Deletion mapping and linkage analysis provide strong indication for the involvement of the human chromosome region 8p12-p22 in breast carcinogenesis

Abstract

Summary We have identified a high frequency of loss of heterozygosity (LOH) on the human chromosome region 8p12-p22 in a panel of microdissected familial (86% LOH) and sporadic (74% LOH) breast tumours. The two most frequently deleted regions were defined around marker D8S1 33 and in a broader centromeric region bounded by markers D8S1 37 and D8S339. We cannot unequivocally characterize the 8p12-p22 loss as an early or a late event in breast carcinogenesis. In parallel, we have performed linkage analysis in four German breast cancer families. A location score greater than 13.67 corresponding to a LOD score of 2.97 at the marker D8S137 has been obtained. Our results considerably strengthen the evidence for a breast cancer susceptibility gene(s) located on the short arm of the chromosome region at 8p1 2-p22.Keywords: breast cancer; breast cancer families; loss of heterozygosity; linkage analysis; chromosome region 8p12-p22; tumoursuppressor geneThe short arm of chromosome 8 is the site of frequent loss of heterozygosity (LOH) in different types of human cancer (Spurr et al, 1995), including prostate (Macoska et al, 1995;Vocke et al, 1996), colon (Yaremko et al, 1994;Farrington et al, 1996), bladder (Takle and Knowles, 1996), liver (Emi et al, 1992), lung (Ohata et al, 1993), ovarian (Cliby et al, 1993), oesophageal (Shibagaki et al, 1994) and breast cancer (Chuaqui et al, 1995; Kerangoueven et al, 1995;Imbert et al, 1996;Yaremko et al, 1996). In several studies, the 8p losses have been mapped to two or more distinct regions in these cancers.Deletion mapping in colorectal cancer has suggested that a region spanning 8p23.2-p22 and a more centromeric region at 8p21.3-pil .2 are lost in more than 50% of sporadic colorectal cancers (Cunningham et al, 1993;Farrington et al, 1996). Similarly, studies in prostate cancer indicate two regions of 8p losses at 8p22 and a more proximal region at 8p2l-pl2 (Macoska et al, 1995;Bova et al, 1996;Vocke et al, 1996). Two independent regions of loss are also supported by mapping data in the other cancers mentioned above. A common region of LOH at 8p2l.3-p22 in colon, lung and liver cancers has been described by Fujiwara et al (1994).Several investigations have found allelic loss of 8p to be associated with a more advanced clinical stage and invasive behaviour

Models of genetic susceptibility to breast cancer

“…Overall, the study found no excess in the number of LOD scores over 1, over that expected by chance, suggesting that all the peaks could be spurious. Other studies have suggested linkage to chromosomes 8p and 13q12-13 regions identified through loss of heterozygosity studies (Kerangueven et al, 1995;Seitz et al, 1997). Neither of these regions was, however, confirmed by either the BCLC study or the Finnish study.…”

Comparative Genomic Hybridization of Microdissected Familial Ovarian Carcinoma: Two Deleted Regions on Chromosome 15q Not Previously Identified in Sporadic Ovarian Carcinoma

“…Losses at 8p21-ter, detected by CGH, were not common in sporadic cancers in the studies of Iwabuchi et al (1995), Arnold et al (1996), and Sonoda et al (1997). There is mounting evidence from the literature that this region harbors an important tumor suppressor gene involved in a range of malignancies (Ishii et al, 1999), including laryngeal tumors (Rizos et al, 1998), prostate cancer (Watanabe et al, 1998), and sporadic female breast cancer Seitz et al, 1997;Wang et al, 1999), as well as male breast cancer (Tirkkonen et al, 1999). One candidate gene for this locus may be the Frizzled-related gene (Ugolini et al, 1999).…”

Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population

“…47 Furthermore, preliminary clinical data suggest, that tumors from Conserved A1 A2 B C D E 3 IVS2-7 Splice 4x 1 1 ? 3 353 A3G Y42C 38x 2 1 1 yes 3 451 G3C A75P 6x 1 1 yes 10 1199 G3C R324T 0x 1 1 yes 10 1206 C3A S326R 7x 1 1 no 10 1239 C3G N337K 0x 1 1 no 10 1379C3T S384F 12x 2 2 no 10 1570 C3T R448C 1x 1 1 no 10 1613 A3G E462G 9x 1 1 yes 11 2192 C3G P655R 23x 1 1 yes 11 2719 A3G V831I 0x 1 1 48 and for 13q21. 49 In summary, the BRCA1/BRCA2 mutation profile established for the German breast/ovarian cancer population facilitates the application of rapid prescreening strategies.…”