Association of Partial Chromosome 3 Deletion in Uveal Melanomas With Metastasis-Free Survival

International audienceImportance: Studies on uveal melanomas (UMs) have demonstrated the prognostic value of 8q gain and monosomy 3, but the prognosis of UMs with partial deletion of chromosome 3 remains to be defined.Objective: To examine the association of partial chromosome 3 deletion in UMs with metastasis-free survival.Design, setting, and participants: This retrospective cohort study of 1088 consecutive comparative genomic hybridization arrays performed from May 1, 2006, to July 31, 2015, assessed patients presenting with UMs with and without partial loss of chromosome 3 at a referral center. Data analysis was performed from September 1, 2017, to November 30, 2017.Exposure: Uveal melanoma with or without partial loss of chromosome 3.Main outcomes and measures: Metastasis-free survival and overall survival at 60 months.Results: Of the 1088 consecutive comparative genomic hybridization arrays that were performed, 43 UMs (4.0%) in 43 patients (median age, 58 years [range, 12-79 years]; 22 [51%] female) carried partial deletions of chromosome 3. Median follow-up was 66 months (range, 1.2-126.2 months). Metastasis-free survival at 60 months was 33.6% (95% CI, 15.8%-71.4%) for UMs that carried a deletion of the BAP1 (BRCA1 associated protein 1) locus (BAP1del; 24 tumors) and 80.5% (95% CI, 64.8%-100%) for UMs without the loss of the BAP1 locus (BAP1 normal [BAP1nl]; 19 tumors) (log-rank P = .001). Overall survival at 60 months was 64.5% (95% CI, 43.5%-95.8%) in the BAP1del group vs 84.1% (95% CI, 69.0%-100%) in the BAP1nl group (log-rank P < .001). In these 43 cases, metastasis-free survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 70.0% (95% CI, 50.5%-96.9%) for UMs that carried 1 of these alterations, and 12.5% (95% CI, 2.1%-73.7%) for those that carried both (log-rank P < .001). Similarly, overall survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 80.8% (95% CI, 63.3%-100%) for UMs that carried 1 of these alterations, and 46.7% (95% CI, 23.3%-93.6%) for those that carried both (log-rank P < .001).Conclusions and relevance: These findings suggest that partial deletion of chromosome 3 encompassing the BAP1 locus is associated with poor prognosis. A cytogenetic classification of UMs could be proposed based on the status of the BAP1 locus instead of the chromosome 3 locus, while also taking chromosome 8q into account

Radiogenomics of neuroblastomas: Relationships between imaging phenotypes, tumor genomic profile and survival.

This study investigated relationships between neuroblastomas (NBs) imaging phenotypes, tumor genomic profile and patient outcome.This IRB-approved retrospective observational study included 133 NB patients (73 M, 60 F; median age 15 months, range 0-151) treated in a single institution between 1998 and 2012. A consensus review of imaging (CT-scan, MRI) categorized tumors according to both the primarily involved compartment (i.e., neck, chest, abdomen or pelvis) and the sympathetic anatomical structure the tumors rose from (i.e., cervical, paravertebral or periarterial chains, or adrenal gland). Tumor shape, volume and image-defined surgical risk factors (IDRFs) at diagnosis were recorded. Genomic profiles were assessed using array-based comparative genomic hybridization and divided into three groups: "numerical-only chromosome alterations" (NCA), "segmental chromosome alterations" (SCA) and "MYCN amplification" (MNA). Statistical analyses included Kruskal-Wallis, Chi2 and Fisher's exact tests and the Kaplan-Meier method with log-rank tests and Cox model for univariate and multivariate survival analyses.A significant association between the sympathetic structure origin of tumors and genomic profiles was demonstrated. NBs arising from cervical sympathetic chains were all NCA. Paravertebral NBs were NCA or SCA in 75% and 25%, respectively and none were MNA. Periarterial NBs were NCA, SCA or MNA in 33%, 56% and 11%, respectively. Adrenal NBs were NCA, SCA or MNA in 16%, 36% and 48%, respectively. Among MNA NBs, 92% originated from the adrenal gland. The sympathetic anatomical classification was significantly better correlated to overall survival than the compartmental classification (P < .0003). The tumor volume of MNA NBs was significantly higher than NCA or SCA NBs (P < .0001). Patients with initial volume less than 160 mL had significantly better overall survival (P < .009). A "single mass" pattern was significantly more frequent in NCA NBs (P = .0003). The number of IDRFs was significantly higher in MNA NBs (P < .0001).Imaging phenotypes of neuroblastomas, including tumor origin along the sympathetic system, correlate with tumor genomic profile and patient outcome

Relationship between anatomical primary tumor location (compartment and sympathetic origin) of neuroblastomas and their genomic profile.

