background staining was limited to non-oncocytic non-neoplastic follicular cells.
The H score in primary MTC was also significantly lower in the 14E15 clone (mean = 204) compared with that in the SC17.14 clone (mean = 224, P = .003). The staining intensity and the percentage of positive tumor cells in primary MTC did not differ between the 2 clones (P > .05).
The staining pattern was cytoplasmic and membranous in most primary MTC (96% using the SC17.14 clone, and 95% using the 14E5 clone), and cytoplasmic only in the remaining 4% to 5% of primary MTCs.
Correlation Between SEZ6 Expression and Clinicopathologic Features of Primary MTCs
A significantly higher H score was seen in male sex, advanced American Joint Committee on Cancer (AJCC) eighth edition prognostic group, the presence of microscopic extrathyroidal extension using both clones (P < .05, Table 2). For example, the mean H score was 192, 224, 262, and 254 for AJCC prognostic group 1, 2, 3, and 4, respectively, using the SC17.14 clone (P = .012), and 172, 224, 238, and 231, respectively, using the 14E5 clone (P = .026). Other clinicopathologic features, including age, grade defined using the International Medullary Thyroid Carcinoma Grade System (7), vascular invasion, and margin status, did not significantly impact SEZ6 expression level.
Table 2.
Immuno-expression of SEZ6 expressed as H score in primary medullary thyroid carcinoma according to clinicopathologic features
| H score (SC17.14 clone) |
P value | H score (14E5 clone) |
P values | |
|---|---|---|---|---|
| Sex | .006 | <.001 | ||
| Male (n = 32) | 244 ± 11 | 237 ± 9 | ||
| Female (n = 24) | 197 ± 14 | 161 ± 15 | ||
| Age | .185 | .569 | ||
| < 55 years (n = 28) | 215 ± 15 | 199 ± 14 | ||
| ≥ 55 years (n = 28) | 232 ± 11 | 210 ± 13 | ||
| AJCC 8th prognostic group | .012 | .026 | ||
| 1 (n = 25) | 192 ± 16 | 172 ± 15 | ||
| 2 (n = 7) | 224 ± 18 | 224 ± 17 | ||
| 3 (n = 3) | 262 ± 23 | 238 ± 11 | ||
| 4 (n = 21) | 256 ± 11 | 231 ± 14 | ||
| Grade | .105 | .419 | ||
| Low grade (n = 46) | 217 ± 11 | 200 ± 11 | ||
| High grade (n = 10) | 256 ± 17 | 221 ± 21 | ||
| Vascular invasion | .365 | .368 | ||
| Absent (n = 41) | 219 ± 11 | 199 ± 11 | ||
| Present (n = 15) | 238 ± 17 | 219 ± 20 | ||
| Microscopic extrathyroidal extension | .002 | .015 | ||
| Absent (n = 41) | 207 ± 11 | 190 ± 12 | ||
| Present (n = 15) | 273 ± 7 | 244 ± 12 | ||
| Margin status | .130 | .463 | ||
| Negative (n = 50) | 219 ± 10 | 202 ± 10 | ||
| Positive (n = 6) | 265 + 12 | 225 + 25 | ||
| RET/RAS mutations | .687 | .875 | ||
| RET and RAS wild-type (n = 12) | 203 ± 28 | 191 ± 26 | ||
| RET germline mutation (n = 1) | 265 | 230 | ||
| RET somatic mutation (n = 24) | 227 ± 12 | 206 ± 14 | ||
| RAS somatic mutation (n = 13) | 230 ± 20 | 214 ± 20 |
P values are obtained using 2-tailed Student's t test or one-way ANOVA.
Abbreviation: SEM, standard error of mean.
Determination of Cutoff for SEZ6 Immunopositivity and Correlation of SEZ6 IHC With Outcomes in Primary MTCs
Follow-up was available in 54 cases of primary MTC with a median follow-up period of 36 months (range, 0.5-250 months). Adverse events included 12 cases with distant metastasis, 12 cases with locoregional recurrence, and 4 cases with disease-specific death.
ROC analysis failed to identify an ideal cutoff of H score correlating with any outcome, including DSS, LRRFS, and DMFS. Therefore, the cutoff for SEZ6 positivity was arbitrarily determined using a H score generating a specificity of > 95% (ie, a false positive rate of < 5% in the non-neoplastic non-oncocytic follicular cells). The threshold for positivity was a H score ≥ 125 for the SC17.14 clone and ≥ 100 for the 14E5 clone. Using these thresholds, the frequency of SEZ6 positivity in MTCs was 91% (51/56) using the SC17.14 clone, and 93% (52/56) using the 14E5 clone. Immunopositivity of SEZ6 was noted in background follicular cells in 2 cases (4%) using either antibody clone. In primary tumors, the sensitivity and specificity of SEZ6 were 91% (95% CI = 84%-99%) and 96% (95% CI = 90%-101%) respectively for the SC17.14 clone, and 93% (95% CI = 86%-100%) and 96% (95% CI = 90%-101%) respectively for the 14E5 clone.
