A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies.

POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape. A directed database search was conducted for individuals referred for genetic counselling from 2018 to 2023. Demographic, clinical, genetic, and pathological data were collected and analyzed. Eleven carriers, 25 to 67 years old, from ten apparently unrelated families were identified. Carriers had a total of 30 primary malignancies (range 1-6); nine carriers (82%) had recurrent melanoma between the ages of 25 and 63 years, three carriers (27%) had desmoid tumors, three (27%) had papillary thyroid cancer (PTC), and five women (63% of female carriers) had breast cancer between the ages of 44 and 67 years. Additional tumors included CLL; sarcomas; endocrine tumors; prostate, urinary, and colorectal cancers; and colonic polyps. A review of a local exome database yielded an allelic frequency of the variant of 0.06% among all ethnicities and of 0.25% in AJs. A shared haplotype was found in all carriers tested. POT1 p.(I78T) is a founder disease-causing variant associated with early-onset melanoma and additional various solid malignancies with a high tumor burden. We advocate testing for this variant in high-risk patients of AJ descent. The inclusion of POT1 in germline panels for various types of cancer is warranted.

PICT-1 regulates p53 splicing and sensitivity of medullary thyroid carcinoma cells to everolimus.

Protein interacting with carboxyl terminus 1 (PICT-1) is a nucleolar protein shown to act as a tumor suppressor that interacts with PTEN, or in a contrasting manner to facilitate the accessibility of p53 to ubiquitination and degradation, thus to function as an oncogene. The aim of the study was to examine the potential role of PICT-1 in neuroendocrine neoplasm (NEN) tumorigenesis and response to mTOR inhibitor treatment. PICT-1 was overexpressed in medullary thyroid (TT) and pancreatic (BON1) NEN cell lines using lentiviral vector. Whereas in BON1 cells PICT-1 overexpression exhibited no significant impact, in TT cells it induced the appearance of p53ß lacking the C-terminus end. This was accompanied by a robust decrease in p21 expression and elevation of cell viability. Remarkably, PICT-1 overexpression completely reversed the reduction in cell viability of medullary thyroid neoplasm cells induced by everolimus, a therapeutic option for patients with progressive NENs. mTOR pathway investigations revealed that PICT-1 overexpression induced a reduction in PTEN expression and a robust increase in the expression level of phospho-Akt-Ser47 only partially inhibited by everolimus. These findings suggest a possible role of PICT-1 in the spliceosome machinery and provide functional involvement of PICT-1 in the complex network of mTOR.

A diagnostic approach to patients with suspected lactose malabsorption.

BACKGROUND: The lactose breath test (LBT) is the standard technique for diagnosis of lactose malabsorption. However, it is time-consuming, strenuous for the patient and has been reported to have low sensitivity. The lactose intolerance quick test (LIQT) measures lactase activity in duodenal biopsies and may be performed as part of upper gastrointestinal endoscopy. AIM: The purpose of this study was to assess the role of the LBT and LIQT in the case management of suspected lactose malabsorption. METHODS: The study group included 69 consecutive patients evaluated by the LBT followed by the LIQT. The test results were compared, and the sensitivity, specificity, and predictive values of the LBT were calculated. RESULTS: Mean age of the patients was 54.4 years, male/female ratio was 1:3, and mean body mass index was 25.2. None had celiac disease on duodenal biopsy. The LIQT was positive for hypolactasia in 55 patients (80 %): mild in 14 (25 %) and severe in 41 (75 %); 10 (18 %) were symptomatic during the LBT. The LBT was positive for lactose malabsorption in 32 patients (46 %). Of the 37 patients with normal findings on the LBT, 24 (65 %) had positive findings on the LIQT: 11 (30 %) mild hypolactasia, 13 (35 %) severe hypolactasia. In one case, the LBT was positive and the LIQT was negative. The LBT had a sensitivity of 56 %, specificity 93 %, positive predictive value 97 %, and negative predictive value 35 %. CONCLUSIONS: The LBT may serve as a diagnostic screening tool for lactose malabsorption. Symptomatic patients with negative LBT results should be referred for second-line testing with the LIQT.