Malignant neoplasms
In the overwhelming majority of cases, malignant tumors develop in genetically predisposed individuals, which at some time were affected by environmental carcinogenic factors. The emergence of such forms of cancer is not susceptible to inheritance under Mendel's law( multifactorial or sporadic forms).
Some forms of cancer are caused by mutations in one gene( monogenic) and are inherited according to the laws of Mendel( hereditary or family forms).Hereditary nature have retinoblastoma, neuroblastoma, Wilms tumor, family polyposis of the colon, some forms of breast cancer and many others.
■ Retinoblastoma is a fairly common malignant tumor in children inherited in an autosomal dominant type( 180200, gene RB1, 13q14.1-q14.2) with a penetrance of more than 90%( that is, only 10% of carriers of a mutant tumor growth gene do not).This tumor develops in early childhood from nerve cells of the retina. It is quite difficult to detect a diagnostic mutation. Approximately 85% are single point mutations, which can only be identified by direct molecular genetic methods. In the case of early diagnosis of retinoblastoma and timely treatment, the likelihood of survival and preservation of the vision of the affected eye( eye) is quite high.
■ Family colon polyposis( * 114500, 5q21, APC gene, ED) is characterized by multiple adenomatous polyps of the large intestine. Polyps appear at an early age and are more often localized in the recto-sigmoid region. The gene of the family polyposis of ARS is currently cloned. Hereditary mutations of the APC gene lead to cancer in 100% of cases [Rozen P. et al., 1999].With family polyposis of the large intestine, papillary thyroid carcinoma, brain tumors, sarcomas, small intestine tumors, stomach, hepatoblastoma, pancreatic carcinoma can also be observed. Close relatives of patients with colon polyposis should be examined for mutations in the gene and be under constant medical supervision from the age of 10-12.
■ A family form of breast cancer accounts for approximately 5% of all cases. The main genes of predisposition to the development of breast cancer are BRCA1( 113705, 17q21, ED) and BRCA2.Analysis of chromosome sections containing BRCA1 and BRCA2 genes in tumor samples of patients with hereditary breast cancer revealed losses of normal( unmutated) allele, which allowed classifying BRCA1 and BRCA2 as tumor suppressor genes [Bell DW et al., 2002].In cells lacking BRCA1 or BRCA2 genes, chromosomal abnormalities accumulate, genome integrity control and gene transcription are compromised, they become more sensitive to radiation exposure, which ultimately contributes to chromosomal instability and malignant cell transformation [Davies AA et al., 2001].The isolation of genes responsible for the hereditary predisposition to the breast cancer
has created fundamentally new opportunities for medical genetic counseling and disease prevention. When detection of BRCA1 and / or BRCA2 mutant genes by DNA diagnostics, the risk of breast cancer is 80-90% [Ford D. et al., 1998].Carrying out periodic inspections of carriers of mutations allows to reveal in time the onset of the disease, which ensures effective treatment. A number of studies have shown the high effectiveness of preventive mastectomy in women with the presence of these mutations. Therefore, timely detection of mutations and surgical intervention are currently considered as highly effective methods for the prevention of breast cancer [Grann V. R. et al., 1998;Hartmann L. C. et al., 1999;Rebbeck T. R. et al., 1999].In addition, the prophylactic efficacy of tamoxifen for the risk of developing malignant breast tumors in women with a genetically increased risk of this disease has been proven( Fisher B. et al., 1998).Other genes that predispose to breast cancer are presented in the table.
Table Hereditary syndromes associated with an increased risk of developing breast cancer
Table Hereditary syndromes associated with an increased risk of developing breast cancer
■ Hereditary factors are important in the development of prostate cancer. Approximately 10% of patients have mutations in the genes of a high-risk prostate cancer;in 20-40% - in genes that cause a moderate risk of disease [Schaid D. J. et al., 1998].Recently, a gene of HPC2 has been cloned, a number of mutations of which lead to a high risk of prostate cancer( approximately 10-fold increase with respect to mean-pulse);the other part of mutations increases the risk of disease only by 2-3 times [Tavtigian S. V. et al., 2001].Approximately 5% of cases of a family form of prostate cancer are associated with mutations of the BRCA2 gene, which determines the hereditary predisposition of
to breast cancer. A moderate risk of prostate cancer is associated with the number of triplet GAG repeats in the androgen receptor gene AR, variants of the genes SRD5A2, GST and polymorphism in the ARE1 region of prostate-specific Ar [Gsur A. et al., 2002;Nam R. K. et al., 2001].Promising results have been obtained to investigate the association of prostate cancer with the gene MSR1( SR-A), which is located on chromosome 8( 8p22).
■ MAN.Several types of MEN are known, all of them are inherited in an auto-somno-dominant type. Type I( Vermeer syndrome, * 131100, 11q13, MEN1 gene, ED) is characterized by the development of tumors of parathyroid glands, islets of Langerhans pancreas and pituitary gland. Type IIa( Sipple syndrome, # 171400, 10q11.2, oncogene ret, [164761], ED) and IIb( # 162300, 10q11.2, oncogene RET, ED) is most often manifested by medullary thyroid carcinoma, as well as pheochromocytoma and hyperplasiaparschitovidnyh glands. In developed countries, genetic screening has been widely used to identify susceptibility to the development of medullary thyroid carcinoma, which most often develops within the framework of MEEN IIa( detection of RET mutation mutations).The material for analysis is the patient's blood leukocytes and biopsy material of the thyroid gland. In case of detection of a mutation in peripheral blood leukocytes, one can be sure that in this patient the medullary thyroid cancer is a manifestation of MEN IIa or has a family character. In the absence of a mutation of RET-protooncogene in leukocytes and its presence in the tumor itself, with great confidence one can speak of sporadic medullary thyroid cancer. If the mutation is absent in both leukocytes and in the tumor itself, it is impossible to make a definitive conclusion and it is necessary to observe the patient.
In Table.other frequent hereditary forms of malignant neoplasms and their corresponding genetic disorders are listed. It should be noted that the establishment of the type of mutation in acute leukemia can be used to determine the prognosis of the course of the disease. Thus, in the presence of translocation( 8, 21) in patients with leukemia M2 according to FAB classification, inversion in 16 chromosome with M4 leukemia, translocation( 8, 21) with M3 leukemia good prognosis;while with inversion in chromosome 3 in patients with M1 or M4 leukemias, genetic mutations in 11q23 with M4 and M5 leukemias are poor.
Table Chromosomal abnormalities in various neoplasms
Table Chromosomal abnormalities in various neoplasms
End of Table.
End of Table.