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

Author(s): Assaad Y. Semaan, Kristin R. Delfino, Andrew C. Wilber, Thomas K. Mathews, Kathy J. Robinson, Laurent Brard, Shaheen R. Alanee*.

Journal Name: Current Pharmacogenomics and Personalized Medicine
Formerly Current Pharmacogenomics

Volume 14 , Issue 2 , 2016

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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.

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Article Details

VOLUME: 14
ISSUE: 2
Year: 2016
Page: [124 - 133]
Pages: 10
DOI: 10.2174/1875692115666170126152349
Price: $58

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