Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek

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Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
Heterogeneity of human germ cell cancers: biology
            and clinical relevance.
   Leendert Looijenga, Department of Pathology, Lab. Exp. Patho-Oncol. Erasmus MC, Rotterdam

                                               OPTIMAL PATIENT CARE

                                               Diagnosis -- Treatment -- Follow-up
                                                    Pathobiology of germ cell tumors
                                             (AC(E) UT – AAA and Biomarkers in Medicine
Menarini Benelux NV/SA, March 14, 2018,   14.00-14.45 hours.
                                                              & CoE DSD)
Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
Context of the work and presentation

 No conflict of interest.
Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
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
    LEPO                           Book chapters etc. 25
Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
The biomarker journey (it is all about details).

                            Langlauf-Drama: Stadlober verläuft sich
                                     am Weg zur Medaille
                            Alois Stadlober (Vater/während des Fehlers von Teresa Stadlober als
                                 Co-Kommentator live im ORF): "Sie ist sich verlaufen, da ist
                             irgendwas passiert. Du bist falsch! Sie ist falsch gelaufen, scheiße
                              verdammte Hütte noch einmal. Wo ist die denn hingelaufen jetzt?
                                 Hattigatti noch einmal. Alles aus - mein Gott na. Ich habe mir
                              gedacht, das gibt es ja gar nicht, dass sie so daherkommt alleine.
                              Das ist jetzt bitter. Nein, alles kann passieren, aber das nicht. Wie
                            gibt es das? Das ist unvorstellbar. Das wollte der Herrgott nicht. Das
                             ist bitter, das habe ich überhaupt noch nicht erlebt. Sie fährt in der
                            Spur herunter. Ich weiß nicht, wo sie da hinfährt. Das ist bitter, in der
                              Traumform. Schade, aber es hilft nichts. Sie hat gut ausgeschaut,
                                überhaupt kein Problem. Es schaut aus, als hätte sie wirklich
                               vielleicht auf die Medaille laufen können. Und dann passiert der
                            unvorstellbare Fehler. Wo war sie mit den Gedanken? War sie schon
                               bei der Medaille? Das darf nicht passieren. Da wäre viel möglich
                                                              gewesen."
Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
Traditional pathology classifications

                       Many reasons to adjust
                        (no biology included)
Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
Germ cell lineage- defined cohorts

           OCT3/4-AP
                               DMRT1

                  KITLG-KIT

Germ cell neoplasia dependent on cell of origin
Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
Traditional classification(s) lack(s) biological basis.

                          Oosterhuis and Looijenga, Nat Rev Cancer 2005
Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
Accepted WHO 2016 classification (testicular)

                                                II

                                   I                 III
Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
Type II (= malignant TGCTs): Epidemiology.
GENERAL POPULATION OBSERVATIONS

                                                            Historical (main) risk factors:
                                                            - Cryptorchidism
                                                            - Sub/infertility
                                                            - Familial predisposition    TDS
                                                            - Inguinal hernia
                                                            - Birth weight
                                                            - Hypospadias
                                                            - DSD –(intersex)
                                                             (THEORETICAL) ASSUMPTION: ALL (??????)

                          High curability (>90%), but long term systemic treatment effect:
                         Infertility, Metabolic Syndrome, Vasc./Heart Damage, 2nd Cancers
Heterogeneity of human germ cell cancers: biology and clinical relevance - Diversiteit in Diagnostiek
Precursor classification: acceptance WHO 2016.

PRECURSOR TERMINOLOGY
   CIS - (TIN) - IGCNU
Overview pathology GCNIS related TGCT.

                                                       COMMON PRECURSOR

PRE-INVASIVE:                                         Blocked PGC/gonocyte
Early gonadal development        GCNIS (GB-DSD)
                                                    (EMBRYONIC GERM CELL)

                     seminoma                     embr. carc.

                                       70%
INTRATUBULAR:                        ~ 7 years

INVASIVE:
 PLURIPOTENT
(TOTI-/OMNI-)
                     seminoma                     embr.carc.

                                                                  germ cells

 PURE or MIXED

                                yolk sac tum.       teratoma     choriocarc.
Overview pathology & biomarkers (serum); selection.

                                                   OCT3/4             COMMON PRECURSOR

 PRE-INVASIVE:                                                       Blocked PGC/gonocyte
 Early gonadal development                      GCNIS (GB-DSD)
                                                                   (EMBRYONIC GERM CELL)

                                   seminoma                      embr. carc.
                                  OCT3/4              70%        OCT3/4
 INTRATUBULAR:                                      ~ 7 years

 INVASIVE:
                                  OCT3/4                         OCT3/4
  PLURIPOTENT
 (TOTI-/OMNI-)
                                   seminoma                      embr.carc.

Palumbo et al., 2001; Looijenga et al.,                                          germ cells
2003, De Jong et al., 2005, Cheng et al.,
2006; De Jong and Looijenga, 2007, Van            AFP                             hCG
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.,
                                               yolk sac tum.       teratoma     choriocarc.
2012, Eini et al., 2014, and many others.
Overview pathology & biomarkers (serum); selection.

                                                   OCT3/4             COMMON PRECURSOR

 PRE-INVASIVE:                                     SOX17             Blocked PGC/gonocyte
 Early gonadal development                      GCNIS (GB-DSD)
                                                                   (EMBRYONIC GERM CELL)

                                   seminoma                      embr. carc.
                                  OCT3/4              70%        OCT3/4
 INTRATUBULAR:                    SOX17             ~ 7 years     SOX2

 INVASIVE:
                                  OCT3/4                         OCT3/4
  PLURIPOTENT                     SOX17                           SOX2             SOX17
 (TOTI-/OMNI-)
                                   seminoma                      embr.carc.

