(Epi)Genetics in normal and malignant germ cell development. - - PowerPoint PPT Presentation

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(Epi)Genetics in normal and malignant germ cell development. - - PowerPoint PPT Presentation

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(Epi)Genetics in normal and malignant germ cell development. Leendert Looijenga, Department of Pathology, Lab. Exp. Patho-Oncol. Erasmus MC, Rotterdam OPTIMAL PATIENT CARE Diagnosis -- Treatment -- Follow-up MM Basic and Transl. Oncol.,

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Leendert Looijenga, Department of Pathology, Lab. Exp. Patho-Oncol. Erasmus MC, Rotterdam

MM Basic and Transl. Oncol., October 23, 2017, 15.00-15.45 hours.

(Epi)Genetics in normal and malignant germ cell development.

OPTIMAL PATIENT CARE

Diagnosis -- Treatment -- Follow-up

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Oosterhuis and Looijenga, Nat Rev Cancer 2005

Traditional classification(s) lack(s) biological basis.

Extragonadal mainly type I & II

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Accepted WHO 2016 classification (testicular)

III II I

Spermatocytic seminoma

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Human (sperm.) seminoma (tumor) [Type II-III]

Stoop et al., Lab. Invest. 2001 mitosis/meiosis: XPA, SYCP1, SSX2-4 (Rajpert de Meyts et al., 2003: Chk2, p53, p16INK4d, MAGE-A4)

Looijenga et al., Cancer Res 2006

Morphology, epidemiology and behavior

Sem./Dysgerm Sperm. Sem.

DMRT1

aCGH (>#9)

(Doublesex and MAB-3 related transcription factor)

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Additional markers Sperm. Seminoma (Tumor)

Animal model DMRT1

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Recent paper NGS (story closed?)

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Historical (main) risk factors:

  • Cryptorchidism
  • Sub/infertility
  • Familial predisposition
  • Inguinal hernia
  • Birth weight
  • Hypospadias
  • DSD –(intersex)

(THEORETICAL) ASSUMPTION: ALL (??????)

TDS

Long term effect because of young patients & life expectancy: Infertility, Metabolic Syndrome, Vasc./Heart Damage, 2nd Cancers

GENERAL POPULATION OBSERVATIONS

Focus Type II (TGCTs): Epidemiology.

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PRECURSOR TERMINOLOGY

Precursor classification: acceptance WHO 2016.

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PRECURSOR TERMINOLOGY

Precursor classification: acceptance WHO 2016.

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teratoma yolk sac tum. choriocarc.

INVASIVE:

seminoma

embr.carc.

PLURIPOTENT (TOTI-/OMNI-)

germ cells

INTRATUBULAR: seminoma

  • embr. carc.

PRE-INVASIVE:

GCNIS (GB-DSD)

Blocked PGC/gonocyte (EMBRYONIC GERM CELL)

COMMON PRECURSOR

Early gonadal development

70% ~ 7 years

PURE or MIXED

Overview pathology GCNIS related TGCT.

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teratoma yolk sac tum. choriocarc.

INVASIVE:

seminoma

embr.carc.

PLURIPOTENT (TOTI-/OMNI-)

germ cells

INTRATUBULAR: seminoma

  • embr. carc.

PRE-INVASIVE:

Blocked PGC/gonocyte (EMBRYONIC GERM CELL)

COMMON PRECURSOR

Early gonadal development

70% ~ 7 years

AFP hCG OCT3/4 OCT3/4 OCT3/4 OCT3/4

Palumbo et al., 2001; Looijenga et al., 2003, De Jong et al., 2005, Cheng et al., 2006; De Jong and Looijenga, 2007, Van Casteren et al., 2008a,b, 2009, De Jong et al., 2008, Nonaka et al., 2009, Sonne et al, 2010, Gillis et al., 2011, Ushida et al., 2012, Eini et al., 2014, and many others. GCNIS (GB-DSD)

OCT3/4 Overview pathology & biomarkers (serum); selection.

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teratoma yolk sac tum. choriocarc.

INVASIVE:

seminoma

embr.carc.

PLURIPOTENT (TOTI-/OMNI-)

germ cells

INTRATUBULAR: seminoma

  • embr. carc.

PRE-INVASIVE:

Blocked PGC/gonocyte (EMBRYONIC GERM CELL)

COMMON PRECURSOR

Early gonadal development

70% ~ 7 years

AFP hCG OCT3/4 OCT3/4 OCT3/4 OCT3/4

Palumbo et al., 2001; Looijenga et al., 2003, De Jong et al., 2005, Cheng et al., 2006; De Jong and Looijenga, 2007, Van Casteren et al., 2008a,b, 2009, De Jong et al., 2008, Nonaka et al., 2009, Sonne et al, 2010, Gillis et al., 2011, Ushida et al., 2012, Eini et al., 2014, and many others.