On univariate survival analysis using log rank test, SEZ6 positivity determined using the above-stated thresholds for positivity and SEZ6 expression levels categorized as high and low using the median SEZ6 H score as cutoff (236 for the SC17.14 clone, and 225 for the 14E5 clone) did not correlate with OS, DSS, LRRFS, or DMFS (P > .05, Fig. 1A and Table 3).
Table 3.
SEZ6 H score does not correlate with outcome in primary medullary thyroid carcinoma
| SC17.14 clone | 14E5 clone | |||
|---|---|---|---|---|
| Positivity (H score ≥ 125) |
High expression (H score ≥ 238) |
Positivity (H score ≥ 100) |
High expression (H score ≥ 225) |
|
| Overall survival | 0.455 | 0.288 | 0.383 | 0.360 |
| Disease-specific survival | 0.455 | 0.088 | 0.510 | 0.810 |
| Distant metastasis-free survival | 0.525 | 0.212 | 0.608 | 0.919 |
| Locoregional recurrence-free survival | 0.737 | 0.637 | 0.870 | 0.549 |
Values are P values obtained using univariate log rank test.
SEZ6 in Recurrent and Metastatic MTCs
In regional recurrence, the mean H score ± standard error of mean (SEM) of SEZ6 using the SC17.14 and 14E5 clone was 224 ± 19 and 204 ± 20 respectively. For distant metastasis, the mean H score SEM using the SC17.14 and 14E5 was 189 ± 27 and 176 ± 28 respectively. The H score did not differ among primary tumors, regional recurrence, and distant metastasis (P = .311 for the SC17.14 clone, and P = .501 for 14E5 clone). Using the same cutoff values of H scores determined above in the primary tumors, SEZ6 immunopositivity was also prevalent in recurrent and metastatic MTCs and was detected in 100% (10/10) of regional recurrence using either clone, and 75% (9/12) and 83% (10/12) of distant metastases using the SC17.14 and the 14E5 clone respectively
One distant metastasis showed cytoplasmic SEZ6 only (8%) using both clones, and one regional recurrence exhibited cytoplasmic SEZ6 only (10%) using the SC17.14 clone. Membranous and cytoplasmic staining was present in all remaining cases.
SEZ6 Immuno-Expression According to RET and RAS Mutation Status
RET germline mutation status was known in all cases. Among them, 3 tumors were familial, including 1 primary tumor harboring the RET C634R germline mutation, 1 regional recurrence with the RET C620Y germline mutation, and 1 distant metastasis with the RET K710R germline mutation. The remaining cases were sporadic.
Somatic mutations for RET and RAS genes were known in 72 cases, including 50 primary tumors, 10 regional recurrences, and 12 distant metastases. Altogether, 44 MTCs harbored RET somatic mutations, 14 with RAS mutations, whereas the remaining 14 were wild-type for RET and RAS. SEZ6 expression did not correlate with underlying RET or RAS mutations in MTC. The mean H score ± SEM was 153 ± 62, 221 ± 10, 232 ± 19, and 203 ± 28, respectively, for MTCs with RET germline mutations, RET somatic mutations, RAS somatic mutations, and wild-type RET/RAS respectively using the SC17.14 clone (P = .335), and 125 ± 60, 202 ± 11, 216 ± 19, and 191 ± 26, respectively, using the 14E5 clone (P = .291).
Among the cases with known genotypes, the frequency of SEZ6 positivity in MTCs that did not harbor RET (somatic or germline) and RAS mutations was 83% (10/12) using either antibody clone. The correlation between genotypes and SEZ6 immunophenotype is shown in Fig. 1B.
SEZ6 in CCH
SEZ6 IHC was performed in 7 cases of incidental CCH diagnosed in the thyroid gland resected for follicular cell-derived carcinoma, including papillary thyroid carcinoma (n = 6) and poorly differentiated thyroid carcinoma (n = 1). SEZ6 positivity was noted in a single case of nodular CCH (1/7, 14%) whereas the remaining 6 cases of CCH were entirely negative for SEZ6.
Discussion
Recently, SEZ6 expression has been reported in neuroendocrine neoplasms, such as SCLC and pheochromocytoma (3, 4, 9). However, the expression of SEZ6 in MTC has not yet been systematically studied. We herein present the first evidence that most MTCs, irrespective of primary, recurrent, or metastatic status, express SEZ6, a target for SEZ6-specific antibody-drug conjugate targeted therapy.
There are 3 isoforms of SEZ6, produced from alternatively spliced mRNA transcripts (10). Among them, SEZ6 type I and type II isoforms are cell-surface proteins tethered by a transmembrane domain, whereas SEZ6 type III isoform is a secretory protein with identical amino terminal sequences except for 18 C-terminal amino acids (10, 11). This soluble isoform SEZ6 isoform type III may contribute to the nonspecific weak staining in thyroid follicular cells and in serum detected by SEZ6 IHC. Indeed, nonspecific cytoplasmic SEZ6 staining was noted using both primary antibody clones. SEZ6 IHC using the SC17.14 clone additionally showed nonspecific staining in lymphocytes. Fortunately, the nonspecific background stain was mostly weak and focal in nature with a mean H score of 67 and 25, respectively, which was significantly different from the strong and diffuse positivity in primary MTCs with a mean H score of 224 and 204, respectively. In our hands, a threshold H score of 125 for the SC17.14 clone and 100 for the 14E5 clone appeared to clearly separate positive staining in MTC from nonspecific labeling in the background tissue with high sensitivity (> 90%) and specificity (> 95%). Giving this high sensitivity and specificity of SEZ6 in detecting MTC, it may serve as a diagnostic marker for MTC in conjunction with other, traditional neuroendocrine markers, such as calcitonin, synaptophysin, and chromogranin, when encountering a thyroid tumor.
