TY - JOUR

T1 - The genetic landscape of 87 ovarian germ cell tumors

AU - Van Nieuwenhuysen, Els

AU - Busschaert, Pieter

AU - Neven, Patrick

AU - Han, Sileny N.

AU - Moerman, Philippe

AU - Liontos, Michalis

AU - Papaspirou, Maria

AU - Kupryjanczyk, Jolanta

AU - Hogdall, Claus

AU - Hogdall, Estrid

AU - Oaknin, Ana

AU - Garcia, Angel

AU - Mahner, Sven

AU - Trillsch, Fabian

AU - Cibula, David

AU - Heitz, Florian

AU - Concin, Nicole

AU - Speiser, Paul

AU - Salvesen, Helga

AU - Sehouli, Jalid

AU - Lambrechts, Diether

AU - Vergote, Ignace

PY - 2018

Y1 - 2018

N2 - Background: Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized. Methods: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape. Results: The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas. Conclusion: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.

AB - Background: Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized. Methods: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape. Results: The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas. Conclusion: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.

KW - Copy number

KW - Exome sequencing

KW - KIT

KW - Mutation rate

KW - Ovarian germ cell tumors

KW - PI3K-AKT-PTEN pathway

U2 - 10.1016/j.ygyno.2018.08.013

DO - 10.1016/j.ygyno.2018.08.013

M3 - Journal article

C2 - 30170975

AN - SCOPUS:85053510414

VL - 151

SP - 61

EP - 68

JO - Gynecologic Oncology

JF - Gynecologic Oncology

SN - 0090-8258

IS - 1

ER -