OCT3/4 SOX17 OCT3/4 SOX2 OCT3/4 SOX17 OCT3/4 SOX2 SOX2 SOX17

GCNIS (GB-DSD)

OCT3/4 OCT3/4 SOX17 Overview pathology & biomarkers (serum); selection.

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SOX2 and 17 critical ES resp. PGC.

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Biomarkers (WHO 2106) and dAP (PGC/ES).

Similar (protein) patterns normal development & (T)GCTs (highly informative diagnostic markers)

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DSD & (T)GCT precursors (relevance pathologists).

DSD guideline 2017: LEPO = referral center (NL/B)

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Stoop et al., 2008 OCT3/4 and SCF (KITLG): Distinction between delayed matured and (pre-)GCNIS

  • - versus ++

delayed maturation: (OCT3/4+/ KITLG-)

Sophia Children’s Hospital: Start 2002= 12/160 (7.5%) = 2 (17%) progressed; Update: ~200 orchidopexy biopsies (till end 2013, >250 to date); pre-GCNIS: 14 (7%); progression n=3 (21.4%; age after puberty), 1 bilateral in follow-up.

Diagnosis based on (gonadal) tissue analysis; GWAS on TGCT cohorts

Possible overdiagnosis GCNIS (delayed maturation).

+ KITLG [OR = 2.69 highest to date] + SPRY4 [inh. MAPK, downstream KITLG] + BAK1 [downstream KITLG] + DMRT1 [sex determination] + TERT, ATFIP [telomere maintenance] + UCK2, HPGDS, CENPE, CLPTM1L, MAD1L1, RFWD3, TEX14, PPM1E Rapley et al., 2009; Kanetsky et al. 2009; Turnbull et al. 2010; Kratz et al., 2011; Ruark et al., 2013; Chung et al., 2013; …..

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TECAC + SNP update TGCT (germline variations).

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SNP and DSD (Hum. Reprod.: 2017 in press).

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Novel susceptibility variants (SNPs) (not GWAS)

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From germline genetics to (T)GCT epigenetics.

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DNA methylation-based TGCT insights.

CNV (heterogeneity) Pathway “activity” Genomic imprinting Lineage similarities

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Optimal” pathological (WHO)/clinical classification (also non-testicular) Identification of (general) risk population(s) ethnic origin (genetic basis) & clinical characteristics (TDS/DSD) (SNPs) Insight into pathogenesis (embryonic germ cell origin, including (epi)genetics) Identification (biology based) biomarkers (Tissue/Serum) OCT3-4/SOX2-17/(KITLG early age)/AFP/hCG (Tissue/Serum)/.....

Conclusions so far and expectations.

Risk stratification: * initial diagnosis * follow-up

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TGCT versus ES/IPS cells – clinical relevance

Potential of malignant behavior = (T)GCT??

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Pre-clinical in vivo model = bridge disciplines (?)

Daniela Salvatori, LUMC

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mRNA profiling (cell lines vitro/vivo & TGCT)

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miRNA profiling (cell lines vitro/vivo)

down

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miRNA profiling (cell lines vitro/vivo sera)

EC TE (YST)

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What we have:

  • “Optimal” pathological (WHO)/clinical classification (also non-testicular)
  • Identification of (general) risk population(s)

ethnic origin (genetic basis) & clinical characteristics (TDS/DSD) (SNPs)

  • Insight into pathogenesis (embryonic germ cell origin)
  • Identification (biology based) biomarkers (Tissue/Serum)

OCT3-4/SOX2-17/(KITLG early age)/AFP/hCG (Tissue/Serum)/..... What we will get:

  • Early stratification diagnosis (defined risk populations)
  • Understanding (genetic) heterogeneity (prim. tumor & metastases)
  • Informative molecular serum biomarkers (non-responders: relapse/resistance)
  • Putative target(s) treatment refractory disease

Overall conclusions and future perspectives Human germ cell tumors; a developmental disease.

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  • Rev. Fund, ESMO, ESPE,

Deutsche KrebsHilfe, EORTC,

  • Dr. Mildred Scheel

Foundation

Urologists and Pathologists, Patients (missing KW, KB JWO, HS YvB)

LEPO

Human germ cell tumors; a developmental disease.