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SCOPUS: ar.j, info:eu-repo/semantics/published

Pathogenic loss-of-function

Background In hepatocellular carcinoma (HCC), histone deacetylases (HDACs) are frequently overexpressed. This results in chromatin compaction and silencing of tumor-relevant genes and microRNAs. Modulation of microRNA expression is a potential treatment option for HCC. Therefore, we aimed to characterize the epigenetically regulated miR-129-5p regarding its functional effects and target genes to understand its relevance for HCC tumorigenesis. Methods Global miRNA expression of HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B) and normal liver cell lines (THLE-2, THLE-3) was analyzed after HDAC inhibition by miRNA sequencing. An in vivo xenograft mouse model and in vitro assays were used to investigate tumor-relevant functional effects following miR-129-5p transfection of HCC cells. To validate hepatoma-derived growth factor (HDGF) as a direct target gene of miR-129-5p, luciferase reporter assays were performed. Survival data and HDGF expression were analyzed in public HCC datasets. After siRNA-mediated knockdown of HDGF, its cancer-related functions were examined. Results HDAC inhibition induced the expression of miR-129-5p. Transfection of miR-129-5p increased the apoptosis of HCC cells, decreased proliferation, migration and ERK signaling in vitro and inhibited tumor growth in vivo. Direct binding of miR-129-5p to the 3′UTR of HDGF via a noncanonical binding site was validated by luciferase reporter assays. HDGF knockdown reduced cell viability and migration and increased apoptosis in Wnt-inactive HCC cells. These in vitro results were in line with the analysis of public HCC datasets showing that HDGF overexpression correlated with a worse survival prognosis, primarily in Wnt-inactive HCCs. Conclusions This study provides detailed insights into the regulatory network of the tumor-suppressive, epigenetically regulated miR-129-5p in HCC. Our results reveal for the first time that the therapeutic application of mir-129-5p may have significant implications for the personalized treatment of patients with Wnt-inactive, advanced HCC by directly regulating HDGF. Therefore, miR-129-5p is a promising candidate for a microRNA replacement therapy to prevent HCC progression and tumor metastasis.

422 Background: ALP is a PI3Kα inhibitor and degrader approved with fulvestrant for the treatment (tx) of patients (pts) with PIK3CA-mutated, HR+, HER2– ABC. Hyperglycemia (HG) and rash are expected adverse events with ALP tx and remain a challenge for physicians and pts. Management guidance is primarily based on clinical trial experience, which is not necessarily reflective of real-world pts. Here we report guidance for optimizing prevention and management of HG and rash in pts taking ALP based on an integrated Delphi panel, a systematic, validated approach to organize consensus from experts in the absence of definitive evidence. Methods: Two modified Delphi panels were conducted, focusing on HG and rash, respectively. Each panel included 4 oncologists, 4 endocrinologists or dermatologists, 1 clinical pharmacist, and 1 pt advocate. Experts were asked to rate appropriateness of 908 interventions for HG and 348 for rash on hypothetical pt scenarios on a 1 (highly inappropriate) to 9 (highly appropriate) scale. Results were reviewed at virtual meetings, after which experts repeated the rating. The level of agreement or disagreement was determined using the median scores and dispersion from the final rating, and this level of agreement was used to develop consensus statements and tx algorithms. Results: Per the HG panel, (a) ALP tx is appropriate in individuals with HbA1c 6.5% to < 8% with a pre-tx endocrinology consult; (b) low carbohydrate diet is appropriate in all pts starting ALP; (c) prophylactic metformin is appropriate in pts with baseline HbA1c 5.7%-6.4%; may also be appropriate in pts with HbA1c < 5.7%; (d) after metformin, an SGLT2 inhibitor or a thiazolidinedione is an appropriate second-/third-line anti-HG agent (or first-line in metformin-intolerant pts), while insulin is not. Per the rash panel, (a) prophylactic nonsedating (NS) H1 antihistamines (standard dose) are appropriate for all pts; (b) starting/escalating NS H1 antihistamines and topical steroids (TS) is the preferred first step for managing rash; (c) it is appropriate to add, but not replace with, a sedating H1 antihistamine, if response to high-dose, NS option is inadequate, and to add an H2 antihistamine if response is still inadequate; (d) it is appropriate to hold ALP and start oral corticosteroids (OCS) if rash affects > 30% body surface area and is recurrent or has moderate/severe symptoms; (e) if angioedema is present, it is appropriate to either hold ALP and start OCS, or permanently discontinue ALP tx. Conclusions: Until further evidence is available, these expert recommendations provide guidance on prevention and management of HG and rash related to ALP tx in routine clinical practice.

Pathogenic loss-of-function RUNX1 germline variants cause autosomal dominantly-inherited familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD). RUNX1-FPD is characterized by incomplete penetrance and a broad spectrum of clinical phenotypes, even within affected families. Heterozygous RUNX1 germline variants set the basis for leukemogenesis, but, on their own, they are not transformation-sufficient. Somatically acquired secondary events targeting RUNX1 and/or other hematologic malignancy-associated genes finally lead to MDS, AML, and rarely other hematologic malignancies including lymphoid diseases. The acquisition of different somatic variants is a possible explanation for the variable penetrance and clinical heterogeneity seen in RUNX1-FPD. However, individual effects of secondary variants are not yet fully understood. Here, we review 91 cases of RUNX1-FPD patients who predominantly harbor somatic variants in genes such as RUNX1, TET2, ASXL1, BCOR, PHF6, SRSF2, NRAS, and DNMT3A. These cases illustrate the importance of secondary events in the development and progression of RUNX1-FPD-associated hematologic malignancies. The leukemia-driving interplay of predisposing germline variants and acquired variants remain to be elucidated to better understand clonal evolution and malignant transformation and finally allow risk-adapted surveillance and targeted therapeutic measures to prevent leukemia.