Objective: Identifying the potential of germline CDKN2A I49T (also known as p.I49T: ATC>ACC) in familial cancer and its potential as a targetable driver mutation in carcinogenesis.
Method: Germline mutational analysis was done using commercially available next generation sequencing (NGS) in kindred affected by cancers of lung, throat, gastrointestinal stromal tumor (GIST) and osteosarcoma using. Treatment of chemo-refractory osteosarcoma was done with CDK4/6 inhibitor palbociclib. Monitoring of response was done by serial computed tomography (CT) imaging.
Results: Two affected members in the kindred, one with GIST and one with osteosarcoma were tested and proven positive for germline CDKN2A I49T alteration. The patient with osteosarcoma experienced progression of the disease despite multiple surgical resections and combination chemotherapy. Patient had a sustainable response to CDK4/6 inhibitor palbociclib, with disease controlled for more than a year.
Conclusion: These findings suggested a familial cancer syndrome associated with germline CDKN2A I49T and showed its potential as a targetable driver mutation.