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Exome Sequencing of Ovarian Cancer Patients to Identify Variants Predictive of Sensitivity to Platinum-based Chemotherapy

[ Vol. 14 , Issue. 2 ]

Author(s):

Assaad Y. Semaan, Kristin R. Delfino, Andrew C. Wilber, Thomas K. Mathews, Kathy J. Robinson, Laurent Brard and Shaheen R. Alanee   Pages 124 - 133 ( 10 )

Abstract:


Background: By using exome sequencing, we envisioned that certain single nucleotide variants (SNVs), predictive of sensitivity to platinum treatment, could be discovered.

Methods: Twenty-two Platinum-Sensitive (Pt-S) and 6 Platinum-Resistant (Pt-R) ovarian cancer patients were tested. Platinum sensitivity was defined as disease free survival greater than 6 months. Next-generation sequencing of exomes was used to compare Pt-S and Pt-R patients. SNVs associated with platinum sensitivity were identified using Ingenuity Variant Analysis.

Results: No SNV was significantly associated with sensitivity to platinum treatment after correcting for multiple comparison, however, three genes included a significantly higher number of SNVs previously shown to have pharmacogenetics associations (pSNV) in Pt-S patients when compared to Pt-R patients. Insulin-like growth factor 1 receptor (IGF1R) contained pSNVs in 59% of Pt-S and 0% of Pt-R (14 variants, p=1.25 E-2). Liproteinrelated protein 2 (LRP2) contained pSNVs in 54% of Pt-S and 0% of Pt-R (12 variants, p=3.20 E-2), and non-SMC condensin I complex subunit D2 (NCAPD2) contained pSNVs in 50% of Pt-S and 0% of Pt-R (7 variants, p=4.71 E-2). Three genes included a significantly higher number of pSNVs in Pt-R when compared to Pt-S patients. AF4/FMR2 family member 1 (AFF1) contained pSNVs in 50% of Pt-R and 0% of Pt-S (3 variants, p=3.20 E-3), breast cancer type 2 susceptibility protein (BRCA2) contained pSNVs in 50% Pt-R and 0% of Pt-S (3 variants, p=2.40 E-3), and DNA-dependent protein kinase (PRKDC) contained pSNVs in 50% of Pt-R and 0% of Pt-S (3 variants, p=2.90 E-3).

Conclusion: pSNVs load in certain genes may be predictive of sensitivity to platinum in ovarian cancer. With validation of these findings, it is possible that a new marker predictive of patient response may be identified.

Keywords:

Chemotherapy, exome, sensitivity, sequencing, single nucleotide polymorphism, ovarian cancer.

Affiliation:

Department of Surgery, Division of Urology, Southern Illinois University School of Medicine, Springfield, IL 62702, Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL 62702, Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62702, Department of Surgery, Division of Urology, Southern Illinois University School of Medicine, Springfield, IL 62702, Simmons Cancer Institute at Southern Illinois University School of Medicine, Springfield, IL 62702, Simmons Cancer Institute at Southern Illinois University School of Medicine, Springfield, IL 62702, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI

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