Detection of Molecular Biomarkers in Fanconi Anemia Mucosa

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.5704-5704
• Main Authors: Berger, Tamar, Lin, Yu-Chien, Donovan, Frank X, Soma, Shivatheja, Bhadresha, Kinjal, Krieg, Christine, Giri, Neelam, McReynolds, Lisa J, Filie, Armando, Khavandgar, Zohreh, Laronde, Denise M, Guillaud, Martial, Savage, Sharon A, Velleuer, Eunike, Chandrasekharappa, Settara C, Smogorzewska, Agata
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-199823

Introduction Fanconi anemia (FA) is the most common cause of inherited bone marrow failure, and a cancer predisposition syndrome caused by impaired DNA interstrand crosslink repair, also known as the FA repair pathway. Hematopoietic stem cell transplantations (HSCT) have improved survival in patients with FA, however, those have also heightened the risk of malignancies. Head and neck squamous cell carcinoma (HNSCC), and specifically oral SCC (oSCC), are the most common solid malignancies and the leading cause of death in adult patients with FA. By 45 years of age, HNSCC has a computed cumulative incidence of 50% and 100% in FA patients who did not and did undergo a HSCT, respectively. Historically, SCC in FA has been mostly diagnosed at an advanced stage of disease conferring poor outcome. FA-associated HNSCC are known to be enriched with p53 and structural variants. We aim to develop molecular screening tools and biomarkers of oSCC development in FA patients, to facilitate measurement of potential prophylactic therapies and allow for earlier detection of premalignant oral lesions and cancer. To that end, we are mapping somatic genetic variants in normal-appearing oral mucosa as well as oral lesions in patients with FA, and we plan to evaluate circulating cancer biomarkers. Methods This is a proof-of-concept study conducted in healthy controls (HC) and FA patients. We use a non-invasive oral brush biopsy to collect oral keratinocytes from six different sites of normal-appearing mucosa: retromolar area, side of the tongue and floor of the mouth, bilaterally. DNA is isolated and the exonic regions of the TP53 gene are sequenced using CleanPlex TP53 Kit on an illumina Miseq platform, to identify single nucleotide variants (SNVs), insertion-deletions (indels) at an allele frequency above 1%. Genome-wide SNP genotyping with Infinium Global Diversity Array (v1.0) is used for copy number variant (CNV) identification. Areas of visible changes/abnormal appearing mucosa are also brushed and are tested for the aforementioned genetic changes, as well as for cytology and DNA ploidy. Circulating plasma and serum biomarkers will be evaluated at the end of the study. Results The study is ongoing. 20 HC and 17 FA patients have completed the study to date. Median age of the HC and FA cohorts were 36.3 years (range 23-61) and 31.8 years (range 15-50), respectively. Sex distribution was similar with males consisting of 44% and 53% in the HC and FA cohorts, respectively. The H