LETTER TO THE EDITOR

Genetic alteration in ovarian cancer

Tae-Hee Kim • Hae-Hyeog Lee • Ji-Young Hwang •

Jin-Ho Kim • Won-Choeul Jang • Arum Lee

Received: 12 June 2014 / Accepted: 21 July 2014 / Published online: 1 August 2014

� Springer-Verlag Berlin Heidelberg 2014

Sir,

We are responding to the article, ‘‘The heterogeneity of

ovarian cancer’’ by Meinhold-Heerlein et al. [1]. Mein-

hold-Heerlein et al. authored a mini review on the heredity

of ovarian cancer focusing on the morphologic, prognostic,

etiopathogenetic, and molecular heterogeneity of ovarian

cancer. In the article, the authors commented on the cor-

relation between high-grade serous ovarian cancers and

specific genetic mutations, such as the well-known BRCA1

and BRCA2 mutations. We would like to provide the

reader with additional genes linked to ovarian cancer.

It is important to consider the genetic component of

ovarian cancer when counseling patients about their current

and future cancer risk. Understanding the genetics of

ovarian cancer will provide the key to prediction, preven-

tion, and the development of personalized, targeted

therapies.

We performed literature searches on the electronic dat-

abases PubMed (The National Center for Biotechnology

Information, National Institute of Health, USA) and Em-

base (Elsevier, Philadelphia, USA) to identify English-

language articles associated with ovarian cancer published

after 1997 using the keywords ‘‘ovarian cancer’’, ‘‘poly-

morphism’’, ‘‘SNP’’, and ‘‘mutation’’. Genes identified in

our literature search are ordered by frequency and assay

method (Table 1). While these genes are of interest to, and

investigated by, researchers throughout the world, these

researched genes do not always correlate with ovarian

cancer risk. However, we can determine trends in the types

of assays used to investigate ovarian cancer genetics. Assay

methods are listed by the frequency with which they

appeared in the articles identified by our literature search

(Table 1). Many genetic assay methods have been devel-

oped and it is unlikely that clinicians know these methods

in detail. Genotyping analyses are divided into hybridiza-

tion and enzyme-based assays and are detailed below

• Hybridization-based genotyping methods include Taq-

Man probes, single nucleotide polymorphisms (SNP)

microarrays, and the GoldenGate assay.

• Enzyme-based genotyping methods include restriction

fragment length polymorphisms (RFLP) and primer

extension.

• Post-amplification-based genotyping methods include

denaturing high performance liquid chromatography

(DHPLC) and high resolution melt (HRM) analysis.

• Other methods include DNA sequencing, multiplex

PCR, and loop mediated isothermal amplification

(LAMP) (Table 2).

Hybridization-based methods, such as microarray, have

a higher throughput than real-time PCR. However, the set-

up costs for hybridization methods are much higher.

T.-H. Kim � H.-H. Lee

Department of Obstetrics and Gynecology, Soonchunhyang

University College of Medicine, Bucheon, Republic of Korea

J.-Y. Hwang (&)

Department of Biomedical Engineering, Korea University

College of Health Science, Seoul, Republic of Korea

e-mail: jyhwang@korea.ac.kr

J.-H. Kim � W.-C. Jang

Institute of Tissue Regeneration Engineering (ITREN),

Dankook University, Cheonan, Republic of Korea

J.-H. Kim � W.-C. Jang

Department of Chemistry, Dankook University,

Cheonan, Republic of Korea

A. Lee

Department of Interdisciplinary Program in Biomedical Science,

Soonchunhyang University, Asan, Republic of Korea

123

Arch Gynecol Obstet (2014) 290:827–830

DOI 10.1007/s00404-014-3392-4

Table 1 Top 100 genes in ovarian cancer

No. Gene Description No. Gene Description

1 BRCA2 Breast cancer 2, early onset 51 NFKBIB Nuclear factor of kappa light polypeptide gene enhancer in

B-cells inhibitor, beta

2 BRCA1 Breast cancer 1, early onset 52 NQO2 NAD(P)H dehydrogenase, quinone 2

3 ARID1A AT rich interactive domain 1A (SWI-

like)

