Detailed mapping and loss of heterozygosity analysis suggests a suppressor locus involved in sporadic breast cancer within a distal region of chromosome band 17p13.3

Abstract

The chromosome region 17p13.3 is thought to encode a tumour suppressor gene involved in sporadic breast cancer and other malignancies. Physical ordering of markers has been carried out by a series of multicolour fluorescent in situ hybridisation (FISH) experiments, using isolated yeast artificial chromosomes (YACs) and cosmids. Eight polymorphic markers ordered within this new physical map and one external marker were used to investigate the pattern of loss of heterozygosity in a panel of 40 sporadic breast tumour patients. The data revealed a region of high loss (60%) within distal 17p13.3, defined by markers D17S926, D17S695 and D17S849 which mapped close together. A contig of YACs was constructed physically linking these three markers.

Allelic imbalance at chromosome 17p13.3 (YNZ22) in breast cancer is independent of p53 mutation or p53 overexpression and is associated with poor prognosis at medium-term follow-up

“…British Journal of Cancer (1998) 77(5) YNZ22 allelic imbalance reported in this study (52%) lies within the range (37-65%) previously published by other groups (Chen et al, 1991;Singh et al, 1993;Thorlacius et al, 1993;Comelis et al, 1994;Harada et al, 1994;Ito et al, 1995;Stack et al, 1995). The proportion of cancers with p53 mutation (20%), p53 allele loss (41%), p53 mRNA expression (54%) and overexpression (28%) or p53 protein expression (32%) are similar to the reported series (Cattoretti et al, 1988;Davidoff, 1991;Iwaya, 1991;Kovach et al, 1991;Osborne et al, 1991;Runnebaum et al, 1991;Varley et al, 1991;Vojtesek et al, 1992;Andersen et al, 1993;Barnes, 1993;Friedrichs, 1993;Martinazzi, 1993;Thorlacius et al, 1993;Tsuda et al, 1993;Marks et al, 1994;Bergh et al, 1995;Borressen et al, 1995;Stenmark-Askmalm et al, 1995).…”

“…Given that YNZ allele imbalance is more common than p53 mutation in breast cancer, the independence of YNZ22 allele imbalance from any p53 changes suggests that the greater discriminatory power of the YNZ22 locus as a marker for disease behaviour is not simply due to chance. Emerging mapping data for 17pl3.3 (Stack et al, 1995;White et al, 1996) have suggested two regions: YNZ22 and a more telomeric region (defined by markers D17S926, D17S695, D17S849) may be of interest in human breast cancer. Alongside the HIC-1 (hypermethylated in cancer), ABR and CRK genes (Heisterkamp et al, 1989;Morris et al, 1995;Wales et al, 1995) in this region, 17pl3.3 may carry a gene or genes of both scientific interest and clinical importance in breast cancer.…”

“…Up to two-thirds of tumours may show allelic imbalance at the YNZ22 locus at 17pl3.3 (Mackay et al, 1988;Devilee et al, 1989;Thompson et al, 1990;Chen et al, 1991;Singh et al, 1993;Thorlacius et al, 1993;Cornelis et al, 1994;Harada et al, 1994;Stack et al, 1995) and this finding has been associated with markers of tumour aggression Chen et al, 1991;Merlo et al, 1992;Harada et al, 1994;Ito et al, 1995).…”

“…Although molecular lesions at p53 and at YNZ22 loci occur independently (Coles et al, 1990), it is not clear to what extent allelic imbalance on chromosome 17p telomeric to the p53 locus may reflect direct or indirect involvement of p53 itself. However, there is increasingly strong evidence for potential tumoursuppressor genes telomeric to p53 (Chen et al, 1991;Thorlacius et al, 1993;Comelis et al, 1994;Harada et al, 1994;Nagai et al, 1995;Stack et al, 1995;Wales et al, 1995;White et al, 1996). To test the hypothesis that allelic imbalance at YNZ22 is an independent predictor of poor prognosis in breast cancer and to examine the associations between YNZ22 allelic imbalance and abnormalities of p53, this study examined YNZ22 allelic imbalance, p53 mutation status, p53 allelic imbalance, p53 mRNA expression, p53 immunostaining and clinical outcome with medium-term follow-up.…”

High levels of loss at the 17p telomere suggest the close proximity of a tumour suppressor

“…However, LOH studies in breast cancer have suggested the presence of another tumoursuppressor gene mapped to chromosomal region 17pl3.3 (Coles et al, 1990;Cornelis et al, 1994;Merlo et al, 1994). Our recent work revealed a complex pattern of LOH in this region in breast tumours (Stack et al, 1995). The highest loss (60-70%), and therefore perhaps the most likely site of the putative suppressor gene, was defined by the three most distal 17p markers, D17S926, D17S695 and D17S849, which were mapped and ordered by fluorescence in situ hybridisation (FISH) to a position near the telomere (for physical map of markers, see Stack et al, 1995).…”