(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 Pathobiology of germ cell tumors

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

  • Mol. Med. October 8, 2018, 15.45-16.30 hours.

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

OPTIMAL PATIENT CARE

Diagnosis -- Treatment -- Follow-up Pathobiology of germ cell tumors (AC(E) UT – AAA and Biomarkers in Medicine & CoE DSD)

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Me + LEPO (Looijenga’s eigen pathologie onderneming)

PhD co-promotor 2 /promotor 12/ongoing 9 = 23 Invited speaker 254; Funded research projects 50 Papers: 1st 39/co 154/last 124 = 317 Book chapters etc. 25

LEPO

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Many reasons to adjust (no biology included)

Traditional pathology classifications

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Germ cell lineage- defined cohorts

KITLG-KIT DMRT1 OCT3/4-AP Germ cell neoplasia dependent on cell of origin

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Animation: Introduction.

www.erasmusmc.nl/pathologie/research/lepo

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Animation: Introduction.

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Animation: Embryonic germ cell loss (< 6 months).

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Oosterhuis and Looijenga, Nat Rev Cancer 2005; Nat Rev Dis Primers 2018 in press; update 2018 in prep.

Classification GCTs (complex: NO).

WHO 2016

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PRECURSOR TERMINOLOGY

Precursor classification: WHO 2016 type II GCT.

CIS - (TIN) - IGCNU

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Overview current status: epidemiology.

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Historical (main) risk factors:

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

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

TDS

High curability (>90%), but long term systemic treatment effect: Infertility, Metabolic Syndrome, Vasc./Heart Damage, 2nd Cancers

GENERAL POPULATION OBSERVATIONS

Type II (= malignant TGCTs): Epidemiology.

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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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Chromosomal/genetic constitution (GBY - TSPY)

GBY: Page 1987 TSPY: Schnieders et al., 1996; Lau et al., 1999; Hildenbrand et al., 1999; Lau et al., 2000; Schubert et al., 2003; Kersemaekers et al., 2005, …

GCNIS/intrat. NS/NS No co-expression normal germ cells Abundant expression GCNIS/GB Predominant loss upon invasive growth, adult GCNIS can be heterogeneous

Adult GCNIS (OCT3/4 + TSPY) Embryo 27 wks (OCT3/4 + TSPY)

X

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Chicago Consensus meeting October 2005

DSD = “INTERSEX”

DSD and GCTs (towards a clinical decision tree).

Risk overdiagnosis early age (<1 y): delayed maturation versus (pre-GCNIS) [OCT3/4 +]

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Discriminate delayed maturation and (pre-)GCNIS.

Stoop et al., 2008

OCT3/4 and SCF (KITLG): Distinction between delayed matured and (pre-)GCNIS

  • - versus ++

Wolffenbuttel et al., 2016

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GWAS and TGCC

Risk alleles are the major alleles (lower in Asian & African = low risk (T)GCC)

Independent: Cryptorchidism; fam. predisposition, spermatogenic function

+ 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

< 1% of patients carry low risk KITLG allele < 3% of patients carry low risk DMRT1 allele

double homozygous high risk alleles KITLG + DMRT1 (28X TGCC)

Rapley et al., 2009; Kanetsky et al. 2009; Turnbull et al. 2010; Kratz et al., 2011; Ruark et al., 2013; Chung et al., 2013.

SUSCEPTIBILITY ALLELE(S)

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TECAC - SNP update TGCT.

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DSD and TGCT related SNPs.

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Current model early pathogenetic step(s).