53 PMS2 PMS2 postmeiotic segregation increased 2 (S. cerevisiae)

4 TP53 Tumor protein p53 54 CDK6 Cyclin-dependent kinase 6

5 ABCB1 ATP-binding cassette, sub-family B

(MDR/TAP), member 1

55 DROSHA drosha, ribonuclease type III

6 RB1 Retinoblastoma 1 56 NMI N-myc (and STAT) interactor

7 PTPRS Protein tyrosine phosphatase, receptor

type, S

57 PARP2 Poly (ADP-ribose) polymerase 2

8 CDKN2A/2B Cyclin-dependent kinase inhibitor

2A/2B

58 SMAD6 SMAD family member 6

9 KLK15 Kallikrein-related peptidase 15 59 TCEAL7 Transcription elongation factor A (SII)-like 7

10 PTEN Phosphatase and tensin homolog 60 DGCR8 DGCR8 microprocessor complex subunit

11 CCND1 Cyclin D1 61 ESR1 Estrogen receptor 1

12 CCND2 Cyclin D2 62 BIRC5 Baculoviral IAP repeat containing 5

13 KRAS Kirsten rat sarcoma viral oncogene

homolog

63 ZNF200 Zinc finger protein 200

14 CDKN1A Cyclin-dependent kinase inhibitor 1A

(p21, Cip1)

64 ATM Ataxia telangiectasia mutated

15 PPARGC1A Peroxisome proliferator-activated

receptor gamma, coactivator 1 alpha

65 BLM Bloom syndrome, RecQ helicase-like

16 ALOX5 Arachidonate 5-lipoxygenase 66 CDK4 Cyclin-dependent kinase 4

17 CCND3 Cyclin D3 67 CDKN2D Cyclin-dependent kinase inhibitor 2D (p19, inhibits CDK4)

18 WWOX WW domain containing

oxidoreductase

68 DDX1 DEAD (Asp-Glu-Ala-Asp) box helicase 1

19 ERCC2 Excision repair cross-complementing

rodent repair deficiency,

complementation group 2

69 DDX20 DEAD (Asp-Glu-Ala-Asp) box polypeptide 20

20 IGF1 Insulin-like growth factor 1

(somatomedin C)

70 E2F2 E2F transcription factor 2

21 BTN3A3 Butyrophilin, subfamily 3, member

A3

71 EIF2B5 Eukaryotic translation initiation factor 2B, subunit 5 epsilon,

82 kDa

22 IGFBP1/

IGFBP3

Insulin-like growth factor binding

protein 1/protein 3

72 ERBB2 v-erb-b2 avian erythroblastic leukemia viral oncogene

homolog 2

23 IL18 Interleukin 18 (interferon-gamma-

inducing factor)

73 ESR2 Estrogen receptor 2 (ER beta)

24 NFKBIA Nuclear factor of kappa light

polypeptide gene enhancer in B-cells

inhibitor, alpha

74 LIN28 lin-28 homolog

25 BRIP1 BRCA1 interacting protein C-terminal

helicase 1

75 MLH1 mutL homolog 1

26 CDKN1B Cyclin-dependent kinase inhibitor 1B

(p27, Kip1)

76 MTHFD1 Methylenetetrahydrofolate dehydrogenase (NADP?

dependent) 1, methenyltetrahydrofolate cyclohydrolase,

formyltetrahydrofolate synthetase

27 MSH3 mutS homolog 3 77 NOLA3 Nucleolar protein family A, member 3 (H/ACA small

nucleolar RNPs)

28 CAMK2D Calcium/calmodulin-dependent

protein kinase II delta

78 PGR Progesterone receptor

29 BRAF v-raf murine sarcoma viral oncogene

homolog B

79 PRKACB Protein kinase, cAMP-dependent, catalytic, beta

30 CDK2 Cyclin-dependent kinase 2 80 SLC46A1 Solute carrier family 46 (folate transporter), member 1

828 Arch Gynecol Obstet (2014) 290:827–830

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Enzyme-based and DNA sequencing methods are inex-

pensive compared to other sequencing methods and also

have the advantage of being easy to use, rapid, and accu-

rate. The majority of genotyping methods have a high

sensitivity, accuracy and specificity. Our table provides

information about trends in ovarian cancer genetic assays.

