Hallmarks of Cancer explored in testicular germ cell tumors (TGCTs) MGC course 07-10-2018 Wolter Oosterhuis
Hallmarks of cancer (Hanahan and Weinberg, Cell 2000)
Hallmarks of cancer (Hanahan and Weinberg, Cell 2011) ▪ Figure 3 (page 658)
Characteristics of seven defined types of germ cell tumors (GCT) Type Age (years) Sex Anatomical site Phenotype/developme Developmental Precursor cell Genomic Karyotype Animal GCT ntal potential state imprinting; model methylation 0 Neonates F/M Retroperitoneum/ Included and parasitic 2C-state Blastomere Biparentental Normal diploid Not available sacrum/skull/hard twins (omnipotent) palate I Neonates and F/M Testis/ovary/sacral (Immature) teratoma Primed-state PGC/gonocyte Biparental Diploid (TE)/ Mouse children < 6; region/ (TE)/yolk sac tumor (pluripotent) before start of partially erased aneuploid (YST): teratoma rarely beyond retroperitoneum/ (YST) global gain: 1q,12(p13),20q childhood anterior demethylation loss: 1p,4,6q mediastinum/ neck/midline brain/other rare sites II After start of >>M Dysgenetic Seminoma/ Naïve-state PGC/gonocyte Erased Aneuploid (+/- triploid) Not available puberty. gonad/testis/ovary/ dysgerminoma/ (totipotent) undergoing global gain: X,7,8,12p,21 In disorders of anterior mediastinum germinoma demethylation loss: Y,1p,11,13,18 sexual developm., (thymus)/midline reprogrammed to in mediastinum and Klinefelter’s - and brain (pineal gland) non-seminoma/ midline brain also Down’s syndrome non-dysgerminoma/ (near)diploid and rarely before non-germinoma (near)tetraploid with gain puberty of 12p III Older men, usually M Testis Spermatocytic tumor Spermatogonium Spermatogonium/ Partially- Gain: 9 Canine > 55 to premeiotic spermatocyte completely seminoma spermatocyte paternal IV After puberty F Ovary Dermoid cyst Maternally Oogonia/oocyte Partially- (Near) diploid Mouse imprinted 2C-state (gynogenote) completely diploid/tetraploid gynogenote maternal peritriploid gain: X,7,12,15 V After puberty F Placenata/uterus Molar pregnancy Paternally Empty ovum/ Completely Diploid (XX and XY) Mouse imprinted 2C-state spermatozoa paternal androgenote (androgenote) VI Older age, F/M Atypical sites for Resembling type I or Primed state or Somatic cell Imprinting Depending on precursor Xenografts usually > 60 GCT non-seminoma non-seminoma induced to pattern of cell derived from components of type II lineages of naïve- pluripotency originating cell iPSC state Oosterhuis and Looijenga, Springer 2017
Characteristics of seven defined types of germ cell tumors (GCT) Type Age (years) Sex Anatomical site Phenotype/developme Developmental Precursor cell Genomic Karyotype Animal GCT ntal potential state imprinting; model methylation 0 Neonates F/M Retroperitoneum/ Included and parasitic 2C-state Blastomere Biparentental Normal diploid Not available sacrum/skull/hard twins (omnipotent) palate I Neonates and F/M Testis/ovary/sacral (Immature) teratoma Primed-state PGC/gonocyte Biparental Diploid (TE)/ Mouse children < 6; region/ (TE)/yolk sac tumor (pluripotent) before start of partially erased aneuploid (YST): teratoma rarely beyond retroperitoneum/ (YST) global gain: 1q,12(p13),20q childhood anterior demethylation loss: 1p,4,6q mediastinum/ neck/midline brain/other rare sites II After start of >>M Dysgenetic Seminoma/ Naïve-state PGC/gonocyte Erased Aneuploid (+/- triploid) Not available puberty. gonad/testis/ovary/ dysgerminoma/ (totipotent) undergoing global gain: X,7,8,12p,21 In disorders of anterior mediastinum germinoma demethylation loss: Y,1p,11,13,18 sexual developm., (thymus)/midline reprogrammed to in mediastinum and Klinefelter’s - and brain (pineal gland) non-seminoma/ midline brain also Down’s syndrome non-dysgerminoma/ (near)diploid and rarely before non-germinoma (near)tetraploid with gain puberty of 12p III Older men, usually M Testis Spermatocytic tumor Spermatogonium Spermatogonium/ Partially- Gain: 9 Canine > 55 to premeiotic spermatocyte completely seminoma spermatocyte paternal IV After puberty F Ovary Dermoid cyst Maternally Oogonia/oocyte Partially- (Near) diploid Mouse imprinted 2C-state (gynogenote) completely diploid/tetraploid gynogenote maternal peritriploid gain: X,7,12,15 V After puberty F Placenata/uterus Molar pregnancy Paternally Empty ovum/ Completely Diploid (XX and XY) Mouse imprinted 2C-state spermatozoa paternal androgenote (androgenote) VI Older age, F/M Atypical sites for Resembling type I or Primed state or Somatic cell Imprinting Depending on precursor Xenografts usually > 60 GCT non-seminoma non-seminoma induced to pattern of cell derived from components of type II lineages of naïve- pluripotency originating cell iPSC state Oosterhuis and Looijenga, Springer 2017
Type II, erased, pluripotent Type II testicular germ cell tumor, histopathology carcinoma in situ germ cell neoplasia (CIS) in situ (GCNIS) default it Sem (dys/ger)SEMINOMA reprogramming NON(dys/ger)SEMINOMA it non-Se embryonal intratubular germ carcinoma cell neoplasia unclass. (ITGCNU) embryoid body germ cell diff. teratoma yolk sac tumor choriocarcinoma
Intratubular seminoma Intratub. non-seminoma intermediate stages between precursor and invasive cance r GCNIS → intratubular seminoma → seminoma GCNIS → intratubular non-seminoma → non-seminoma Reprogramming occurs also within seminiferous tubules
TGCTs: bell-shaped age distribution Median age at NS S presentation (lump in testis) of seminoma (35) non-seminoma (25) (intratub. reprogamming) CT combined tumors (30) (reprogramming of invasive seminoma, or two separate tumors)
TGCTs: Clinical presentation, diagnosis, treatment ▪ Rare, but most frequent cause of death due to malignancy in age range 17- 45, despite high curability ▪ Serum tumor markers AFP (yolk sac tumor) HCG (choriocarcinoma) (> 85% one or both positive), and specific micro RNA’s (100% positive) ▪ Combined treatment: surgery (orchidectomy) followed by irradiation (seminoma) or cisplatin-based chemotherapy (non-seminoma) if necessary followed by removal of metstatic residual masses (usually retroperitoneal)
TGCTs: famous survivor Lance Amstrong, lucky to have the most curable solid cancer you can have; even with metastases cure rate >80%
Epidemiology: rise of incidence, decline sperm quality ▪ Rising incidence of TGCTs in affluent Western societies ▪ Decline of sperm quality in affluent Western societies ▪ Common cause? Hypovirilizing factors in environment? Xeno-estrogens?
TGCTs origin, testicular dysgenesis syndrome (TDS) ▪ Characteristics of TDS: features of hypo-virilization ▪ Hypospadias ▪ Cryptorchidism ▪ Small testis ▪ infertility ▪ Microlithiasis (ultra-soundpicture) ▪ Histology: features of hypo-virilisation as in partial androgen insensitivity (Sertoli cell only nodules; suboptimal spermatogenesis) ▪ Increased risk of TGCTs ▪ TGCT is developmental cancer: initiation in primordial germ cells due to disturbed embryonic development; somatic mutations play minor role.
Hallmark: replicative immortality Telomerase is ON in normal primordial germ cells, GCNIS, seminoma, normal ES cells, embryonal carcinoma, and other tumors, and OFF in normal somatic tissue and mature teratoma Albanell et al, JNCI 1999
Hallmark: sustaining proliferative signaling (I) ▪ Lowest mutation rate of solid cancers in adults ▪ Only driver mutations (initiating event): ▪ cKIT mutations in bilateral testicular cancer (genetic mechanism) ▪ KRAS (downstream from cKIT) ▪ Accounting for about 2% of TGCT; rest due to disturbed embryonal development
Hallmark: sustaining proliferative signaling (II) ▪ delayed maturation (epigenetic mechanism) ▪ window for co-expression of OCT3/4 (survival factor) and TSPY (stimulating cell cycle) and SCF ▪ autocrine loop SCF and cKIT (SCF receptor) expressed by GCNIS cells ▪ role of variants in cKIT that are associated with higher risk for TGCT? (GWAS-studies Rapley et al.)
GCNIS OCT3/4 TSPY Stem cell factor-receptor (cKIT) SCF
Cryptorchid testis: normal germ cell development H & E TSPY OCT3/4 SCF
cryptorchid testis: delayed maturation H & E TSPY OCT3/4 SCF
Cryptorchid testis: pre-GCNIS H & E TSPY OCT3/4 SCF
GCNIS OCT3/4 TSPY Stem cell factor-receptor (cKIT) SCF
Migrating primordial germ cells depend on KIT-signalling for survival and proliferation In bilateral testicular GCT c-KIT mutations do play a role, and problably take place before the migrating primordial germ cells reach the genital ridges
Enabling characteristicsustaining proliferative signaling (III) ▪ polyploidization ▪ in itself advantageous? (compare: polyploidization of plant cells in stressful conditions) ▪ causing chromosomal instability by asymmetrical distribution of chromosomes over daughter cells ▪ resulting in extra copies of #12 and 12p (mainly as i(12p)) convey survival and growth advantage
Peri
Gain of 12p in human type II TGCT Banding Schematic FISH CGH i(12p) amplicon on12p11.2-2.1 ITGCN invasive GCNIS Rosenberg et al ., 2000; Summersgill et al. 2001
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