27. Five-year experience of evaluating individuals at-risk for underlying genetic predisposition to hematologic malignancy

Min Fang


Min Fanga, Mercy Laurinoa, Xiaoyu Qua, Kate Kroegera, Michele Beaumonta, Natasha Carreraa, Amanda Weatherforda, Marshall Horwitzb, Sioḃán Keela

aFred Hutchinson Cancer Center, Seattle, WA, United States; bUniversity of Washington, Seattle, WA, United States

In 2018, the Fred Hutchinson Cancer Center Hematologic Malignancy Genetics and Surveillance clinic was established. This is a multidisciplinary clinic which offers personalized diagnosis, risk assessment, and surveillance care to adult patients and family members with known or suspected genetic predisposition for hematologic cancers. From January 2018 to February 2023, 190 patients (ages 16-73 yo, average age 45 yo) from 74 families completed consultations. Utilizing the Fred Hutch’s Myeloid Malignancy program’s approved criteria, the main indications for referral were the diagnosis of AML or MDS at < 50 years of age (30%), diagnosed with other blood cancer (15%), carrier of a known pathogenic variant (12%), family history of cancer (7%), and suspected short telomere syndrome diagnosis (5%). Germline genetic testing showed 31% of patients (59/190) harbored a pathogenic variant in the following genes: DDX41 (29%), RUNX1 (24%), TERT (14%), GATA2 (13%), and other genes (ETV6, SFTPA1, RPS10, CTLA4, and TERC). In addition, variants of unknown significance were reported in 13% of patients. Unique to this patient population, testing of blood in a subset of patients cannot be used for germline genetic testing as the hematopoietic cells contain both germline and tumor-associated somatic mutations. Therefore, one cannot discern whether a mutation is acquired or constitutional. A workflow was developed to obtain skin biopsies and fibroblast cultures to accomplish reliable and timely germline genetic testing. A multidisciplinary team approach is required to effectively deliver timely personalized hereditary hematologic malignancy patient counseling and care.