Candidate tumour suppressor genes at 11q23–q24 in breast cancer: evidence of alterations in PIG8, a gene involved in p53-induced apoptosis

Abstract

One of the most consistently deleted chromosomal regions in solid tumours is 11q23 ± q25, which consequently has been postulated to harbour one or more tumour suppressor loci. Despite large eorts to identify the responsible genes, the goal remains elusive, but as knowledge accumulates new candidates are emerging. The present study was undertaken in an attempt to assess the possible implication of four genes residing at 11q23 ± q24, in a population of early onset breast cancer (n=41). The coding sequence of PIG8, CHK1, LOH11CR2A and PPP2R1B were screened for mutations using the protein truncation test or single-strand conformational polymorphism, in combination with direct DNA sequencing. Varying proportions of alterations were detected, ranging from 6% in PPP2R1B to 39% in PIG8. Many of these changes were deletions, in some cases corresponding to complete exons, thus likely to represent splice variants, while others were presumed to arise from aberrant splicing, since they occurred at sites with resemblance to exon/intron borders. Considering only bona ®de mutations, the highest alteration frequency (17%) was again found in PIG8. Most of these alterations were likely to have an adverse impact on the translated protein as they either altered the reading frame or aected phylogenetically conserved residues. Our data represent the ®rst evidence of alterations in the PIG8 gene in human malignancies, a ®nding that substantiates its role as a potential tumour suppressor gene as suggested by its involvement in p53-induced apoptosis. Oncogene (2001) 20, 7753 ± 7760.

Inactivation of CHEK1 and EI24 is associated with the development of invasive cervical carcinoma: Clinical and prognostic implications

“…However, in PTT analysis, mutation in EI24 was detected in 17% (7/41) of the breast cancer samples. 19 Sequencing analysis of the exons also revealed the presence of major alleles only in the SNPs present in CHEK1 exon 10: rs34097480 (G/A), rs2847422 (C/T) and EI24 exon 3: rs11538202 (A/G), rs1043914 (G/C). However, more samples should be analyzed to find out the association of these SNPs with this tumor.…”

“…16,18 PTT analysis revealed 9% mutation of this gene in breast cancer. 19 However, no such association of LOH11CR2A with CACX has yet been reported. Within 1.5 Mb telomeric to LOH11CR2A lies a cluster of candidate TSGs, such as ROBO3, ROBO4, EI24 and CHEK1.…”

“…23,24 The Bcl-2-binding domain of EI24 is encoded by the exons 3, 4 and 5. Frequent mutation (17%) of EI24 is reported in breast cancer 19 and is suggested to be associated with tumor invasiveness. 24 However, involvement of EI24 in CACX is not yet studied.…”

PIG7/LITAF gene mutation and overexpression of its gene product in extramammary Paget's disease

“…It is yet unclear whether PIGs may act as tumor-suppressor genes or not. Gentile et al 6 reported that 16 (39%) of 41 primary breast cancers contained either deletion or single-base substitutions in PIG8. The study did not show whether the other allele of the PIG8 locus was lost or mutated or whether its mRNA or protein level was altered.…”

“…Among 108 candidate cancer-related genes, we focused on PIG7/LITAF for the following reasons: (i) higher expression of it was observed in 3 of 4 EMPD lesions examined, indicating that it could be involved in the common EMPD carcinogenesis pathway; (ii) mutation or dysfunction of other PIG genes has been suspected in human internal cancers; [5][6][7] and (iii) it was identified as the causative gene for CMT1C, which is an autosomal dominant disease with peripheral nerve degeneration, and its mutation is implied to cause aberrant proliferation and apoptosis in Schwann cells. 8 Considering PIG genes are the important mediators in the p53-induced apoptotic pathway, 9 PIG7/LITAF could be a candidate gene for involvement in EMPD carcinogenesis.…”