RESUMEN
Germ cell tumor (GCT) is the most common genitourinary malignancy of men between the ages of 18 and 35 years. Therapy is ultimately successful in over 90% of patients, however significant morbidity and mortality can be associated with adjuvant treatment and relapse. Molecular markers that predict treatment response and/or poor outcome would have immediate clinical benefit since adjuvant treatment could be selectively reserved for patients at higher risk for relapse and those patients most likely to respond to treatment. In order to identify potential prognostic molecular markers, we evaluated 118 GCT for microsatellite instability (MSI), loss of heterozygosity (LOH) and MSH2 immunostaining to identify tumors associated with relapse and/or poor outcome following initial surgical, medical and/or radiation therapy. MSI in 3 or more markers and/or low MSH2 staining were associated with relapse while LOH in the absence of MSI and/or high MSH2 staining were not. Twenty-five percent of GCT exhibited genetic instability in 3 or more microsatellite markers (MSI+ tumors), 15% exhibited LOH in the absence of MSI (LOH only tumors) and 44% exhibited decreased or absent MSH2 immunostaining (low MSH2 staining tumors). Thirty-six patients (30%) relapsed and 27 of these patients (75%) had MSI+ and/or low MSH2 staining tumors. Only one patient (3%) with an LOH only tumor and no patients with high MSH2 staining and LOH only tumors relapsed. Therefore distinct GCT subpopulations identified by detection of MSI, LOH and MMR expression are associated with different clinical outcomes. MMR deficient testicular GCT with increased frequency of MSI had an increased association with tumor recurrence compared to GCT with an intact MMR system and LOH in the absence of MSI.
Asunto(s)
Inestabilidad Genómica , Germinoma , Repeticiones de Microsatélite , Recurrencia Local de Neoplasia , Neoplasias Testiculares , Adulto , Biomarcadores de Tumor/genética , Reparación del ADN , Proteínas de Unión al ADN/genética , Germinoma/diagnóstico , Germinoma/genética , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Proteína 2 Homóloga a MutS , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Pronóstico , Proteínas Proto-Oncogénicas/genética , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/genéticaRESUMEN
We tested for azoospermia factor (AZF) deletions 17 loci corresponding to AZF subintervals a-d in 17 cases of testicular tumors occurring in Finns. While DNA samples from 48 CEPH and 32 Finnish males showed no deletions, patients with testicular cancer displayed AZF deletion mosaicisms in various non-tumor tissues (13 cases) and specific deletion haplotypes in tumor tissues (10 cases). Two of the cases with AZF deletions were testicular non-Hodgkin lymphomas indicating that Y-microdeletions appear also in malignancies other than seminoma and non-seminoma tumors. In good agreement with this assumption, we detected one AZF deletion in normal cells from 1 of 5 HNPCC cases, heterozygous for an MLH1 mutation. We propose that AZF deletions occur in early embryogenesis due to mutations of TSPY, mismatch repair (MMR), or X-specific genes. Since fathers of testicular, tumor cases did not exhibit AZF deletions, we assumed they were not carriers of the mutation inducing AZF deletion-mosaicisms. Therefore, tumor cases should have received the MMR gene or X mutations via the maternal lineage, or for the case of TSPY and MMR genes via a sperm carrying a mutation occurred in the paternal germ-cell line. We consider AZF microdeletions in non-tumor cells to be part of a broader pattern of chromosome instability producing susceptibility to testicular tumors. Clonal transformation and expansion of one of these tumor-susceptible cell lineages give rise to testicular tumors showing genome anomalies characteristic of testicular cancers (i12p, LOH and genetic imbalance for various autosomal regions, Y- and autosomal MSI, specific AZF deletion haplotypes).
Asunto(s)
Eliminación de Gen , Predisposición Genética a la Enfermedad , Proteínas de Plasma Seminal/genética , Neoplasias Testiculares/genética , Disparidad de Par Base , Reparación del ADN/genética , Sitios Genéticos , Germinoma/genética , Humanos , Masculino , Repeticiones de Microsatélite , Mosaicismo , Reacción en Cadena de la PolimerasaRESUMEN
Primary intracranial germ cell tumors are the result of the transformation of primordial cells that are unable to migrate to their normal place. These tumors are rare, accounting for less than 5% of all intracranial tumors and less than 3% of childhood neoplasias. In this paper, we have studied cytogenetically two primary intracranial germ cell tumors, a pineal region germinoma, and a mature teratoma in the right lateral ventricle. Neither tumor presented polyploidy or isochromosome 12p, considered to be characteristic of gonadal germ cell tumors. In the five reports in the literature, only one intracranial germ cell tumor presented i(12p). Perhaps i(12p) negative cases characterize a subtype of germ cell tumors.