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.
Graphical Abstract