BIRC2–BIRC3 amplification: a potentially druggable feature of a subset of head and neck cancers in patients with Fanconi anemia

Abstract

Head-and-neck squamous cell carcinomas (HNSCCs) are relatively common in patients with Fanconi anemia (FA), a hereditary chromosomal instability disorder. Standard chemo-radiation therapy is not tolerated in FA due to an overall somatic hypersensitivity to such treatment. The question is how to find a suitable alternative treatment. We used whole-exome and whole genome mRNA sequencing to identify major genomic and transcriptomic events associated with FA-HNSCC. CRISPR-engineered FA-knockout models were used to validate a number of top hits that were likely to be druggable. We identified deletion of 18q21.2 and amplification of 11q22.2 as prevailing copy-number alterations in FA HNSCCs, the latter of which was associated with strong overexpression of the cancer-related genes YAP1, BIRC2, BIRC3 (at 11q22.1-2). We then found the drug AZD5582, a known small molecule inhibitor of BIRC2-3, to selectively kill FA tumor cells that overexpressed BIRC2-3. This occurred at drug concentrations that did not affect the viability of untransformed FA cells. Our data indicate that 11q22.2 amplifications are relatively common oncogenic events in FA-HNSCCs, as holds for non FA-HNSCC. Therefore, chemotherapeutic inhibition of overexpressed BIRC2-3 may provide the basis for an approach to develop a clinically realistic treatment of FA-HNSCCs that carry 11q22.2 amplifications.

Development of a mouse model for spontaneous oral squamous cell carcinoma in Fanconi anemia

“…In addition, we also found the germline mutations in the FANCA gene that had previously been diagnosed in all three FA patients [27] (Supplementary Table 3). These results are in line with the frequent detection of TP53 alterations in SCC from FA patients [19][20][21]. Therefore, animal models resembling germline FANCA and somatic TP53 mutations might model SCC in FA.…”

“…Therefore, additional genetic events are needed. We have found TP53 mutations in all five HNSCC from three FA patients (Supplementary Table 3, Supplementary Table 4), which is in agreement with the high frequency of mutations or deletions in TP53 described in HPVnegative, FA [18][19][20][21] and non-FA patients [34][35][36]. In addition, TP53 mutations are early events during HPV-negative HNSCC carcinogenesis in non-FA patients [37,38].…”

“…Most HNSCCs from FA patients display alterations typically found in HPVnegative HNSCC tumors from the general population, such as mutations in the TP53 gene [18][19][20][21]. Here, we also detected mutations in TP53 in all five SCCs analyzed from the oral cavity of three FA patients.…”

Fanconi anemia-isogenic head and neck cancer cell line pairs - a basic and translational science resource

“…FA-CCLR cell lines displayed both HNSCC- as well as FA-associated genomic alterations (9,12,13,31–33). Figure 2 summarizes cell line-specific single nucleotide (SNV) and copy number (CNV) variant data for cell lines where we had full data access and compares these lines with HPV-negative HNSCC samples included in TCGA data (n = 426; (19)).…”

“…Copy-number amplifications and deletions for OHSU-SCC-974, CCH-SCC-FA1 and CCH-SCC-FA2 were called using CNVkit (16) to compare tumor cell line and patient matched WGS data. SNV/indels and copy-number amplifications and deletions were called for FA patient-derived cell lines VU-SCC-1604, VU-SCC-1365 and VU-SCC1131 using, respectively, Mutect2 (17) and CNVkit to compare tumor cell line and patient matched fibroblast whole-exome sequencing (WES) data (13), with a focus on variant calling in significantly mutated genes considered to be HNSCC drivers when altered (9,18,19). Somatic mutation data for sporadic HNSCC cell lines JHU-SCC-FaDu, CAL-SCC-27, CAL-SCC-33, SFCI-SCC-09 and UM-SCC-01 were extracted from the Broad Institute Cancer Cell Line Encyclopedia (CCLE)(10), employing Mutect2 and Absolute (20) for SNV/indel and copy-number analyses.…”