Two genes found to confer multidrug chemoresistance in head and neck cancers

11th September 2023

Two genes appear to be responsible for conferring chemoresistance in the majority of drug-resistant cell strains of patients with head and neck cancers, and silencing either gene leads to a complete reversal of drug resistance, researchers at Queen Mary University of London (QMUL) have found.

In the study, published in the journal Molecular Cancer, the team used transcriptome data-mining to identify potential genes that may be affecting tumour responsiveness to drug therapy. They identified a total of 28 genes in 12 strains of chemoresistant cell lines each against cisplatin, 5-fluorouracil, paclitaxel and docetaxel chemotherapies.

A total of 10 multi-drug chemoresistance genes were identified, four of which – TOP2A, DNMT1, INHBA and NEK2 – were up-regulated in a cohort of 221 head and neck cancer patients.

The INHBA and NEK2 genes appeared to be pan-cancer prognostic markers for predicting poor survival outcome in the majority of cancer types. But the team also identified two compounds – sirodesmin A and carfilzomib – from drug library screens, which were able to target both INHBA and NEK2 and re-sensitise cisplatin-resistant cells.

Dr Muy-Teck Teh, senior author of the study from QMUL, said: ‘These results are a promising step towards cancer patients in the future receiving personalised treatment based on their genes and tumour type that give them a better survival rate and treatment outcome.

‘Unfortunately, there are lots of people out there who do not respond to chemotherapy or radiation. But our study has shown that in head and neck cancers at least it is these two particular genes that could be behind this, which can then be targeted to fight against chemoresistance.‘

In Europe, head and neck cancers affect around 22 people per 100,000. While the cure rate is high for early-stage disease, around two-thirds of patients present with advanced-stage disease with a poor survival outcome. An additional and important cause of treatment failure leading to a poor survival, is the development of resistance to chemo and/or radiotherapy, although the underlying genes responsible for chemoresistance have previously been unclear.

Genes responsible for premature ovarian insufficiency questioned by researchers

6th July 2023

Premature ovarian insufficiency (POI) in the majority of women is not due to autosomal dominant variants in genes, according to a recent analysis.

Published in the journal Nature Medicine, researchers set out to systematically evaluate the penetrance of purported pathogenic gene variants using exome sequence data in women with POI.

They considered 67 genes used in the Genomics England diagnostic gene panel for POI, and identified an additional 38 genes from additional literature.

The team used exome sequence data in 104,733 women from the UK Biobank, 2,231 of whom (1.14%) reported natural menopause under the age of 40 years.

The analysis showed limited evidence to support any previously reported autosomal dominant effect. In fact, for nearly all heterozygous effects on previously reported POI genes, researchers were able to rule out even modest penetrance. For instance, 99.9% of all protein-truncating variants were present in reproductively healthy women.

Taken together, these results suggest that in the vast majority of women, POI is not actually caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels.

In other words, while there are specific genetic variants in women who experience premature menopause, it is unlikely that these variants are the underlying cause, since many are also found in those who experience a normal age menopause.

POI in context

POI affects an estimated 1% of the general population and results in cessation of ovarian function before the age of 40 years. Moreover, women with POI find that menstruation also stops around the same age. In recent years, it has become clear that POI is likely to have a genetic basis and although several candidate genes have been identified, it appears that POI is a genetically heterogeneous condition.