Genomic Analysis Reveals Complex Alterations in HGSC

A new report offers a deeper understanding of germline and somatic variation in patients with high-grade serous ovarian cancer (HGSC).

The report is based on an analysis of 71 patients with HGSC. It was published in Journal of Ovarian Research.

Patients with HGSC often receive their diagnosis at a late stage, noted the study authors, and typically undergo both surgical cytoreduction and chemotherapy, they said, although targeted therapies are becoming more and more common. Still, they noted that the 5-year survival rate is only 20% to 30%.

“These dismal statistics underscore the need for earlier detection and new treatments following diagnosis,” they said.

HGSC is characterized by complex genetic alterations, the authors said. The goal of the new study was to better understand those alterations, as well as their associations with relapse and survival rates.

The authors recruited 71 participants with stage III or IV HGSC who were treated at City of Hope and who underwent their first debulking surgery between 2002 and 2014. In most cases, tumor tissue was sequenced from the first debulking surgery, including 63 from the primary site and 6 from metastatic sites. In the other 2 patients, tumor tissue was only available from the second debulking. Fifteen patients had tumor tissue available from the first and second debulking surgeries, and in 3 cases, tumor tissue was available from 3 surgeries. Twelve patients had samples taken from multiple tumor sites during the same primary surgery, the authors said.

The investigators performed targeted germline and tumor sequencing on the patients and a comprehensive analysis of 557 genes involved in DNA damage response and the PI3K/AKT/mTOR pathways. They also performed OncoScan assays on tumor DNA from 61 patients to examine somatic copy number alterations (SCNAs).

“Approximately one-third of tumors had loss-of-function (LOF) germline (18/71, 25.4%) or somatic (7/71, 9.9%) variants in the DNA homologous recombination repair pathway genes BRCA1, BRCA2, CHEK2, MRE11A, BLM, and PALB2,” the authors said.

LOF germline variants were also found in other Fanconi anemia genes and in MAPK and PI3K/AKT/mTOR pathway genes, they said. Almost all (65/71) tumors harbored somatic TP53 variants, they said. The OncoScan analysis showed focal homozygous deletions in BRCA1, BRCA2, MAP2K4, PTEN, RB1, SLX4, STK11, CREBBP, and NF1, they said.

“In total, 38% (27/71) of HGSC patients harbored pathogenic variants in DNA homologous recombination repair genes,” they found.

The authors noted they found that somatic mutations were generally maintained among patients with multiple tissues, “suggesting that tumor evolution was not true somatic mutations.” They also said they found a significant association between LOF variants in homologous recombination repair pathway genes and high-amplitude SCNAs.

“Using GISTIC analysis, we identified NOTCH3, ZNF536, and PIK3R2 in these regions that were significantly associated with an increase in cancer recurrence and a reduction in overall survival,” they said.

The investigators said these findings add to the scientific understanding of HGSC and provide insights into genetic alterations and their impact on patient outcomes.

“Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival,” they concluded.

Reference

Adamson AW, Ding YC, Steele L, et al. Genomic analyses of germline and somatic variation in high-grade serous ovarian cancer. J Ovarian Res. Published online July 17, 2023. doi:10.1186/s13048-023-01234-x