Genomic and Transcriptomic Characterization Links Cell Lines with Aggressive Head and Neck Cancers

Abstract

SUMMARY Cell lines are important tools for biological and preclinical investigation, and establishing their relationship to genomic alterations in tumors could accelerate functional and therapeutic discoveries. We conducted integrated analyses of genomic and transcriptomic profiles of 15 human papillomavirus (HPV)-negative and 11 HPV-positive head and neck squamous cell carcinoma (HNSCC) lines to compare with 279 tumors from The Cancer Genome Atlas (TCGA). We identified recurrent amplifications on chromosomes 3q22–29, 5p15, 11q13/22, and 8p11 that drive increased expression of more than 100 genes in cell lines and tumors. These alterations, together with loss or mutations of tumor suppressor genes, converge on important signaling pathways, recapitulating the genomic landscape of aggressive HNSCCs. Among these, concurrent 3q26.3 amplification and TP53 mutation in most HPV(–) cell lines reflect tumors with worse survival. Our findings elucidate and validate genomic alterations underpinning numerous discoveries made with HNSCC lines and provide valuable models for future studies.

HPV‐negative and HPV‐positive HNSCC cell lines show similar numerical but different structural chromosomal aberrations

“…This was shown for the total amount of chromosomal aberrations as well as the loss of 16q or 16q24.3, which were associated with a better prognosis . In contrast, loss of 5q35.1 or 17p12 or amplification of 3q26.3 was associated with poor prognosis . Another chromosomal aberration, the amplification of chromosome 7, is mutually exclusive for HPV‐negative tumors .…”

“…19 In contrast, loss of 5q35.1 or 17p12 or amplification of 3q26.3 was associated with poor prognosis. 12,16,20 Another chromosomal aberration, the amplification of chromosome 7, is mutually exclusive for HPV-negative tumors. 15 However, so far, for none of these markers, neither the underlying mechanisms are clear nor can they be used for diagnosis.…”

Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models

“…The two other mutants (E970K and N1044K) were in the catalytic domain and are previously described as hotspots in a population-scale cohort of tumor samples (31,32), with N1044K identified by targeted sequencing of the HPV+ PDX that failed WES. Finally, the 3q amplicon spanning PIK3CA, TP63, and SOX2 that appears de novo during HNSCC cell line generation (11,12) was not enriched the HPV+ PDXs ( Figure 1F). Together, these findings supported the superior fidelity of the PDXs over cell lines in representing key genetic traits of HPV+ HNSCC and thus their distinct utility as HPV+ cancer models.…”

“…Furthermore, the HPV+ PDXs retained the increase in alterations predicted to activate the PI3-kinase pathway that are a hallmark of HPV+ HNSCC ( Figure 1D). PIK3CA hotspot mutations, which are lost in HPV+ cell lines (11,12), were identified in 3 HPV+ PDXs, including a canonical activating E545K helical domain mutant ( Figure 1E, Supplemental Table S4). The two other mutants (E970K and N1044K) were in the catalytic domain and are previously described as hotspots in a population-scale cohort of tumor samples (31,32), with N1044K identified by targeted sequencing of the HPV+ PDX that failed WES.…”

“…Artifacts in existing HPV+ cell lines include loss of the canonical PIK3CA activating mutations and TRAF3 deletions that are more abundant in the HPV+ subtype of HNSCC. Most HPV+ HNSCC cell lines also acquire EGFR amplifications, which are uncommon in HPV+ HNSCCs, as well as copy gains in the 3q region spanning TP63, SOX2, and PIK3CA (11,12). Infrequent surgical treatment of HPV+ HNSCCs in the past and their intrinsically poor engraftment rates in immune-deficient mice (13) have impeded development of patient-derived xenograft (PDX) models.…”