Clonal landscape and clinical outcomes of telomere biology disorders: somatic rescuing and cancer mutations.

Telomere biology disorders (TBD), caused by pathogenic germline variants in telomere-related genes, present with multi-organ disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBD is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 TBD patients with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, and splicing factor genes associated with poorer overall survival. Chr1q+, and splicing factor or TP53 mutations significantly increased the risk of hematologic malignancies, regardless of the clonal burden. Chr1q+ and U2AF1S34 mutated clones were pre-malignant events associated with the secondary acquisition of mutations in genes related to hematologic malignancies. Like known effects of Chr1q+ and TP53-CH, functional studies demonstrated that U2AF1S34 mutations primarily compensated for aberrant upregulation of TP53 and interferon pathways in telomere-dysfunctional hematopoietic stem cells, highlighting the TP53 pathway as a canonical route of malignancy in TBD. In contrast, somatic POT1/PPM1D/TERTp-CH had distinct trajectories unrelated to cancer development. With implications beyond TBD, our data show that telomere dysfunction is a strong selective pressure for CH. In TBD, CH is a poor prognostic marker associated with worse overall survival. The identification of key regulatory pathways that drive clonal transformation in TBD allows the identification of patients at a higher risk of cancer development.

Relationship between Fitzpatrick Skin Type and The Cancer Genome Atlas Classification with Melanoma-Related Metastasis and Death in 854 Patients at a Single Ocular Oncology Center.

BACKGROUND: The Fitzpatrick Skin Type (FST) is an objective method of classifying patients based on skin color and sunburn sensitivity. The Cancer Genome Atlas (TCGA) is a method of determining the prognosis of patients with uveal melanoma based on genetic composition of the tumor. There is no literature studying the relationship of FST and TCGA groups. MATERIALS AND METHODS: Retrospective cohort study on 854 patients with uveal melanoma treated at a single tertiary ocular oncology center between April 2006 and June 2020, classified based on FST on a scale of I-VI and based on genetic analysis with TCGA classification on a scale of A, B, C, and D. Outcome measures included uveal melanoma-related metastasis and death per FST and TCGA group. RESULTS: Patients classified as FST I (compared to FST II and III-V) had higher odds of being TCGA group D (OR 2.34, p = 0.002). Patients classified as FST III-V (compared to FST I and II) had higher odds of being TCGA group B (OR 2.26, p = 0.002). Kaplan-Meier survival analysis showed no difference in melanoma-related metastasis or death comparing FST I vs. II vs. III-V within each TCGA group at 5, 10, and 15 years. CONCLUSIONS: Patients classified as FST I are more likely to have a higher grade melanoma on genetic testing whereas those classified as FST III-V show lower grade melanoma. Despite differences in tumor features and genetic profile with various FST, survival analysis at 5, 10, and 15 years revealed no difference in melanoma-related metastasis or death within each TCGA group per skin tone.