(P 50) CHARACTERIZATION OF A FAMILIAL GIST KINDRED INTOLERANT TO IMATINIB

Objective:

Objective: Gastrointestinal stromal tumors (GISTs) are rare tumors which can occur throughout the gastrointestinal tract and for which a significant proportion have been found to harbor mutations in the KIT oncogene permitting targeted therapy with the use of imatinib. We sought to characterize the molecular and clinical characteristics of a family with multiple generations affected by multifocal GISTs with imatinib intolerance.

Methods:

Methods: A complete chart review was conducted including clinical, pathologic and radiologic review for the proband, her mother and additional family members where information available and used to construct a pedigree. Tumors were sequenced through the SickKids Cancer Sequencing Program, KiCS (Toronto, Ontario, Canada) on banked frozen tumor tissue from the proband as well as her mother, as well as matched germline blood sample for each patient. Data processing was performed using previously described methods. Somatic mutational burden was assessed for each patient, and whole-genome sequencing data was utilized to assess for copy number changes.

Results:

Results: Within our familial kindred affected by multifocal GISTs across generations, we noted a severe intolerance to imatinib after 8 weeks of therapy. We identified a novel germline variant in KIT not previously c.1965T>G; p.Asn655Lys, not previously seen in population databases but which has been seen as a somatic mutation in jejunal GIST, acral melanoma and acute myeloid leukemia. We also concomitantly identified a germline variant in the MSR1 gene, macrophage receptor scavenger 1, encoding a stopgain variant in exon 6 (c877C>T; p.Arg293*) rs41341748 shared between patients over 3 generations of this family.

Conclusion:

Conclusions: We suspect this novel germline variant of KIT may have resulted in a hereditary predisposition to multifocal GISTs as well as variably penetrant additional phenotypes including altered gut motility and immune dysregulation. The identification of a germline stopgain variant in MSR1 across this familial kindred presents an opportunity for further investigation for additional pathways at play in hereditary cancer development in this family.