Utility of the SNaPshot Assay in Ovarian Carcinoma Genotyping
Joana Loureiro, Darrell Borger, Koen Van de Vijver, Dora Dias-Santagata, Richard Penson, John Iafrate, Esther Oliva. Massachusetts General Hospital, Boston, MA
Background: Ovarian carcinoma (OC) is the leading cause of death among gynecological malignancies with a 46% overall 5 year survival. Lack of effective methods for its prevention/early detection (75% stage III/IV at diagnosis) and common development of resistance to first line agents has launched studies to better understand its pathogenesis and identify targeted therapies. TP53 and KRAS are among the most frequently mutated genes while PIK3CA, although not as prevalent, is actively being investigated as promising therapeutic target. Recently, a multiplexed allele-specific assay (SNaPshot) has been developed to detect simultaneous somatic mutations in tumor DNA extracted from formalin-fixed paraffin-embedded specimens to obtain rapid/effective tumor genotyping and select patients that may respond to specific therapies. The aim of this study is to determine prevalence of mutant genes in resistant OC using this new assay.
Design: The cohort included 63 tumors from 62 patients (1 with 2 different tumors) with resistant OC and ECOG 0-2 performance score. Samples were tested for common hot-spot mutations using SNaPshot assay that detects mutations in 68 different loci as well as insertions and deletions from 15 cancer genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, PTEN and TP53).
Results: Most patients (47/62) had high-grade (HG) serous or mixed serous and transitional cell carcinoma (SE-TCC), 5 HG endometrioid carcinoma (EC), 3 clear cell carcinoma, 2 MMMT, 2 small cell carcinoma of hypercalcemic type, and 1 low-grade (LG) EC, LG serous, TCC, and mucinous carcinoma (Muc-Ca) respectively. 18 tumors (29%) showed one or more mutations with a total of 28 mutations identified: TP53 in 10 (6 HG serous or SE-TCC, 1 TCC, 1 MMMT, 1 HG EC, and 1 Muc-Ca), KRAS in 7 (3 serous or SE-TCC, 2 HG EC, and 1 LG serous and 1 Muc-Ca), PIK3CA in 5 (2 HG EC, 2 serous or SE-TCC, and 1 clear cell carcinoma), CTNNB1 in 3 (2 HG and 1 LG EC), PTEN in HG EC, AKT1 in LG EC and NRAS in HG serous or SE-TCC.
Conclusions: TP53, KRAS and PIK3CA were the most frequently mutated genes in OC, TP53 being most common in HG serous carcinomas and KRAS in LG and HG serous carcinomas, while mutations in CTNNB1 and PTEN were only seen in ECs and PIK3CA mutations in HG tumors. As patients with PIK3CA mutations have been considered for enrolment in clinical trials with PI3 kinases inhibitors, this assay can be used in clinical settings to determine the prevalence of mutant genes in resistant OC and identify patients that may respond to target therapies.
Category: Gynecologic & Obstetrics
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 150, Wednesday Morning