Burden of rare genetic variants in genes associated with cancer among Malawian cervical cancer patients.

BACKGROUND

Cervical cancer (CC) is one of the most common cancer types affecting women globally. Cervical cancer is largely associated with human papillomavirus infections; however, approximately 5% to 11% of CC cases are non-human papillomavirus virus-related. Malawi has the second highest CC prevalence and mortality rate worldwide.

OBJECTIVE

This study investigated the burden of rare genetic variants in genes associated with CC among Malawian women.

METHODS

Ethical approval was obtained from the National Health Science Research committee on 28 August 2023. Whole-genome sequencing was performed on 20 Malawian CC patients, followed by variant discovery and annotation using the Genome Analysis Toolkit and Ensembl's Variant Effector Predictor. Test for Rare Variants Against Public Database was performed on qualifying variants using 76 156 genomes from the Genome Aggregation database as controls. Bonferroni correction was applied to account for multiple testing.

RESULTS

We identified 372 genes with a significant burden of rare variants (p < 0.05), including FAT1 (p = 0.0003), a known tumour suppressor gene associated with CC. After Bonferroni correction (p < 6.7×10-05), significance shifted to HTR3B, EPHA8, ABCC2, and SEC23B genes linked to various cancer types.

CONCLUSION

A significant burden of rare variants associated with CC was observed in known genes associated with lung, ovarian and osteosarcoma cancers, suggesting an increased population risk of developing CC and other cancers among Malawian women that needs further investigation.

WHAT THIS STUDY ADDS: The high burden of rare variants in the FAT1 gene, and a significant rare-variant burden in other cancer associated genes, supports a broader CC genetic risk and possible novel roles requiring further exploration.