​CHICAGO—The POT1 gene is mutated in approximately 4 percent of chronic lymphocytic leukemia (CLL) patients. Recent studies have reported germline variants in POT1 in patients with familial CLL and in familial melanoma, cardiac angiosarcoma, and glioma. In a recently presented study at the 2019 ASCO Annual Meeting, researchers evaluated patient characteristics and the presence of other cancers (OC) in CLL patients with POT1 mutation (Abstract 7529).

The researchers performed a targeted next-generation sequencing-based analysis for the detection of mutations in 29 genes frequently mutated in CLL patients using blood and/or bone marrow samples containing a minimum of 10 percent clonal B-cells from 1,467 patients diagnosed with the disease.

"Paired-end sequencing was performed on [the] Illumina MiSeq platform with integration of molecular barcodes-based de-duplication for improved sensitivity (1.5% to 5% based on clonal vs. subclonal nature of mutations) and specificity for routine clinical use," the study authors outlined.

Among CLL patients with the mutation, clinical characteristics, prognostic factors (FISH and IGHV status), and personal and familial history of other cancers were collected. Of the 1,467 patients studied, 52 (3.5%) had mutations in POT1.

Patients who had the POT1 mutation were young with a median age of 59 years and commonly presented with early-stage disease (Binet stage A 69% vs. B/C 31%: p=0.0046 and Rai stage 0-I 65% vs. II-IV 35%; p=0.043). They were also predominantly male (37 male vs. 15 female). The more frequent abnormalities were del13q (33%), no abnormalities (25%), and del11q (21%), according to FISH. Researchers reported that IGHV status was more commonly unmutated (69%).

"The most frequent DNA mutations associated with POT1 were NOTCH1 (44%), TP53 (27%), and SF3B1 (23%)," study authors noted. "Other cancers (excluding non-melanoma skin cancer) were reported in 19 of the 52 patients with POT1 mutation (37%). The most common types were prostate cancer (12%), malignant melanoma (10%), and kidney cancer (8%).

"Twelve (23%) patients were diagnosed with OC before and seven patients (13%) after the diagnosis CLL. Four (8%) had more than one other cancer diagnoses. Twenty-eight (54%) patients had one of more first degree relatives with history of cancer."

Molica, et al, concluded, "We observed a high occurrence of other cancers, particularly malignant melanoma and kidney cancer in these patients. Additional studies are ongoing to determine the proportion of patients with germline POT1 mutation, the distribution of variant allelic frequencies, and additional chromosomal abnormalities in patients with other cancers."