<p>Relationship between anatomical primary tumor location (compartment and sympathetic origin) of neuroblastomas and their genomic profile.</p

Imaging phenotypes of abdominal neuroblastomas.

<p><b>(a)</b> 18-month-old girl with M-stage right <b>adrenal MNA neuroblastoma</b>. Enhanced CT scan at diagnosis. The primary tumor (<b>*</b>) is centered on the right adrenal gland between the right kidney and the inferior vena cava (arrow) and extends medially in contact with the aorta (arrowhead). <b>(b)</b> 12-month-old girl with M-stage retroperitoneal <b>periarterial SCA neuroblastoma</b>. Enhanced CT scan at diagnosis. The primary tumor (<b>*</b>) is centered in the median retroperitoneum around the aorta (arrowhead) and behind the inferior vena cava (arrow). <b>(c)</b> Newborn with L2-stage lumbar dumbbell <b>paravertebral NCA neuroblastoma</b>. Axial T2-weighted MRI at diagnosis. The primary tumor (<b>*</b>) is centered on the right paravertebral chain and invades the psoas and spinal muscles and fills the spinal canal, compressing the spinal cord (dotted arrow). The tumor is totally separated from the inferior vena cava (arrow) and the aorta (arrowhead).</p

Imaging phenotypes of chest neuroblastomas.

<p><b>(a, b, c)</b> Newborn with L2-stage left posterior <b>mediastinal NCA neuroblastoma</b>. MRI at diagnosis (a, b: sagittal and axial T2-weighted sequences). The primary tumor is a unique well-delineated mass (*) with focal contact with the thoracic aorta (arrowhead) and intra-spinal extension (arrow). Follow-up MRI 3 months later (c) after neoadjuvant chemotherapy (2 courses of cyclophosphamide-vincristine and 2 courses of etoposide-carboplatin) shows the tumor residue precisely located at the costo-vertebral junction, i.e., a paravertebral sympathetic chain location. <b>(d, e)</b> 9-year-old girl with M-stage <b>mediastinal SCA neuroblastoma</b>. Enhanced CT scan at diagnosis (axial and coronal views). The primary tumor (*) is ill-defined and diffusely infiltrates the posterior mediastinum, pleura and chest wall (arrows), crosses the midline and encases the thoracic aorta (arrowhead). The presumed origins are the mediastinal sympathetic fibers surrounding the descending aorta.</p

Study cohort characteristics and relationships between patient age, INPC, stage and genomic profile.

<p>Study cohort characteristics and relationships between patient age, INPC, stage and genomic profile.</p

Relationships between imaging phenotypes of neuroblastomas and outcome (univariate analysis).

<p>Relationships between imaging phenotypes of neuroblastomas and outcome (univariate analysis).</p

Radiogenomics classification of neuroblastomas according to anatomical origin.

<p>Neuroblastomas may be classified based on the anatomical compartment (i.e., neck, chest, abdomen or pelvis) or according to the sympathetic structure the tumors arise from, i.e., (1) the cervical sympathetic chains (i.e., including the superior, middle and inferior cervical and the cervicothoracic ganglia (g.)); (2) the paravertebral (PV) sympathetic chains (i.e., including all thoracic, lumbar and sacral ganglia); (3) the periarterial (PA) sympathetic pathways (i.e., including the thoracic aortic, abdominal aortic and celiac plexus (pl.)), the aorticorenal ganglia, and the superior and inferior mesenteric, superior hypogastric and iliac plexus); and (4) the adrenal glands. For each compartment or sympathetic group, the pie charts show the distribution of the genomic profile of the tumors, i.e., numerical-only chromosome alterations (NCA), segmental chromosome alterations (SCA) or <i>MYCN</i> amplification (MNA).</p

Kaplan-Meier survival analysis according to anatomical classifications of primary tumors.

<p>Event-free survival (EFS) and overall survival (OS) according to the anatomical compartment (a, b) and sympathetic system origin (c, d) of the primary tumor.</p