It is estimated that approximately 5 - 10 % of breast carcinomas are conditioned by a family genetic burden. The term hereditary carcinoma (HC) is preferred - familial occurrence of tumors does not have to have a real inherited genetic background.

Highly penetrant pathogenic gene mutations are responsible for the emergence of the breast HC . These, under standard conditions, are responsible mainly for regulating individual stages of the cell cycle and corrective mechanisms of the damaged DNA. As a result, they lead to the genomic instability and cumulation of other gene alternations (e.g. fusion oncogenes, inactivation of tumor suppressor genes, amplification of the regulators of cell proliferation, apoptosis, drug resistence etc.). Breast HC may be, moreover, a part of multiple tumor associated syndromes - such as Li-Fraumeni, Lynch, Fanconi anemia, familial diffuse gastric cancer, Cowden syndrome, etc.

The most numerous known, and up to now, the best explored genetic substrate for the breast HC are mutations of the genes BRCA1/BRCA2 which are responsible for about 15 % of all cases. It concerns a relatively "large" tumor suppressor gene with autosomal dominanat type of inheritance. Women carrying BRCA1/BRCA2 gene mutations have a lifetime risk of the occurrence of early breast and ovarian carcinoma (in BRCA1 approximately 85 or 60 % and in BRCA2 85 or 35 %). Men with germ-line mutation of BRCA1 are accompanied by higher incidence of prostate carcinoma whilst BRCA2 mutation is associated with a risk of male breast cancer (lifelong about 40 %). BRCA1/BRCA2 mutations are then in both sexes increasingly connected to the occurrence of other carcinomas, such as melanoma, larynx carcinoma, esophagus, stomach, intestine etc.. Unfortunately, clinically relevant prediction of the carcinoma occurrence in a specific carrier of germ-line mutation is not possible. Even within a high-risk family with a specific BRCA1/BRCA2 gene mutation exist individuals who do not get sick with carcinoma during their life. The offspring of persons with a germ-line mutation of BRCA1/BRCA2 have a 50 % chance to inherit a defective gene. If both parents are the carriers there is a theoretical possibility of transmission of the two pathogenic mutations.

Clinically it concerns breast and ovarian / tube carcinomas that typically manifest before 50th or 40th year of life and are often bilateral or multiple. Variable organ tumor multiplicities are not rare. In comparison with corresponding controls (age, stage) it is obvious that they do not significantly differ prognostically nor biologically from the sporadic carcinomas. In the BRCA1 positive carcinomas totally dominate characteristic triple-negative, basal-like tumours whilst histotype of the BRCA2 positive patients is completely non-specific. The dominant morphology of ovarian / tubal lesions is high-grade serous carcinoma.

Demographic data confirm an indispensable ethnic projection. The prevalence of BRCA1/2 mutation is evident in Ashkenazi Jews and also some specific mutations are bound with population – e.g. BRCA1 in Danes or BRCA2 in Iceland.

From a clinical point of view the two aspects are essential: rational and effective detection of potentional carriers of the BRCA1/2 mutation and following prophylactic - preventive measures and dispensarization of positive individuals.

Selection of the suspected patients to genetic testing is governed locally by diverse algoritms. Economic factors in the context with ethnic-social aspects do not have to be a priority. The most general criteria for selecting probands are follows:

1. early (under 50 years) occurrence of breast / ovarian / tube carcinoma (triple-negative basal-like breast carcinoma at any age ??)
2. bilateral
3. family anamnesis of breast / ovarian / tube carcinoma with the autosomal dominant features of inheritance
4. family anamnesis of breast carcinoma in men
5. synchronous / metachronous tumor multiplicity, mostly in younger individuals

Care of individuals positive for the BRCA1/2 consists in life long dispensarization, prevention of primary manifestation of tumor and possibility of targeted genetic family screening.

