Bilateral breast cancer (biBC) is a common form of breast cancer; however, it has not been subjected to systematic comparative genetic studies. We allelotyped 28 biBCs on 14 chromosomal arms, addressing 2 lines of questions: (

Dear Sirp53 codon 72 Arg/Pro polymorphism appears to be one of the most promising low-penetrance candidates for breast cancer predisposition. Indeed, p53 Pro allele is among a very few genetic variants, which retain the unfavorable significance upon the systematic meta-analysis of breast cancer polymorphic genes. 1 In addition, there is sound biological evidence arguing for the functional difference between Arg and Pro alleles. These variants have the distinct ability to mediate HPV E6 protein degradation, activate transcription of p53-responsive genes, induce apoptosis and suppress malignant transformation in at least some experimental systems. 2-4 Furthermore, p53 codon 72 polymorphism may be a subject of natural selection by the level of sun exposure, as its frequency gradually changes with latitude. 5 In recognition of the crucial impact of the p53 gene in tumor development, the epidemiology of the Arg/Pro allele variations was tested intensively for all major cancer types, including lung, cervical, colorectal, bladder and other neoplasms. Unfortunately, none of the reported gene-disease associations demonstrated consistency in the literature. 2,4,6 -9 Despite promising assumptions, the role of the Arg/Pro allelism in breast cancer susceptibility was examined in only a few reports and some of these had a very small number of observations. 10 -15 We have re-assessed the hypothesis on involvement of p53 polymorphism in the determination of breast cancer risk. In addition to a traditional comparison of breast cancer patients (n ϭ 448; mean age ϭ 55.4 years; age range: 29 -83 years) and healthy female donors (n ϭ 249; mean age ϭ 38.5 years; age range: 18 -54 years), we attempted to increase the demonstrability of the study by invoking the subjects with extreme degrees of either breast cancer predisposition or cancer tolerance. In particular, we also genotyped 81 bilateral breast cancer patients (mean age at onset of the first tumor: 49.5 years; age range: 30 -85 years; mean age at onset of the contralateral tumor: 56.5 years; age range: 37-87 years) as well as 144 elderly tumor-free women (mean age ϭ 79.5 years; age range: 75-90 years). Histologically confirmed cases of unilateral and bilateral breast cancer were collected in N.N. Petrov Institute of Oncology (St.-Petersburg, Russia). Female donors were randomly recruited from the blood transfusion unit located in the same hospital; a medical permit to donate blood was considered to be sufficient proof of their healthy status. Elderly tumor-free women were enrolled from various hospitals of St.-Petersburg; results of the current clinical examination, previous records of health professionals and information obtained by questionnaires were taken into consideration to ensure the lack of cancer history for elderly subjects. All affected and non-affected subjects were Caucasians of Slavic origin residing in St.-Petersburg, Russia. Peripheral leukocytes were the source of normal DNA for unilateral breast cancer patients as well as for middle-aged and elderly contro...

Thus, CYP19 polymorphism might be one of the genetic risk factors for endometrial cancer development.

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Association between the rate of apoptosis and expression of the several relevant molecules (Bcl-2, pro-and active caspase-3, and caspase-7) was studied in 61 primary breast carcinomas. The rate of apoptosis detected both morphologically and by the TUNEL assay appeared to be high in 18 (30%), moderate in 14 (23%), and low in 29 (48%) carcinomas. High apoptotic index was strongly associated with advanced tumor grade and estrogen receptor positive (ER+) status but not with other investigated clinical or morphological parameters. Among the molecules studied, only the Bcl-2 protein expression demonstrated strong (inverse) correlation with the apoptotic index (p = 0.032). The data of this expected correlation was served as internal control in the study. Interestingly, high levels of the anti-apoptotic protein Bcl-2 was frequently co-incident with increased expression of pro-apoptotic molecules, such as active caspase-3 (p = 0.004) and caspase-7 (p = 0.001). However, expression of caspase-3 or caspase-7 did not show correlation with the extent of apoptosis or any clinico-morphological features, except overrepresentation of ER+ status in tumors expressing caspase-3 (p = 0.009). Thus, these findings indicate a general dysregulation of spontaneous apoptosis in primary breast tumors.

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MSI-H is detected with a noticeable frequency in bilateral but not in unilateral breast cancers. Preferable occurrence of MSI-H in second metachronous tumors from biBC patients allows to hypothesize that the development of some contralateral breast neoplasms is casually related to the adjuvant treatment of the initial malignancy.

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