Loss of heterozygosity in sporadic parathyroid tumours: involvement of chromosome 1 and the MEN1 gene locus in 11q13.
OBJECTIVE
Hyperparathyroidism (HPT) is a common endocrine disorder. Several loci of genetic interest have been identified in parathyroid tumours, including the MEN1 gene locus at 11q13; the HPT-JT region at 1q21-q32; and a putative tumour suppressor gene on 1p. We analysed these intervals, which harbour known genes or putative loci associated with familial hyperparathyroidism, in order to clarify the involvement of the respective regions in parathyroid tumourigenesis.


METHODS
We performed loss of heterozygosity (LOH) studies on 33 sporadic parathyroid tumours using a PCR based technique. A total of 22 microsatellite markers were used to analyse loci at 11q13, 1q21-q32 and 1p. Ten markers located distal on 1p, eight markers encompassed the HPT-JT region at 1q21-q32 and four markers surrounded the MEN1 gene locus at 11q13. MEN1 mutations were screened for using Single Strand Conformation Polymorphism analysis (SSCP) and automated sequencing of SSCP variants.


METHODS
Thirty-three parathyroid glands and the corresponding blood samples were obtained from 33 patients (26 females and seven males) who underwent parathyroidectomy for primary hyperparathyroidism.


RESULTS
Loss of heterozygosity was detected in 13 of 33 (39%) cases at 11q13, 6 of 33 (18%) cases at 1p, and in three of 33 (9%) cases at 1q (in conjunction with 1p loss). Only one of the 18 tumours in which LOH was detected, showed LOH at both chromosome 1 and chromosome 11. Additionally, those tumours found to exhibit LOH at 11q13 were screened for MEN1 mutations using single strand conformation polymorphism analysis (SSCP) and automated sequencing. Nine novel somatic mutations were found on the remaining allele in 13 (69%) tumours.


CONCLUSIONS
This study consolidates the role of multiple loci in the pathogenesis of sporadic parathyroid tumours. The results indicate that there are at least two genetic loci involved in sporadic parathyroid tumourigenesis on chromosome 1, one of which has been linked to the distinct familial parathyroid condition, hyperparathyroidism-jaw tumour (HPT-JT) syndrome. The high frequency of loss of heterozygosity at 1p suggests the presence of a tumour suppressor at this locus.
Cancer Genetics Unit, Kolling Institute of Medical Research, University of Sydney, Australia.
T
T
Dwight
S
S
Twigg
L
L
Delbridge
F K
FK
Wong
F
F
Farnebo
A L
AL
Richardson
A
A
Nelson
J
J
Zedenius
J
J
Philips
C
C
Larsson
B T
BT
Teh
B
B
Robinson
D000236:Adenoma / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010282:Parathyroid Neoplasms / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins
C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins