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.
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)
Context of the work and presentation No conflict of interest.
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
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."
Traditional pathology classifications
Many reasons to adjust
(no biology included)
Germ cell lineage- defined cohorts
OCT3/4-AP
DMRT1
KITLG-KIT
Germ cell neoplasia dependent on cell of origin
Traditional classification(s) lack(s) biological basis.
Oosterhuis and Looijenga, Nat Rev Cancer 2005
Accepted WHO 2016 classification (testicular)
II
I III
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
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., 2011Diagnosis 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 analysisGWAS 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 ThumSecreted 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 exosomesmiRNA 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)
CNVMutational profile and heterogeneity (submitted).
CG- NSTumor heterogeneity and DepArray (submitted).
GCNIS and DepArray (submitted).
H&E OCT3/4 panKER VimentinComparison different approaches CNV data.
Tumor metastasis and DepArray (submitted).
Tumor metastasis and DepArray (Unpubl.).
RMT
Methylation-based CNVTumor metastasis and DepArray summary.
Overall conclusion heterogeneity and progression.
Acknowledgements.
LEPO
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