Pan-Cancer Analysis of Loss-of-Function Alterations and Their Association with the Focal Tandem-Duplicator Phenotype.

BACKGROUND

loss-of-function (LOF) genomic alterations are associated with focal tandem duplications (FTDs) in ovarian and prostate cancers. Because these FTDs may produce fusion-induced neoantigens (FINAs), alteration is a candidate biomarker for immune checkpoint inhibitor sensitivity. Here we determine the prevalence of LOF alterations and their association with FTDs across diverse tumor types.

MATERIALS AND METHODS

A total of 142,133 tumor samples comprising 379 cancer types were sequenced (August 2014 to April 2018) by hybrid capture-based comprehensive genomic profiling (Foundation Medicine, Cambridge, MA) as part of routine clinical care. Results were analyzed for base substitutions, short insertions/deletions, rearrangements, and copy number alterations. LOF genomic alterations were assessed for zygosity status and association with FTDs/focal copy number gain.

RESULTS

genomic alterations were detected in 1.1% of all cases, most frequently in prostate cancer (5.6%), but were also observed at >1% frequency in 11 cancer types. Across multiple cancer types, including prostate, gastric/esophageal, ovarian, breast, and endometrial cancer, the number of FTDs was significantly increased in LOF versus wild-type cases. Notably, -LOF was not consistently associated with a homologous recombination deficiency genomic signature. Quantitative assessment of associated FTDs by measurement of single copy number gains identified novel likely deleterious kinase-domain mutations in prostate and ovarian cancers.

CONCLUSION

Detection of LOF genomic alterations and their association with FTDs in a diverse spectrum of malignancies suggests that immunotherapy approaches targeting FINAs derived from associated FTDs may be a broadly applicable strategy that could be explored across cancer types in a tumor-agnostic manner.

IMPLICATIONS FOR PRACTICE

inactivation in ovarian and prostate cancer results in the generation of focal tandem duplications, which can cause fusion-induced neoantigens. In prostate cancer, alterations have demonstrated promise as a potential predictive biomarker for response to immune checkpoint blockade. This study evaluated genomic profiling data from >142,000 tumors to determine the prevalence of loss-of-function genomic alterations across tumor types and demonstrated that alterations are associated with the tandem-duplicator phenotype in cancer types other than ovarian and prostate cancer. The association of alterations with focal tandem duplications across broad cancer types suggests that inactivation warrants further investigation as a pan-cancer biomarker for immunotherapy benefit.