Palumbo et al., 2001; Looijenga et al.,                                          germ cells
2003, De Jong et al., 2005, Cheng et al.,
2006; De Jong and Looijenga, 2007, Van            AFP             SOX2            hCG
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.,
                                               yolk sac tum.       teratoma     choriocarc.
2012, Eini et al., 2014, and many others.
SOX2 and 17 critical ES resp. PGC
WHO OCT3/4–NANOG-SOX2/17
Frozen tissue diagnosis (unique)

                                   Direct Alkaline Phosphatase
                                        Stoop et al., 2011
Diagnosis earliest (pre-)malignant cell

Stoop et al., 2008

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

                     Diagnosis based on (gonadal) tissue analysis
GWAS and 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.

                    + 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

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

               Independent:
    Cryptorchidism; fam. predisposition,
          spermatogenic function

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

  double homozygous high risk alleles                SUSCEPTIBILITY ALLELE(S)
     KITLG + DMRT1 (28X TGCC)
TECAC - SNP update TGCT.
Further into the depth. Liquid biopsy biomarkers.
From histology to novel serum/plasma biomarkers.

                                                   OCT3/4
 PRE-INVASIVE:                                     SOX17
                                                GCNIS (GB-DSD)

                                   seminoma                      embr. carc.
                                  OCT3/4                         OCT3/4
 INTRATUBULAR:                    SOX17                           SOX2

 INVASIVE:
                                  OCT3/4                         OCT3/4
                                  SOX17                           SOX2            SOX17
                                   seminoma                      embr.carc.

Palumbo et al., 2001; Looijenga et al.,                                         germ cells
2003, De Jong et al., 2005, Cheng et al.,
2006; De Jong and Looijenga, 2007, Van            AFP             SOX2           hCG
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.,
                                               yolk sac tum.       teratoma    choriocarc.
2012, Eini et al., 2014, and many others.
Reality about serum AFP & hCG (besides (T)GCT).

AFP:   ~ 15 µg/L (~10 kU/L) after the first year of life half-life ~ 4-5 days
       may be elevated in:           - benign liver
                                     - hepatocellular carcinoma
                                     - gastric, colon, biliary, pancreatic, lung cancers
                                        (~20% of patients)
hCG:   ~ 5 U/L men/pre-menopausal women (post-menopausal women ~10 U/L)
       half-life (intact) 16-24 hours
       may be elevated in:           - hydatidiform moles ("molar" pregnancies)
                                     - pancreatic adenocarcinomas
                                     - islet cell tumors
                                     - tumors of the small and large bowel
                                     - hepatoma, stomach, lung, ovarian, breast and
                                       renal cancer

         Literature:                       sensitivity (%)
                                      TGCT           SE             NS
         AFP                           36             3             45
         hCG                           57            62             66
                          ?? - UNIVERSAL MARKER - ??
Secreted miRNAs: a new form of intercellular communication
 History liquid biopsies: specified publications.
microRNA as potential biomarker?

Voorhoeve et al., 2006   Also Eini et al., 2013
Summary miR profiling (T)GCT: summary.

                                      OCT3/4
PRE-INVASIVE:                         SOX17
                                 miR-371-3/302/367
                                   GCNIS (GB-DSD)

                     seminoma                        embr. carc.
                     OCT3/4       70%        OCT3/4
INTRATUBULAR:        SOX17 miR-371-3/302/367
                                ~ 7 years     SOX2

INVASIVE:
                     OCT3/4                 OCT3/4
                     SOX17 miR-371-3/302/367 SOX2                          SOX17
                      seminoma                       embr.carc.

                                                                         germ cells

                                     AFP              SOX2                hCG
                           miR-371-3/302/367                       miR-371-3/302/367
                                  yolk sac tum.        teratoma         choriocarc.
Secreted miRNAs: a new form of intercellular communication
              Presence of miR as target for liquid biopsies.

Regalla Kumarswamy, Thomas Thum
Secreted miRNAs: a new form of intercellular communication
 Some published data on miR-371-3 in sera TGCTs.

                                      isolation/amplification
“LEPO” approach and comparison value AFP and hCG

                         No effect on pre-isolation exosomes
miRNA serum results – current status

** p< 0.000
   n= 238     n= 60   n= 104
Start international consortium (ASCO).
Further into the depth. Tumor genome.
Mutational load and TGCTs (driver(s)?).
Genetics TGCC – low frequency
Treatment resistance and heterogeneity (subm.).

                  Whole genome
                  & targeted seq.
                     RNA Seq.
                  Methyl. Profiling

                  42 samples of

                                                  450 K methylation
                  4 resistent NS

                   (chemo-naive)

                                                        CNV
Mutational profile and heterogeneity (submitted).

                                                    CG- NS
Tumor heterogeneity and DepArray (submitted).
GCNIS and DepArray (submitted).

    H&E             OCT3/4        panKER   Vimentin
Comparison different approaches CNV data.
Tumor metastasis and DepArray (submitted).
Tumor metastasis and DepArray (Unpubl.).

                                              RMT

                      Methylation-based CNV
Tumor metastasis and DepArray summary.
Overall conclusion heterogeneity and progression.
Acknowledgements.

                                          LEPO
                    (missing KW, KB, JWO, HS, YvB)
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