A combination of genetic alterations makes melanoma immortal

Article 1: TPP1 promoter mutations cooperate with TERT promoter mutations to lengthen telomeres in melanoma

Telomeres, protective caps at the end of the chromosome, are required to prevent DNA from degrading. In healthy cells, telomeres become shorter with each cycle of replication until they become so short that the cell can no longer divide. Disruptions in the maintenance of the length of the telomeres can lead to severe disease. Short telomere syndromes lead to premature aging and death, but extra-long telomeres are associated with cancer. Scientists have observed strikingly long telomeres in melanoma tumours, especially in comparison with other cancer types.

The enzyme telomerase maintains telomere length so that cells can continue dividing. Cancer cells often have high telomerase activity, and noncoding mutations in the TERT gene (which encodes telomerase) are frequently found in tumours. The researchers studied melanomas and identified mutations in the promoter of TPP1, which encodes the telomere-binding protein TPP1 that recruits telomerase to the telomere. Such promoter mutations created a transcription factor site similar to mutations previously identified in the TERT gene promoter. Co-expression of TERT and TPP1 leads to synergistic telomere lengthening, indicating that TPP1 and TERT promoter mutations cooperate to immortalise melanoma cells. Read the full article .

In summary: A combination of genetic alterations makes melanoma immortal

Article 2: Inherited cancer susceptibility gene sequence variations among patients with appendix cancer

A portion of appendiceal cancer patients harbor germline cancer predisposition variants, suggesting that these patients should undergo testing for hereditary cancer. The researchers tested 131 appendiceal cancer patients for germline variants in 14* cancer susceptibility genes and found that 15 patients (11.5%) had a deleterious variant. Additionally, about 3% of the appendiceal cancer patient cohort had, all of whom had MLH1 gene variants. Further, of those with a deleterious variant, 60% were over 50 at appendiceal cancer diagnosis. In conclusion, these findings support the consideration of genetic testing for all patients with appendiceal cancer irrespective of age or family history. Read the full article .

*Genes tested: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53

In summary: Patients with appendix cancer are recommended to test for hereditary cancer

Article 3: XNAzymes targeting the SARS-CoV-2 genome inhibit viral infection

Artificial enzymes that can precisely cut long RNA molecules, called XNAzymes, could be used to develop antiviral therapies. Scientists from the University of Cambridge designed site-specific RNA endonuclease XNAzymes that target different parts of the SARS-CoV-2 RNA genome. The team reports that they were able to design, synthesise, and screen a number of RNA endonuclease XNAzymes targeting five SARS-CoV-2 sites in about a week. Three of these XNAzymes were further active under physiological conditions and could knock down the SARS-CoV-2 RNA genome both in vitro and in vivo, showing a proof-of-concept of their approach. In conclusion, they were able to make XNAzymes work as enzymes inside cells, inhibiting the replication of the live virus. Read the full article .

In summary: Artificial enzymes may be used to knock down viruses, develop antiviral therapies

Article 4: Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Alzheimer’s disease is the leading cause of dementia with an estimated heritability of approximately 70%. Rare variants in ATP8B4 and ABCA1 may increase the risk of developing Alzheimer’s disease. A team of researchers compared the gene-based burden of rare damaging variants in 16,036 individuals with Alzheimer’s disease and 16,522 controls who had all undergone exome sequencing. They uncovered half a dozen genes with a differential burden of rare variants between cases and controls, five of which they confirmed in additional analyses. Those five also mapped to genome-wide association study loci, leading the researchers to look for potential driver genes and homing in on RIN3, CLU, ZCWPW1, and ACE. However, they note that the GWAS sentinel variants and the rare-variant burden appear to be independent. The researchers note that their analysis points to ATP8B4 and ABCA1 as new risk factors for Alzheimer’s and also underscores the role of amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism, and microglial function in the disease. Read the full article .

In summary: Rare variants in ATP8B4 and ABCA1 may increase the risk of developing Alzheimer’s disease

New in Genetics issue December 2022. Every month, Medicover Genetics curates the most important peer-reviewed scientific publications related to genetics.