Loss of heterozygosity on chromosome 13q ...

Breast Cancer Research and Treatment 83: 143–148, 2004. © 2004 Kluwer Academic Publishers. Printed in the Netherlands.

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Loss of heterozygosity on chromosome 13q: suggestion of a candidate tumor suppressor gene in sporadic breast cancer Dan Tong1 , Eva Schuster1 , Klaus Czerwenka2 , Sepp Leodolter1,3 , and Robert Zeillinger1,3 1 Department

of Obstetrics and Gynecology, Division of Gynecology, 2 Department of Clinical Pathology, University of Vienna; 3 Ludwig-Boltzmann Institute for Gynecology and Gynecological Oncology, Vienna, Austria

Key words: LOH, 13q, sporadic breast cancer, tumor suppressor gene

Summary In order to corroborate the assumption that a candidate tumor suppressor gene is located on chromosome 13q21–22 between D13S1313 and D13S162, we examined loss of heterozygosity of six microsatellite markers in this region in 98 sporadic breast tumors. Our data demonstrate that loss of heterozygosity at 13q21–22 is not solely caused by genetic changes in BRCA2, but is also attributable to another gene in this region. There is strong indication of a new tumor suppressor gene located between D13S1313 and D13S162, most probably adjacent to D13S1308, which could play a role in sporadic breast cancer.

Introduction Chromosomal deletion frequently occurs in cancer cells. The recurrent loss of heterozygosity (LOH) at certain loci indicates the existence of tumor suppressor gene(s) at these loci. Tumor suppressor genes act in a recessive way since the occurrence of the tumor seems to require complete loss of the gene expression. Indeed, loss of function of tumor suppressor genes is often accompanied by mutational or regulatory inactivation of one allele and consequently loss of the wild type one. This inactivation of both copies of the gene fit the tumor suppressor hypothesis [1]. In breast cancer, alterations on chromosomes are frequently observed [2–4]. So far, two tumor suppressor genes, BRCA1 and BRCA2, which are involved in hereditary breast and ovarian carcinomas, have been identified and characterized. They are located on chromosome 17q21 and 13q12–13, respectively [5, 6]. BRCA1 and BRCA2 account for most families segregating early-onset breast and ovarian cancer. However, a significant proportion of hereditary breast cancer can still not be explained by the two known major susceptibility genes. In addition, the implication of

these two genes in sporadic breast cancer remains largely unknown. Consequently, there is the hypothesis of the existence of other tumor susceptibility genes. A population-based study supplied evidence for such genes, in addition to BRCA1 and BRCA2 [7, 8]. Several candidate regions potentially harboring such genes have been reported using linkage and mutational analysis, including 6q25, where the estrogen receptor gene is located [9], and 8p12–22 [10]. Using mathematical models and targeted linkage analysis, a recent study on breast cancer families lacking germ line mutations in the BRCA1 and BRCA2 genes, demonstrates that a putative candidate predisposition gene lies at 13q21–q22 [11]. To investigate if this region might also be involved in the initiation and development of sporadic breast cancer, we analyzed LOH of six microsatellite markers (D13S1296, D13S1308, D13S1257, D13S1303, D13S791, and D13S162) at this region, and LOH affecting BRCA1 and BRCA2 in 98 sporadic breast carcinomas. The results were correlated with histopathological data, age of the patients and the status of the estrogen receptor and progesterone receptor.

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D Tong et al. Table 1. Histopathological characteristics of 98 sporadic breast tumors and patients Number of samples

LOH of BRCAX Yes

No

p

Histological type Infiltrating ductal carcinoma Infiltrating lobular carcinoma

78 20

21 4

57 16

NSa

Differentiation grade G1 G2 G3

7 63 28

0 16 9

7 47 19

NS

Tumor size pT1 pT2 pT3 pT4

39 51 3 5

10 12 1 2

29 39 2 3

NS

Nodal status pN0 pN1

57 41

14 11

43 30

NS

ER positive negative

79 19

19 6

60 13

NS

PgR positive negative

58 40

14 11

44 29

NS

Age