Malignancies of the female genital tract are a consequence of genomic alterations influenced by heritable and acquired mutations, transcriptional deviations, and epigenetic factors. Understanding the genomic and molecular foundation of gynecologic malignancies is essential for the discovery of novel biomarkers for screening and prevention, molecular understanding, and development of more effective treatment strategies. Traditionally, genetic analysis of solid tumors involved analyzing small, single portions of DNA, known as Sanger sequencing.1 Although Sanger sequencing has proven validation for determining the sequence of a known particular gene, its use in sequencing multiple genes concurrently is limited, time-consuming, and costly. Next-generation sequencing (NGS) allows thousands to millions of DNA fragments to be sequenced simultaneously in a single assay, thereby expanding the amount of genetic information obtained and decreasing both time to perform the assay and cost.2,3 For certain malignancies, such as lung cancer, the clinical implications of NGS have been profound and have led to rationale-targeted therapy development4; in gynecologic cancers, the use of NGS has yielded important genomic understanding of cancers and identification of high-risk inherited genes, but its use in treatment remains limited.5,6 This review discusses the impact of NGS on the understanding of molecular pathogenesis, cancer screening and prevention, diagnosis, and therapeutic strategies for gynecologic malignancies.
The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Matulonis has disclosed that she is a scientific advisor for Genentech, Inc./Roche, ImmunoGen, Merck & Co, Inc., and Pfizer Inc.; receives consulting fees from AstraZeneca Pharmaceuticals LP; and is an unpaid consultant for AstraZeneca Pharmaceuticals LP.
HagemannISFuchsSMonoranuCM. Design of targeted, capture-based, next generation sequencing tests for precision cancer therapy. Cancer Genet2013;206:420–431.
LovlyCMShawAT. Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. Clin Cancer Res2014;20:2249–2256.
LuiJKonstantinopoulosPMatulonisUA. Genomic testing and precision medicine-what does this mean for gynecologic oncology?Gynecol Oncol2016;140:3–5.
Cancer Genome Atlas Research NetworkWeinsteinJNCollissonEA. The Cancer Genome Atlas Pan-Cancer Analysis Project. Nat Genet2013;45:1113–1120.
KonstantinopoulosPACeccaldiRShapiroGI. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov2015;5:1137–1154.
AhmedAAEtemadmoghadamDTempleJ. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol2010;221:49–56.
SeagleBLEngKHDandapaniM. Survival of patients with structurally-grouped TP53 mutations in ovarian and breast cancers. Oncotarget2015;6:18641–18652.
HunterSMAnglesioMSRylandGL. Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget2015;10:37663–37677.
Callegaro-FilhoDGershensonDMNickAM. Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT): a review of 47 cases. Gynecol Oncol2016;140:53–57.
RamosPKarnezisANCraigDW. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet2014;46:427–429.
HelstenTElkinSArthurE. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res2016;22:259–267.
ParishASchwaederleMDanielsG. Fibroblast growth factor family aberrations in cancers: clinical and molecular characteristics. Cell Cycle2015;13:2121–2128.
TrietschMDNooijLSGaarenstroomKN. Genetic and epigenetic changes in vulvar squamous cell carcinoma and its precursor lesions: a review of the current literature. Gynecol Oncol2015;136:143–157.
WalshTCasadeiSLeeMK. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A2011;108:18032–18037.
SongHDicksERamusSJ. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol2015;33:2901–2907.
RamusSJSongHDicksE. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst2015;107:djv214.
DalyMBPilarskiRAxilbundJE. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Accessed August 6 2016. To view the most recent version of these guidelines visit http://www.nccn.org.
ChongHKWangTLuHM. The validation and clinical implementation of BRCAplus: a comprehensive high-risk breast cancer diagnostic assay. PLoS One2014;9:e97408.
FramptonGMFichtenholtzAOttoGA. Development and validation of clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol2013;31:1023–1031.
KurianAWHareEEMillsMA. Clinical evaluation of multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol2014;32:2001–2009.
KurianAWKinghamKEFordJM. Next-generation sequencing for hereditary breast and gynecologic cancer risk assessment. Curr Opin Obstet Gynecol2015;27:23–33.
EcclesDMMitchellGMonteiroAN. BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. Ann Oncol2015;26:2057–2065.
KhanMJCastlePELorinczAT. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type specific HPV testing in clinical practice. J Natl Cancer Inst2005;97:1072–1079.
de SanjoseSQuintWGAlemanyL. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol2010;11:1048–1056.
