13 research outputs found
Evaluation of Retinoblastoma and Ki-67 Immunostaining as Diagnostic Markers of Benign and Malignant Parathyroid Disease
RID="" ID="" Correspondence to: F. Farnebo, M.D., Ph.D.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42410/1/268-23-1-68_23n1p68.pd
Molecular Mechanisms of tumor development in hyperparathyroidism
Loss of heterozygosity (LOH) analysis and comparative genomic
hybridization (CGH) were used in an attempt to identify recurrent
chromosomal alterations in different types of parathyroid tumors. These
included familial and sporadic, benign and malignant, as well as primary,
irradiation associated and secondary tumors. Hitherto unidentified tumor
suppressor genes were implicated on chromosomes 1p, 6q, 9p, 11p, 11q,
13q, 15q, 18q and X, as well as a putative oncogene locus represented by
a gain of DNA copy number on chromosome 19 (Papers I and V). Since many
genes responsible for familial cancer syndromes also are mutated in their
sporadic counterparts, another approach was to search for deletions of
chromosomal regions to which familial syndromes are mapped. The 11q13
region, which harbors the multiple endocrine neoplasia type 1 (MEN 1)
tumor suppressor gene, is deleted in the majority of parathyroid tumors
from MEN 1 patients. Similarly, a third of tumors from patients with
sporadic primary HPT showed LOH at 11q13 (Papers 1 and II) and in half of
these cases a somatic MEN1 mutation could be demonstrated (Paper II). The
sporadic adenomas with MEN1 involvement also displayed a significantly
higher number of CGH aberrations as compared with the non-MEN1 associated
group (p< 0.05) (Paper V). The genetic profile obtained for the radiation
associated adenomas closely resembled that of the ordinary adenomas with
involvement of the MEN1 gene, i.e. multiple CGH alterations and frequent
losses of 11q. Indeed, inactivating mutations of the MEN1 gene were
identified in four of the eight irradiation associated tumors analyzed
(Paper V).
Changes in the calcium receptor (CaR) have been proposed to be
responsible for the increase in set-point of parathyroid hormone
secretion seen in primary HPT. The level of CaR mRNA in the adenomas was
in the range of 41-98 % (median of 64 %) of the expression level in the
normal parathyroid tissue (Paper VI). The mRNA level was not found to
correlate with serum calcium, parathyroid hormone or adenoma weight. It
seems likely that the reduced levels of receptor mRNAs and protein is a
secondary phenomenon, rather than a primary event.
Two families with HPT-JT syndrome were investigated and in both families
renal hamartomas or cystic kidney disease were prominent associated
features, possibly representing a new phenotypic variant of the HPT-JT
syndrome. A sex dependent penetrance of HPT was seen, resulting in mainly
male affected cases (Paper III). Three large previously unreported
FIHPfamilies in whom the disease was linked to the chromosome 1q21-q32
region were analyzed and two of these families were considered to be true
FIHP families, i.e. there was no evidence of jaw or renal lesions despite
careful radiological investigations. In the third family, a parathyroid
cancer and two cases of polycystic kidney disease were found and that
family was therefore considered as being affected by the classical HPT-JT
syndrome. The same sex-dependent penetrance of HPT was seen in the FIHP
families as in the HPT-JT families reported in paper III. LOH analysis
showed loss in the l q region of the wild type allele in the renal
hamartomas and in some of the parathyroid tumors, including the
parathyroid cancer, suggesting that this gene is a tumor suppressor gene.
Parathyroid cancer is a rare cause of primary HPT. Nevertheless this
group creates diagnostic and therapeu- tic problems, since in the absence
of invasion of adjacent organs or structures and/or metastases, the
diagnosis of parathyroid cancer can not be definitely established based
on histopathology. The expression of Ki-67, RB and Gelatinase A were
investigated as possible tumor markers in parathyroid cancers. However,
none of these markers was suitable for reliable differentiation between
benign and malignant parathyroid tumors (Papers VII and VIII)
Identification of numerical and structural chromosome aberrations in 15 high hyperdiploid childhood acute lymphoblastic leukemias using spectral karyotyping
Spectral karyotyping (SKY) on metaphase spreads from 15 high hyperdiploid (>51 chromosomes) childhood acute lymphoblastic leukemias (ALL), which typically display a poor chromosome morphology, was performed in order to investigate the pattern of numerical abnormalities, reveal the chromosomal origin of marker chromosomes, and identify translocations and other interchromosomal rearrangements not detected by G-banding analysis. In all cases the numerical changes could be fully characterized, and a non-random pattern of chromosomal gain was identified, with chromosomes X, 21, 14, 17, 6, 18, 4, and 10 being most frequently gained. The numerical changes had been partly misinterpreted in 12 of the 15 ALL patients using G-banding, and the present study hence emphasizes the importance of SKY in identifying such anomalies, some of which, i.e. +4 and +10, have been suggested to be prognostically important. The chromosomal origin of all marker chromosomes and of seven structural rearrangements, one of which was the prognostically important Philadelphia chromosome, could be identified. Five rearrangements [der(1)t(1;14)(q32;q21), der(2)t(2;8)(q36;?), der(3)t(2;3)(q21;?), der(8)t(8;14)(?;?), and t(9;21)(q12;q22)] have previously not been reported in ALL, emphasizing the value of SKY in identifying novel chromosomal rearrangements