Identification of a Cancer-Predisposing Germline POT1 p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma

Abstract

Germline disruptive variants in Protection of Telomeres 1 (POT1) predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marginal zone lymphoma (SMZL) arising in a patient with a germline POT1 variant: a 65-year-old male with an extensive history of cancer, including melanoma and papillary thyroid carcinoma, who presented with circulating atypical lymphocytosis. Bone marrow biopsy revealed 20% involvement by a CD5^-CD10^- B-cell lymphoma that was difficult to classify. During the clinical workup of his low-grade lymphoma, targeted next-generation sequencing (NGS) identified POT1 p.I49Mfs*7 (NM_015450:c. 147delT) at a variant allele frequency (VAF) of 51%. NGS of skin fibroblasts confirmed the POT1 variant was germline. This likely pathogenic POT1 loss-of-function variant has only been reported once before as a germline variant in a patient with glioma and likely represents one of the most deleterious germline POT1 variants ever linked to familial cancer. The spectrum of cancers associated with germline pathogenic POT1 variants (i.e., autosomal dominant POT1 tumor predisposition syndrome) should potentially be expanded to include SMZL, a disease often associated with the loss of chromosome 7q: the location of the POT1 genetic locus (7q31.33).

Keywords: cancer genetics; germline POT1 alteration; hereditary cancer predisposition; splenic marginal zone lymphoma.

Figure 1

Blood and bone marrow involvement by SMZL with 17p deletion. Circulating atypical lymphocytes displayed condensed chromatin and moderately abundant pale blue cytoplasm (A). Lymphocytes lacked prominent cell surface projections and showed no evidence of plasmacytic differentiation. The bone marrow showed 20% involvement by a B-cell lymphoma that formed multiple ill-defined nodular aggregates (B). FISH demonstrated 17p (TP53) deletion in 20% of bone marrow cells (C).

Figure 2

Family pedigree illustrating an extensive history of cancer and location of the POT1 p.Ile49Metfs*7 variant. To date, the proband (arrow) has developed six primary tumors: melanoma (diagnosed at age 48), cutaneous squamous cell carcinoma (diagnosed at age 52), papillary thyroid carcinoma (diagnosed at age 55), cutaneous basal cell carcinoma (diagnosed at age 62), SMZL (diagnosed at age 65), and prostatic adenocarcinoma (diagnosed at age 66) (A). By patient report, almost all of the proband’s paternal relatives have developed cancer (A). A paternal aunt developed cervical cancer in her 50s and melanoma in her late 50s/early 60s; she also had two sons who developed leukemia in their 50s. An additional five paternal aunts and uncles, all of whom were smokers, developed lung cancer (ages at diagnosis unknown). Notably, the proband’s father died from mesothelioma at age 54 (age at diagnosis unknown), and his brother died from lung cancer at age 44 (diagnosed at age 42). The proband’s sister was diagnosed with multiple myeloma at age 54, and his daughter was diagnosed with Hodgkin lymphoma at age 27. (A). Only the proband’s son, who is unaffected by cancer, has been tested for the germline POT1 p.Ile49Metfs*7 and found to be negative. (B). POT1 binds to the single-stranded G-rich telomeric overhang via its two N-terminal oligonucleotide/oligosaccharide binding (OB)-folds. The C-terminus contains another OB-fold and a Holliday junction resolvase-like (HJRL) domain which binds to telomere protection protein 1 (TTP1), anchoring POT1 to the shelterin complex. POT1 p.Ile49Metfs*7 (red arrow) is the most upstream (5′) germline frameshift variant ever reported and leads to a premature stop codon in the seventh codon of the new reading frame (B).