CastlePESadorraMLauT. Evaluation of a prototype real-time PCR assay for carcinogenic human papillomavirus (HPV) detection and simultaneous HPV genotype 16 (HPV16) and HPV18 genotyping. J Clin Microbiol2009;47:3344–3347.
HeidemanDAHesselinkATBerkhofJ. Clinical validation of the cobas®4800 HPV Test for cervical screening purposes. J Clin Microbiol2011;49:3983–3985.
MirabelloLFrimerMHarariA. HPV16 methyl-haplotypes determined by a novel next-generation sequencing method are associated with cervical precancer. Int J Cancer2015:136:E146–153.
ChandraniPKulkamiVIyerP. NGS-based approach to determine the presence of HPV and their sites of integration in human cancer genome. Br J Cancer2015;112:1958–1965.
BarzonLMillitelloVLavezzoE. Human papillomavirus genotyping by 454 next generation sequencing technology. J Clin Virol201;52:93–97.
YiXZouJXuJ. Development and validation of a new HPV genotyping assay based on next-generation sequencing. Am J Clin Pathol2014;141:796–804.
ClarkeMAWentzensenNMirabelloL. Human papillomavirus DNA methylation as a potential biomarker for cervical cancer. Cancer Epidemiol Biomarkers Prev2012;21:2125–2137.
BoltonKLChenevix-TrenchGGohC. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA2012;307:382–390.
JonesSWangTLShihleM. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science2010;330:228–231.
KatagiriANakayamaKRahmanMT. Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma. Mod Pathol2012;25:282–288.
LiuJMatulonisUA. New strategies in ovarian cancer: translating the molecular complexity of ovarian cancer into treatment advances. Clin Cancer Res2014;20:5150–5156.
GalicVColemanRLHerzogTJ. Unmet needs in ovarian cancer: dividing histologic subtypes to exploit novel targets and pathways. Curr Cancer Drug Targets2013;13:698–707.
LedermannJHarterPGourleyC. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med2012;366:1382–1392.
LedermannJHarterPGourleyC. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol2014;15:852–861.
KaufmanBShapira-FrommerRSchmutzlerRK. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol2015;33:244–250.
KimGIsonGMcKeeAE. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res2015;21:4257–4261.
FarleyJBradyWEVathipadiekalV. Selumetanib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol2013;14:134–140.
KauffNDDomchekSMFriebelTM. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective studyJ Clin Oncol2008;26:1331–1337.
WalkerJLPowellCBChenLM. Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. Cancer2015;121:2108–2120.
RebbeckTRMitraNWanF. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA2015;313:347–361.
Johansen TaberKADickinsonBDWilsonM. The promise and challenges of next generation genome sequencing for clinical care. JAMA Intern Med2014;174:275–280.
GeskinALegowskiEChakkaA. Needs assessment for research use of high-throughput sequencing at a large academic medical center. PLoS One2015;10:e0131166.
GallegoCJShirtsBHBennetteCS. Next generation sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost-effectiveness analysis. J Clin Oncol2015;33:2084–2091.
ManchandaRLegoodRBurnellM. Cost-effectiveness of population screening for BRCA mutations in Ashkenazi Jewish women compared with family history-based testing. J Natl Cancer Inst2014;107:380.
EmersonJOSherwoodAMRiederMJ. High-throughput sequencing of T-cell receptors reveals a homogeneous repertoire of tumour-infiltrating lymphocytes in ovarian cancer. J Pathol2013;231:433–440.
StevanovicSDraperLMLanghanMM. Complete regression of metastatic cervical cancer after treatment with human papilloma-virus-targeted tumor-infiltrating T cells. J Clin Oncol2015;33:1543–1550.
StricklandKCHowittBEShuklaSA. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancerOncotarget2016;7:13587–13598.
HowittBShuklaSASholiLM. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol2015;1:1319–1323.
FaderANDiazLAArmstrongDK. Preliminary results of a phase II study: PD-1 blockade in mismatch repair-deficient recurrent or persistent endometrial cancer [abstract]. Presented at the 47th Annual Meeting of the Society of Gynecologic Oncology; March19–222016; San Diego, California. Abstract LBA 3.
GargisAKalmanLBerryMW. Assuring the quality of next generation sequencing in clinical laboratory practice. Nat Biotechnol2012;30:1033–1036.
EspositoABardelliACriscitielloC. Monitoring tumor-derived cell-free DNA in patients with solid tumors: clinical perspectives and research opportunities. Cancer Treat Rev2014;648–655.
PereiraECamacho-VanegasOAnandS. Personalized circulating tumor DNA biomarkers dynamically predict treatment response and survival in gynecologic cancers. PLoS One2015;10:e0145754.