bims-lifras 2022-07-03 papers

Leukemia. 2022 Jun 27.

Rare germline alterations of myeloperoxidase predispose to myeloid neoplasms.

Myeloperoxidase (MPO) gene alterations with variable clinical penetrance have been found in hereditary MPO deficiency, but their leukemia association in patients and carriers has not been established. Germline MPO alterations were found to be significantly enriched in myeloid neoplasms: 28 pathogenic/likely pathogenic variants were identified in 100 patients. The most common alterations were c.2031-2 A > C, R569W, M519fs* and Y173C accounting for about half of the cases. While functional experiments showed that the marrow stem cell pool of Mpo-/- mice was not increased, using competitive repopulation demonstrated that Mpo-/- grafts gained growth advantage over MPO wild type cells. This finding also correlated with increased clonogenic potential after serial replating in the setting of H2O2-induced oxidative stress. Furthermore, we demonstrated that H2O2-induced DNA damage and activation of error-prone DNA repair may result in secondary genetic damage potentially predisposing to leukemia leukemic evolution. In conclusion, our study for the first time demonstrates that germline MPO variants may constitute risk alleles for MN evolution.

DOI: https://doi.org/10.1038/s41375-022-01630-0

Cureus. 2022 May;14(5): e25372

A Systematic Review of the Role of Runt-Related Transcription Factor 1 (RUNX1) in the Pathogenesis of Hematological Malignancies in Patients With Inherited Bone Marrow Failure Syndromes.

Janan Illango, Archana Sreekantan Nair, Rajvi Gor, Ransirini Wijeratne Fernando, Mushrin Malik, Nabeel A Siddiqui, Pousette Hamid.

Somatic runt-related transcription factor 1 (RUNX1) mutations are the most common mutations in various hematological malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Mono-allelic RUNX1 mutations in germline cells may cause familial platelet disorder (FPD), an inherited bone marrow failure syndrome (IBMFS) associated with an increased lifetime risk of AML. It is suspected that additional RUNX1 mutations may play a role in the pathogenesis of hematological malignancies in IBMFS. This review aims to study the role of RUNX1 mutations in the pathogenesis of hematological malignancies in patients with IBMFS. A PubMed database search was conducted using the following medical subject heading (MeSH) terms: "inherited bone marrow failure syndromes," "hematological neoplasms," "gene expression regulation, leukemic," "RUNX1 protein, human," "RUNX1 protein, mouse," and "Neutropenia, Severe Congenital, Autosomal recessive." Three studies published in 2020 were identified as meeting our inclusion and exclusion criteria. Leukemic progression in severe congenital neutropenia was used as a disease model to evaluate the clinical, molecular, and mechanistic basis of RUNX1 mutations identified in hematological malignancies. Studies in mice and genetically reprogrammed or induced pluripotent stem cells (iPSCs) have shown that isolated RUNX1 mutations are weakly leukemogenic and only initiate hyperproduction of immature hematopoietic cells when in combination with granulocyte colony-stimulating factor 3 receptor (GCSF3R) mutations. Despite this, whole-exome sequencing (WES) performed on leukemogenic transformed cells revealed that all AML cells had an additional mutation in the CXXC finger protein 4 (CXXC4) gene that caused hyperproduction of the ten-eleven translocation (TET2) protein. This protein causes inflammation in cells with RUNX1 mutations. This process is thought to be critical for clonal myeloid malignant transformation (CMMT) of leukemogenic cells. In conclusion, the combinations of GCSF3R and RUNX1 mutations have a prominent effect on myeloid differentiation resulting in the hyperproduction of myeloblasts. In other studies, it has been noted that the mutations in GCSF3R and RUNX1 genes are not sufficient for the full transformation of leukemogenic cells to AML, and an additional clonal mutation in the CXXC4 gene is essential for full transformation to occur. These data have implicitly demonstrated that RUNX1 mutations are critical in the pathogenesis of various hematological malignancies, and further investigations into the role of RUNX1 are paramount for the development of new cancer treatments.

Keywords: hematological malignancies; inherited bone marrow failure syndromes; mutations and polymorphisms; pathogenesis; runx1 gene

DOI: https://doi.org/10.7759/cureus.25372

Nat Commun. 2022 Jun 28. 13(1): 3724

The impact of rare germline variants on human somatic mutation processes.

Mischan Vali-Pour, Ben Lehner, Fran Supek.

Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a false discovery rate of 1%. We associate rare inherited deleterious variants in genes such as MSH3, EXO1, SETD2, and MTOR with two phenotypically different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, RIF1, and WRN with deficiency in homologous recombination repair. In addition, we identify associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.

DOI: https://doi.org/10.1038/s41467-022-31483-1

Chemotherapy. 2022 Jun 28.

Lung adenocarcinoma harboring triple rare EGFR exon18 mutations rapidly developed resistance to multiple therapies.

Yuyao Liu, Yuanqiang Wu, Fang Wu, Chunhong Hu.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer related deaths worldwide. Its medical significance has spurred broad investigations into its treatment and prognosis. Shortly after the oncogenic driver mutations were identified, targeted therapies for NSCLC developed rapidly, including the discovery of tyrosine kinase inhibitors (TKIs). Epidermal growth factor receptor TKIs (EGFR-TKIs) have revolutionized the treatment era of NSCLC with common EGFR mutations, especially for non-smoking Asian women. However, it is challenging to tackle NSCLC harboring uncommon mutations, particularly the co-existence of rare EGFR mutations. Although a standard therapy has not yet been established for rare EGFR mutations, there are increasing reports of promising discoveries on the efficacy of second-generation or third-generation EGFR-TKIs on certain EGFR mutations. Here we report a female patient who was diagnosed as lung adenocarcinoma with three mutations of G724S, E709K, and V689I in exon 18. The patient responded to, but also showed rapid development of resistance to multiple therapies, including a second-generation EGFR-TKI of afatinib, a platinum based doublet chemotherapy, and a multiple target TKI of anlotinib. As such, she ended up with a short overall survival (OS) time. Further research is required to understand the resistance mechanism(s) of these complex gene mutations.

DOI: https://doi.org/10.1159/000525623