Although uncommon, thyroid nodules (TN) in pediatric and young adult patients carry higher malignancy risk and often present with a high burden of metastatic disease than adults. The molecular features underlying this distinct clinical behavior remain unclear. We analyzed Afirma Genomic Sequencing Classifier (GSC) data from 283,621 TN, comparing patients <21 and ≥21 years. Cytology (Bethesda), GSC benign (B) vs suspicious (S) calls, and Afirma Xpression Atlas (XA) variant/fusion profiles were evaluated in GSC-S and Bethesda V/VI samples. Genome-wide expression was used to derive pathway signatures and thyroid cancer-related scores: BRAF-RAS score (BRS), ERK, follicular and epithelial-to-mesenchymal transition (FMT, EMT) and thyroid differentiation scores (TDS). Among 2,397 patients <21 (median age 18.9; 81.4% female) and 281,224 adults ≥21 (median age 59.8; 77.1% female), <21 samples showed more Bethesda V/VI cytology (14.5% vs 5.0%; p<0.0001) and a lower GSC-B rate (43.5% vs 68.8%; p<0.0001). In GSC-S samples, total variant detection was higher in <21 (45.3% vs 37.4%), with enriched BRAF p.V600E, TSHR, and DICER1 variants, while HRAS variants were more common in adults (all p<0.01). Gene fusions involving RET, NTRK3 and ALK were enriched in <21 (14.5% vs 5.5%; p<0.0001). TERT promoter mutations were absent in <21 yrs GSC-S and Bethesda V/VI samples (vs 4.2% and 9.3% in adults). GSC-S <21 showed cell-cycle pathway enrichment. RET/NTRK/ALK-positive <21 demonstrated enrichment of angiogenesis and EMT pathways, higher ERK/EMT/FMT scores, and lower BRS/TDS scores vs genotyped-matched adults. These molecular differences provide mechanistic insight into the more invasive phenotype in pediatric and young adult TN.
J. Ricarte-Filho, L. Castellanos, Steven G. Waguespack et al.· Endocrine-Related Cancer· 0 citations
INTRODUCTION
Homozygous deletion of 9p21, containing CDKN2A/B and MTAP (CMdel), underlies emerging therapeutic strategies including PRMT5/MAT2A inhibition. The clinicogenomic context and treatment outcomes of CMdel in NSCLC remain incompletely defined.
METHODS
We analyzed Tempus Lens records with paired DNA/RNA sequencing. After quality filtering, 16,947 patients were included in the primary dataset and 10,996 in the validation dataset, and stratified by deletion status (CMdel vs CMwt). Interferon status was defined by interferon-kappa (IFNK) expression (log2[TPM+1]) using the 25th percentile of CMwt as threshold. Immune composition was inferred by quanTIseq. First-line regimens were grouped as ICI-mono, ICI-chemo, chemotherapy, or TKI. Best response and time-to-next-treatment with risk-set adjustment were assessed.
RESULTS
CMdel occurred in 11.7% (n=1,991) and 15% (n=1,676), and was enriched in mucinous histology, stage IV disease, and never-smokers. CMdel associated with EGFR, TERT, and SMARCA4 alterations, whereas CMwt associated with RB1, SETD2 and ARID2. >50% of CMdel tumors harbored targetable co-alterations, enriched in EGFR/ALK/RET and relatively depleted in KRAS. CMdel tumors exhibited lower PD-L1, mutation burden, and immune infiltration. TTNT did not differ by CM status for ICI-mono or TKI, but was shorter in CMdel for ICI-chemo and chemotherapy. Discordant and broad deletions were less common and had weaker TTNT association. IFNK-low expression marked immune-excluded subgroups with worse treatment outcomes.
CONCLUSIONS
CDKN2A/MTAP loss defines a prevalent, genomically distinct NSCLC subset enriched in actionable drivers. CMdel associates with worse outcomes to ICI/chemotherapy-containing regimens. These findings highlight convergent biology at 9p21 and support biomarker-guided development of PRMT5/MAT2A inhibitors in MTAP-deleted NSCLC.
N. Vokes, J. Symons, Brooke Rhead et al.· Clinical Cancer Research· 0 citations
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