Wiedemeyer et al (4) reported a mean SEZ6 H score of 66.8 in SCLC using an internally developed SEZ6 antibody. This H score was much lower than the mean SEZ6 H score in MTC, being 224 for the SC17.14 clone, and 204 for the 14E5 clone. Such results imply that SEZ6 immuno-expression is stronger and more diffuse in MTC compared with SCLC.
The ABBV-011 and ABBV-076 are novel SEZ6-targeted calicheamicin or topoisomerase 1 inhibitor-based antibody-drug conjugates (4, 5, 12). Currently, ABBV-011 and ABBV-076 are studied in phase I trials as single agent or combined therapy for patients with relapsed or refractory SCLC, central nerve system tumors, and neuroendocrine neoplasms, including MTC (ABBV-011: NCT03639194, https://clinicaltrials.gov/study/NCT03639194, ABBV-076: NCT05599984, https://clinicaltrials.gov/study/NCT05599984) (4, 5). According to the current National Comprehensive Cancer Network (NCCN) guidelines (13), targeted therapies for progressive or metastatic MTCs, either FDA-approved or in the setting of clinical trials, include RET inhibitors such as selpercatinib and pralsetinib for RET-mutated MTC, multitargeted kinase inhibitors vandetanib and cabozantinib, and small-molecule kinase inhibitors such as sorafenib, sunitinib, lenvatinib, or pazopanib. However, the choices of kinase inhibitors are limited for RET and RAS wild-type MTC. In the study herein, SEZ6 was positive in > 90% of MTCs, including 83% of those lacking RET or RAS mutations. Furthermore, immuno-expression of SEZ6 was retained in regional recurrence and distant metastasis. Together, these data suggest that SEZ6-targeted therapy is potentially useful in patients with MTC, particularly those with recurrent and metastatic disease, regardless of the underlying genotype.
When correlating SEZ6 expression in MTC with clinicopathologic features in primary MTC, a significantly higher level of expression was seen in male patients, tumors of advanced stage/prognostic group, and tumors with microscopic extrathyroidal extension. This is in congruence with the adverse prognostic effect of high SEZ6 RNA expression in SCLC (4). The fact that SEZ6 expression was increased in advanced MTC is promising, as these are the patients with poorer outcome and higher frequency of recurrence (7).
In our cohort, SEZ6 IHC, both positivity/negativity and high/low expression, failed to predict outcome of MTC. Therefore, the expression of SEZ6 may not be prognostically relevant in MTC.
In conclusion, we herein report SEZ6 as a novel biomarker for MTCs. SEZ6 IHC appears to be a highly sensitive and specific immunomarker for MTC using 2 different primary antibody clones (17.14 and 14E5). Although SEZ6 lacks any prognostic values in MTC, its positivity in 91% to 93% of MTCs, including MTCs without RET and RAS mutations, renders SEZ6-targeted antibody-drug conjugate therapy a promising targeted therapy for MTCs.
Abbreviations
- AJCC
American Joint Committee on Cancer
- ANOVA
analysis of variance
- CCH
C cell hyperplasia
- DMFS
distant metastasis-free survival
- DSS
disease-specific survival
- LRRFS
locoregional recurrence-free survival
- MTC
medullary thyroid carcinoma
- OS
overall survival
- ROC
receiver operating characteristic
- SCLC
small cell lung carcinoma
- SEZ6
seizure-related 6 homolog
Contributor Information
Bin Xu, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Marina K Baine, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Achim Jungbluth, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Anas Alabkaa, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Rene Serrette, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Dibisha Roy, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Charles M Rudin, Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Alan L Ho, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Eric Sherman, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Snjezana Dogan, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Ian Ganly, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Natasha Rekhtman, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Ronald Ghossein, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Funding
Research reported in this publication was supported in part by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748.
Author Contributions
Study Conception: B.X., M.K.B., N.R., R.G.; Database management: B.X.; Pathology review and data collection: B.X., A.A., D.R., R.G.; Immunohistochemistry: R.S., A.J.; Molecular analysis: S.D., I.G.; Statistics: B.X.; Manuscript drafting: B.X.; Manuscript editing: M.K.B., A.J., A.A., C.M.R., A.L.H, E.S., S.D., I.G., N.R., R.G.
Disclosures
No competing financial interests exist for all contributory authors. Research reported in this publication was supported in part by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748.
Ethics Approval
The research is approved by the Institutional Review Board (IRB 17-103).
Data Availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