The authors of the articles identified in our literature

search agreed with Meinhold-Heerlein et al.’s comments

about the lack of early ovarian cancer screening and per-

sonalized drug targets negatively affecting ovarian cancer

prognosis. The authors of the articles identified in our lit-

erature search also suggested that identifying genes

Table 1 continued

No. Gene Description No. Gene Description

31 ch.9p22 Chromosomes 9p22 81 SMAD3 SMAD family member 3

32 VEGF Vascular endothelial growth factor 82 VHL von Hippel-Lindau tumor suppressor, E3 ubiquitin protein

ligase

33 ATIC 5-Aminoimidazole-4-carboxamide

ribonucleotide formyltransferase/

IMP cyclohydrolase

83 XPC Xeroderma pigmentosum, complementation group C

34 IGF2 Insulin-like growth factor 2

(somatomedin A)

84 AGO2 Argonaute RISC catalytic component 2

35 TERF1 Telomeric repeat binding factor

(NIMA-interacting) 1

85 ch.11p Chromosomes 11p

36 TNKS Tankyrase, TRF1-interacting ankyrin-

related ADP-ribose polymerase

86 CYP19A1 Cytochrome P450, family 19, subfamily A, polypeptide 1

37 CC2D1A Coiled-coil and C2 domain containing

1A

87 DCP1 Decapping mRNA 1

38 CCL2 Chemokine (C-C motif) ligand 2 88 DICER dicer, ribonuclease type III

39 CCNE1 Cyclin E1 89 DNMT3A DNA (cytosine-5-)-methyltransferase 3 alpha

40 IL1B Interleukin 1, beta 90 ERCC5 Excision repair cross-complementing rodent repair deficiency,

complementation group 5

41 PIK3CA Phosphatidylinositol-4,5-bisphosphate

3-kinase, catalytic subunit alpha

91 ERCC6 Excision repair cross-complementing rodent repair deficiency,

complementation group 6

42 PRPF31 Pre-mRNA processing factor 31 92 GALNT1 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-

acetylgalactosaminyltransferase 1 (GalNAc-T1)

43 c-KIT c-v-kit Hardy-Zuckerman 4 feline

sarcoma viral oncogene homolog

93 HEXIM1 Hexamethylene bis-acetamide inducible 1

44 DROSHA drosha, ribonuclease type III 94 LD3 Linkage disequilibrium block 3

45 GEMIN4 gem (nuclear organelle) associated

protein 4

95 MFSD7 Major facilitator superfamily domain containing 7

46 HGF Hepatocyte growth factor (hepapoietin

A; scatter factor)

96 MGAT5 Mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-

glucosaminyltransferase

47 LD1 Linkage disequilibrium block 1 97 MTHFR Methylenetetrahydrofolate reductase (NAD(P)H)

48 MSH2 mutS homolog 2 98 NOLA2 Nucleolar protein family A, member 2 (H/ACA small

nucleolar RNPs)

49 MTERF Mitochondrial transcription

termination factor

99 NQO1 NAD(P)H dehydrogenase, quinone 1

50 NDUFA12 NADH dehydrogenase (ubiquinone) 1

alpha subcomplex, 12

100 NRF1 Nuclear respiratory factor 1

Arch Gynecol Obstet (2014) 290:827–830 829

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associated with ovarian cancer is essential to the develop-

ment of screening methods and treatments to decrease

ovarian cancer mortality.

Acknowledgments This work was supported in part by the Soon-

chunhyang University Research Fund.

Conflict of interest No competing financial interests exist.

Reference

1. Meinhold-Heerlein I, Hauptmann S (2014) The heterogeneity of

ovarian cancer. Arch Gynecol Obstet 289:237–239

Table 2 Assay methods in ovarian cancer

Assay methods Frequency

tagSNP 562

Sequencing 476

Illumina 387

PCR 207

DHPLC 155

Quantitative real time PCR 153

Massarray 84

htSNPs 29

Microarray 26

Expression 26

Immunohistochemistry 23

RFLP 19

Genotyping assay 15

Taqman real time PCR 14

Golden helix SVS PCA function 12

Dot blotting 3

ELISA 1

tagSNP tag single nucleotide polymorphism, PCR polymerase chain

reaction, DHPLC denaturing high performance liquid chromatogra-

phy, htSNPs haplotype-tagging single nucleotide polymorphisms,

RFLP restriction fragment length polymorphism, SVS SNP and var-

iation suite, PCA principal component analysis, ELISA enzyme-linked

immunosorbent assay

830 Arch Gynecol Obstet (2014) 290:827–830

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