Case report: Germline POT1 mutation in a patient with GIST and lung adenocarcinoma

Abstract

The gene protection of telomere 1 (POT1) is involved in telomere maintenance and stability and plays a crucial role in the preservation of genomic stability. POT1 is considered a high-penetrance melanoma susceptibility gene; however, the number of cancer types associated with the pathogenic germline variants of POT1 is gradually increasing, including chronic lymphocytic leukemia (CLL), angiosarcomas, and gliomas, even though many associations are still elusive. Here, we reported a case of a 60-year-old man who showed early-onset multiple neoplasms, including multiple melanomas, gastrointestinal stromal tumor (GIST), and lung adenocarcinoma. Next-generation sequencing (NGS) analyses revealed a germline heterozygous pathogenic variant in the POT1 gene. Notably, GIST and lung adenocarcinoma were not previously reported in association with the POT1 germline variant. Lung cancer susceptibility syndrome is very rare and the actual knowledge is limited to a few genes although major genetic factors are unidentified. Recently, genome-wide association studies (GWAS) have pointed out an association between POT1 variants and lung cancer. This case report highlights the clinical relevance of POT1 alterations, particularly their potential involvement in lung cancer. It also suggests that POT1 testing may be warranted in patients with familial cancer syndrome, particularly those with a history of melanoma and other solid tumors.

Keywords: GIST; POT1; case report; lung adenocarcinoma; tumor predisposition syndrome.

Figure 1

Family tree. The proband is indicated with an arrow (III_10). Melanoma cases are reported in the father (II-5), sister (III-11), and paternal aunt (II-2). The mother (II-6) has been reported to have a not well-defined “skin cancer.” In the family, other cancer types are present: breast cancer (BC; II-9, III-9), lung cancer (III-11), gastric cancer (III-19, I-4), colorectal cancer (CRC, II-1), and thyroid cancer (III-11, III-4).

Figure 2

IGV screenshot and Sanger sequencing. On the top, the IGV screenshot is depicted (A), showing the variant R363* in POT1, in a heterozygous state, identified in the NGS analyses. On the bottom, an electropherogram of Sanger sequencing confirms the NGS results (B).

Figure 3

Segregation analysis for the POT1 variant R363*. The proband is indicated with an arrow. In the father, daughter, and son, segregation analysis by Sanger sequencing was performed. The daughter, who was positive for the POT1 variant, underwent exportation of two basal cell carcinoma after the test.