P108: Myelodysplastic syndrome (MDS) detected by germline genetic testing for hereditary cancer

Hereditary cancer genetic testing using massively parallel sequencing can reveal incidental findings such as mosaicism, clonal hematopoiesis, or hematologic malignancies. We report a case of a patient who had germline genetic testing which revealed a contiguous gene deletion of the long arm of chromosome 5 at low allele fraction, leading to a diagnosis of myelodysplastic syndrome (MDS). The patient is a 68-year-old male with Ewing’s sarcoma at age 16, male breast cancer at age 53, and papillary thyroid cancer at age 57. He has a family history of young breast cancer, prostate cancer, oligodendroglioma, glioblastoma and pituitary adenoma. The patient had next-generation sequencing multi-cancer panel testing for 76 genes completed using a blood sample. This initial test revealed three heterozygous variants of uncertain significance (VUSs) in POT1, MLH3 and ATM, as well as whole gene deletions of both APC and CTNNA1 at low allele fraction (∼20%). The APC and CTNNA1 genes are located on the long arm of chromosome 5 (5q) approximately 26 Mb apart, which suggested that these deletions may reflect a contiguous gene deletion. These results therefore raised a few possible differential diagnoses: mosaicism, a somatic hematologic event such as clonal hematopoiesis, or a hematologic malignancy. To further investigate the origin and significance of the deletion, the patient underwent a skin biopsy and had the multi-cancer panel repeated on cultured fibroblasts. Fibroblast testing did not reveal the APC or CTNNA1 deletions, nor did it reveal the VUS in ATM, suggesting these variants were limited to the blood. A complete blood count was reviewed, and the patient was found to have a Hgb 119 g/L (normal 140-180) and lymphocyte count of 1.0x10ˆ9 (normal 1.5-4x10ˆ9). Given this constellation of findings, the patient was then referred to a hematologist. A bone marrow biopsy was completed which showed normocellular bone marrow with trilineage hematopoiesis, megakaryopoiesis demonstrating a significant number of hypolobulated forms, CD34+ blasts up to 4% by IHC, and peripheral blood demonstrating mild macrocytic anemia. Fluorescence in situ hybridization (FISH) analysis also showed a 5q deletion in 52.5% of nuclei. These features were consistent with a diagnosis of MDS. This case highlights the importance of considering hematologic disorders when incidental findings are revealed through hereditary cancer genetic testing. The patient was found to have a rare contiguous gene deletion of chromosome 5q at low allele fraction in blood that was not subsequently detected in cultured fibroblasts from a skin biopsy. This suggested that the deletion was acquired somatically and reflected a clonal hematopoietic disorder, and the patient was subsequently diagnosed with MDS based on his clinical and laboratory features. This case illustrates the need for multidisciplinary collaboration and follow-up investigations when germline genetic testing for hereditary cancer reveals unexpected findings.

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