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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Profiling of actionable gene alterations in ovarian cancer by targeted deep sequencing
Masataka Takenaka1, Motonobu Saito1, Reika Iwakawa1
1Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Abstract:
To construct a profile of therapeutically actionable gene alterations in the major histological types of ovarian cancer, 72 Japanese patients with surgically resected ovarian cancers were selected from an original cohort consisting of 267 patients who had not received pre-treatment before surgery. Somatic mutations and copy number alterations at 740 hotspots in 46 cancer-related genes were detected by deep sequencing of genomic DNAs obtained from snap-frozen tumor tissues using a next generation sequencer. The alterations were verified by Sanger sequencing and quantitative genomic PCR. Mutations and/or copy number aberrations which will make tumors respond to molecular targeting drugs were detected in nine genes of 35/72 (48.6%) patients; PIK3CA (25.0%), KRAS (13.9%), ERBB2 (4.3%), PTEN (2.8%), RB1 (2.8%), CDKN2A (2.8%), AKT1 (1.4%), CTNNB1 (1.4%) and NRAS (1.4%). These mutations tended to occur in a mutually exclusive manner. Non-serous histological type tumors showed such actionable gene alterations frequently (32/47; 68.1%). Therefore, ovarian cancers, particularly of non-serous types, frequently carry gene aberrations that link to therapy using molecular targeting drugs.
Insights
Ovarian cancers frequently harbor actionable gene alterations, particularly in non-serous types. These genetic changes, identified through deep sequencing, suggest potential responses to targeted therapies for 48.6% of patients.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Ovarian cancer presents diverse histological subtypes.
- Identifying therapeutically actionable gene alterations is crucial for personalized medicine.
Purpose of the Study:
- To profile actionable genetic alterations in major ovarian cancer histological types.
- To correlate these alterations with potential targeted drug responses.
Main Methods:
- Deep sequencing of 46 cancer-related genes in 72 Japanese ovarian cancer patients.
- Analysis of somatic mutations and copy number alterations.
- Verification using Sanger sequencing and quantitative genomic PCR.
Main Results:
- Actionable mutations in nine genes were found in 48.6% of patients.
- PIK3CA (25.0%) and KRAS (13.9%) were the most frequent alterations.
- Non-serous ovarian tumors frequently exhibited actionable alterations (68.1%).
Conclusions:
- Ovarian cancers frequently possess therapeutically actionable gene alterations.
- Non-serous subtypes show a higher prevalence of these alterations.
- Findings support the use of molecular targeted drugs in ovarian cancer treatment.
