Identification of novel cervical cancer risk variants and genes.

• Applicants: Dr. Thilo Dörk-Bousset; Dr. Dhanya Ramachandran
• Subject Area: Gynaecology and Obstetrics ; Epidemiology and Medical Biometry/Statistics ; Hematology, Oncology ; Human Genetics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558212970

Infection with the human papillomavirus (HPV) is understood to be a major factor for cervical cancer and dysplasia, but only a minority of infected women develop invasive cancer. The risk factors involved in the prognosis are not well understood, however, there are indications of genetic predisposition. So far, four chromosomal regions have been associated with the risk of cervical cancer - far fewer than for other common cancers such as breast cancer. With the project applied for here, we aim to conduct a genome-wide association study in 1000 patients with invasive cervical cancer, 1000 patients with cervical dysplasia and 6300 healthy women. This should reveal novel cervical cancer risk loci. The results will be further merged with our own previous GWAS and other publicly available datasets for a combined analysis of 12,599 patients and 458,086 controls. In a parallel approach, we will determine genome-wide methylation status in 192 tumor samples and test its association with risk variants and transcript levels. In a third work package, we will investigate the occurrence of rare mutations with potentially higher impact in 100 highly selected patients (HPV-negative, familial cervical carcinoma, or very early age of onset) by exome sequencing. Candidate genes arising from these approaches will be followed by targeted deep sequencing in 1000 cervical cancer cases and 1000 controls to validate their impact. At the end of this project, we expect a significantly increased number of known genetic risk variants, more information about potential disease mechanisms, and an improved informative polygenic risk score for cervical cancer. These additional insights into risk loci and genes involved in the occurrence and progression of cervical cancers will provide valuable information for future personalized medicine strategies.

• DFG Programme: Research Grants
• International Connection: France, United Kingdom
• Co-Investigators: Dr. Ronny Baber; Professor Dr. Klaus Berger; Robert Geffers, Ph.D.; Dr. Norman Häfner; Dr. Rebecca Kraemer
• Cooperation Partners: Professor Dr. Douglas Easton; Professorin Dr. Susy Scholl