Coamplification of DAD-R, SOX5, and EKI1 in human testicular seminomas, with specific overexpression of DAD-R, correlates with reduced levels of apoptosis and earlier clinical manifestation
Seminomas and nonseminomas represent the invasive stages of testicular
(TGCTs) of adolescents and adults. Although TGCTs are characterized by
extra copies of the short arm of chromosome 12, the genetic basis for gain
of 12p in the pathogenesis of this cancer is not yet understood. We have
demonstrated that gain of 12p is related to invasive growth and that
amplification of specific 12p sequences, i.e., 12p11.2-p12.1, correlates
with reduced apoptosis in the tumors. Here we show that three known genes
map within the newly determined shortest region of overlap of
amplification (SROA): DAD-R, SOX5, and EKI1. Whereas EKI1 maps close to
the telomeric region of the SROA, DAD-R is the first gene at the
centromeric region within the 12p amplicon. Although all three genes are
amplified to the same level within the SROA, expression of DAD-R is
significantly up-regulated in seminomas with the restricted 12p
amplification compared with seminomas without this amplicon. DAD-R is also
highly expressed in nonseminomas of various histologies and derived cell
lines, both lacking such amplification. This finding is of particular
interest because seminomas with the restricted 12p amplification and
nonseminomas are manifested clinically in the third decade of life and
show a low degree of apoptosis. In contrast, seminomas lacking a
restricted 12p amplification, showing significantly lower levels of DAD-R
with pronounced apoptosis, manifest clinically in the fourth decade of
life. A low level of DAD-R expression is also observed in normal
testicular parenchyma and in parenchyma containing the precursor cells of
this cancer, i.e., carcinoma in situ. Therefore, elevated DAD-R expression
in seminomas and nonseminomas correlates with invasive growth and a
reduced level of apoptosis associated with an earlier clinical
presentation. These data implicate DAD-R as a candidate gene responsible
in part for the pathological effects resulting from gain of 12p sequences
in TGCTs. In addition, our results also imply differences in expression
regulation of DAD-R between seminomas and nonseminomas