A monitoring of the individuals consists of a regular semi-annual radiological examination of breast (mastogram, sonography, MRI) and ovaria / adnexa (transvaginal sonography) together with a monitoring of serum Ca125 and Ca19-9. Prevention includes the possibility of prophylactic mastectomy or adnexetomi with consideration of individual age and reproductive aspects. Surgical intervention decreasing the risk of carcinoma occurrence up to 95 %. Chemoprevention uses a hormonal manipulation with the antiestrogens (tamoxifen, raloxifene) or LHRH analogs (goserelin).

Strategy of the genetic examination is defined in genetic counseling, where are patients with a manifesting carcinoma or their family members referenced on the oncologist referral.Selection of a detection method depends on diverse factors - ethnic, personal and familial oncological anamnesis (localization and type of carcinoma), de novo diagnosis of mutation or genealogical screening etc..For example, in the population of Ashkenazi Jews are primarily investigated 3 specific (prevalent) mutations. Contrary, in the case of the primary detection of mutation in suspect individual, sequencing analysis of the whole gene BRCA1/2 is performed. In a family members of the positive suspect proband is the detection targeted on the concrete germ-line "familiar mutation". Prevalence of the BRCA1 and BRCA2 mutations among a general population is approximately 1:500-1000 or 1-2:1000. The genes BRCA1/2 are relatively large and consist of 24 - 27 exons. In both of them there were found about 800 mutations including 5 extensive specific gene rearrangements in BRCA1. By far not all the alterations are pathogenic. It is estimated that about a half of them are just some polymorfism without the risk of carcinoma formation or still with the unclear clinical significance. In proband with detected, but till now undescribed mutation it is appropriate to examine relatives and try to find its possible pathogenic potencial. The negative result of BRCA1/2 sequencing analysis is necessary to interprete carefully because it does not automatically mean that familial occurrence of malignancy has not a hereditary genetic substrate (till now unknown?!). The reason may be for example, a sensitivity of used testing methodology or alteration of another (unexamined) "susceptible" gene.

Genetic counseling and testing is managed by precise rules which take into account medical, ethic-moral, psychosocial and legal aspects. Examination is possible for individuals over 18 years.

The genetic department of our laboratory offers a routine examination of the BRCA1/2 gene mutation which are the most common known genetic basis of the hereditary breast carcinoma (up to 16 % of all hereditary breast carcinoma). Disorder of the BRCA1/2 genes is combined with the frequent occurrence of ovarian / tube carcinoma. Both of the tumor types may occur together and typically in a younger population (under 50 or 40 years of age).In the carriers (mostly women) of the BRCA1/2 gene mutation there is proven a life long risk of the formation of carcinomas mentioned above, reaching 85 % of breast carcinoma and 65 % of ovarian carcinoma at the age of 70. The defective gene is inherited autosomal dominantly and the offspring have a 50 % chance to get the mutation from a positive parent.

Genetic examination / testing indicates (recommends) an oncologist or a member of genetic counseling in the following cases:

6. early (under 50 years) occurrence of breast / ovarian / tube carcinoma (triple-negative basal-like breast carcinoma at any age)
7. bilateral breast carcinoma or duplicate breast and ovarian / tube carcinoma at any age
8. family anamnesis of breast / ovarian / tube carcinoma with the autosomal dominant features of inheritance
9. family anamnesis of breast carcinoma in men
10. synchronous / metachronous tumor multiplicity, mostly in younger individuals
11. selected blood relatives of the BRCA1 mutation carrier

When detecting a congenital pathogen mutation, these individuals have to undergo a lifelong dispensarization and can take a number of preventive measures (regular breast / internal genitalia investigating regime, prophylactic mastectomy / adnexectomie, chemoprevention, etc). Genealogical research is recommended.

Examination of BRCA1/2 genes

In our laboratory we provide an extensive sequencing mutation analysis of BRCA1/2 genes (upon the initial detection in suspect patient) or a targeted detection of the specific germ-line mutation (relatives of the carrier, selected ethnic group). Mutation analysis of the individuals over 18 years of age is performed from the peripheral blood (1 x 7 ml into the tubes with EDTA).