Clinicopathologic characteristics of HRAS-mutant head and neck squamous cell carcinoma (HNSCC).
Authors: Olazagasti Coral , Rodriguez Estelamari , Trabolsi Asaad , Kareff Samuel , Yin Jun , Walker Phillip , Wise-Draper Trisha Michel , Chernock Rebecca , Hanna Glenn J. , Spetzler David , Lopes Gilberto 
Published: October 2024

6043

Background:
RAS mutations are often associated with tumor development and immune evasion and therefore unfavorable clinical outcomes. Farnesyl transferase inhibitors (FTI) are an emerging therapeutic option for HRAS mutant HNSCC (Hm), thus understanding the genomic and immunologic landscape of Hm is important for further development of this therapeutic approach.
Methods:
A total of 2,407 HNSCC tissue went through tumor molecular profiling at Caris Life Science (Phoenix, AZ). Analyses included next-generation sequencing of DNA (NextSeq, 592 Gene or NovaSeq, WES) and RNA (NovaSeq, WTS), and immunohistochemistry (IHC). HPV 16/18 status was assessed using WES. MAPK pathway activation and the likelihood of a tumor’s response to anti PD1 therapy were tested via MPAS and IFN signatures, respectively. Wilcoxon, Fisher’s exact were used for statistical significance (p without and q values with multiple comparison correction). Overall survival was calculated from date of tissue collection to last contact from insurance claims data and compared using Kaplan-Meier method. All comparisons were made between Hm and the entire HNSCC general cohort (GC).
Results:
Of the 2,407 HSNCC tested, 69 (2.87%) were pathogenic/likely pathogenic Hm. The most prevalent mutation (mt) was G12 (34.8%), G12 (31.9%) and Q61 (30.3%). Hm significantly correlated with male gender (59.4%, q <0.01) and older age (median 68.6 vs 64.1, q <0.01). No difference in HPV status was observed. Hm had worse prognosis (HR 1.49, 95 CI: 1.03 -2.13, p<0.05) and correlated with more TERT, FAT1 mt, lower p16, PD-L1 expression and TMB-H (cutoff: >=10mt/MB) (Table). Interestingly, PIK3CA Hm were mutually exclusive with TMB-H tumors in Hm (p<.0001). All Hm had higher MPAS scores (all: 0.88, Q61: 0.88, G13: 1.07 vs -0.34, q <0.05) compared to GC. Hm showed higher immunogenicity, evidenced by higher IFN score (all: -0.1, G12: -0.04 vs GC: -0.21, q < 0.05), higher ratio of macrophage M(MM)1 to MM2 (Fold change = 2.27, q <0.0001), more CD8+ T cells and elevated expression level of MHC1 class I genes (Table).
Conclusions:
Hm was associated with poor outcomes, higher MAPK activation, PD-L1 levels, TMB and IFN scores. This points to the oncogenic and immunomodulatory role of HRAS in HNSCC. Our findings provide additional evidence for ongoing clinical trials on combinatorial immunotherapy or PI3KCA inhibitors with FTI and demonstrate unique landscape of different point mutations; further evaluation is warranted. Differentially regulated features between Hm and GC (*p<0.05, q<0.05) for all results.

alteration (%)
Hm
GC
TME
Hm
GC
genes (TPM)
Hm
GC

TERT
64.9
23.3
MM1
0.075
0.054
*HLA-A
234.4
185.0

FAT1
39.5
12.5
MM2
0.027
0.035
*HLA-B
251.1
199.2

*PIK3CA
27.9
15.5
Neutrophil
0.068
0.054
*HLA-C
206.2
153.8

*CDK2A
28.1
17.7
CD8+
0.016
0.011
*HLA-E
86.5
67.9

*p16 (IHC)
23.4
42.0
NK
0.02
0.027
HLA-F
46.7
31.6

PD-L1
100.0
50.3
Bcells
0.038
0.053

TMB-H
30.3
16.6
mDC
0.01
0.017