Basics of Medical Genetics - Buzhiyevska T.I. 2001

Hereditary Diseases
Heredity in Onco-pathology

When discussing the clinical course of Primary immunodeficiencies, we noted The Link Between this genetic pathology and carcinogenesis. Tumors are, first of all, molecular diseases of a mutational nature. The genetic program contains numerous genes that encode or regulate Cell proliferation, cell mass increase, and the differentiation of Cells that form specialized Tissues and Organs. These genes (oncogenes and antioncogenes) operate most intensively during embryonic development; regulated by a complex system of expression control, they are differentially switched off when the genetic program shifts after birth. Today, a multitude of oncogenes and antioncogenes (tumor suppressor genes) involved in controlling cell proliferation are known and classified into 4 main groups: 1) genes encoding soluble growth factors (the sis group); 2) genes encoding cell-surface growth factor receptors (the ErbB, fms, neu groups); 3) genes whose products ensure intracellular signal Transduction (the ras, src, abl families); 4) genes encoding Nuclear Proteins involved in METABOLISM/36.html">DNA Replication and Gene Transcription (myc, fos, myb, Rb, Wilms, p53, etc.).

Most commonly, the characteristic of cellular malignancy (loss of differentiation, inability to respond to signals from other cells in the Organism, and uncontrolled proliferation) is caused by a homozygous complex of mutant alleles—that is, the presence of two Mutations at a specific locus on homologous Chromosomes. If both mutations occur in somatic cells, a malignant tumor develops relatively rarely, later in life, because a random mutation in an oncogene (initiation) is followed by a lengthy promotion period required for the similarly coincidental occurrence of a second mutation in the same gene on the homologous chromosome. During the promotion period, cells carrying the first mutation may be eliminated or the mutation may be repaired, preventing tumor formation. Even if such a malignant cell does form, it may fail to produce progeny if the body's immune system recognizes it as non-self and destroys it. Oncogenic Viruses carry pre-formed mutant oncogenes in their genetic program and are capable of inserting them into corresponding sites (replacing or positioning alongside cellular oncogenes via a complementarity mechanism) in both homologues simultaneously, thereby establishing homozygosity. In such cases, oncogenesis bypasses the promotion period, and tumors develop much more rapidly (as seen in HIV infection). This virus simultaneously damages the body's immune cells and causes Acquired Immunodeficiency Syndrome (AIDS), the clinical picture of which is characterized by malignant neoplasms (Kaposi's Sarcoma, malignant lymphoma, and potentially Squamous Cell Carcinoma of the Oral Cavity and adenocarcinoma of the rectum in HIV-infected homosexual men).

Not only acquired but also inherited immunodeficiency states, DNA Repair defects, and Chromosomal diseases are accompanied by blastomogenic processes.

It is also possible to inherit one or two mutant oncogenes from parents during Fertilization. In this scenario, the initiation or both initiation and promotion periods are bypassed, and tumors manifest during the Embryonic period, childhood, or youth. All cells of such an organism—being clones of a single zygote—contain the mutant oncogen. It has been empirically established that one-third of embryonic tumors are hereditary forms.

Retinoblastoma is a malignant neoplasm originating from the neural Cells of the retina, typically diagnosed at 1.5 years of age. The disease manifests with a characteristic whitish reflection of the pupil in the light (cat's eye reflex), a sluggish pupillary light reflex, strabismus, Vision loss, and eventual blindness. Metastases, involvement of the contralateral eye, and tumor calcification are possible. The condition is accompanied by intellectual disability. An autosomal dominant (AD) inheritance pattern with greater than 90% penetrance is described. The retinoblastoma gene is located on chromosome 13q14, and retinoblastoma is associated with microdeletions in this locus. Treatment includes photolaser coagulation, enucleation followed by chemo- and radiotherapy. With timely intervention, Clinical Recovery is achievable.

Nephroblastoma (Wilms' Tumor) is a Kidney tumor accompanied by renal and Urinary Bladder malformations, as well as aniridia. The gene encoding nephroblastoma is located on chromosome 11p13, adjacent to the genes for aniridia, catalase, Lactate dehydrogenase, and all Hemoglobin chains. It exhibits an AD inheritance pattern with 63% penetrance, meaning that 37% of individuals carrying the mutation remain clinically unaffected. DNA-based Diagnostics are available for oncogenetic diseases and the detection of carrier states.

In cases where all cells of the organism harbor a single mutant oncogene inherited from the zygote, the localization of malignant tumors depends on which organ's cells experience the second allelic mutation. Two Types of familial Cancer are described: Type 1 includes tumors of the endometrium, Ovaries, breast, prostate, Pancreas, colon, Stomach, Skin, and Lungs—some of which are part of Li-Fraumeni syndrome, characterized by germline nucleotide substitutions in the p53 antioncogene; Type 2 includes breast cancer, sarcomas, leukemias, Brain Tumors, and Bladder cancer.

Additionally, familial Ovarian cancer exists as a Mendelian pathology associated with a mutation in the erbB-2 gene. Mutations in this same gene have been described in malignant colorectal tumors. In cases of breast cancer, mutations have been identified in the Ha-ras oncogene (involving the p21 protein, specifically an adenine-to-guanine substitution in codon 12).

Geneticists are familiar with hereditary multiple endocrine neoplasia (MEN) syndromes: MEN I (Wermer's syndrome), MEN IIa (Sipple's syndrome), and MEN IIb (characterized by mucosal neuroma syndrome). These Mendelian pathological processes typically feature tumors of the thyroid, pancreas, Parathyroid glands, pituitary, and Adrenal Glands. They exhibit an AD mode of inheritance with very high (nearly 100%) penetrance. The gene responsible for MEN I is localized to chromosome 11q, while MEN II maps to chromosome 10q.

Currently, more than 200 hereditary syndromes are known to feature a predisposition to malignant tumors, including immunodeficiencies, DNA repair defects, and phakomatoses (belonging to the genodermatosis group).

R.F. Garkavtseva (1992) outlines the following MOLECULAR MECHANISMS OF oncogenesis: point mutations in Proto-oncogenes or antioncogenes; chromosomal rearrangements that place a proto-oncogene under the control of a constitutively active promoter; oncogene Amplification (observed up to 34-fold in Lung Cancer); proto-oncogene activation via retroviral insertion; and proto-oncogene activation or somatic mutation driven by chemical, physical, and biological carcinogens. Disruptions in Genomic Imprinting are also possible.

We will not dwell on genodermatoses—genetically determined skin disorders—as they are thoroughly covered in specialized literature. The same applies to Hereditary diseases affecting individual Organ Systems (such as the nervous, cardiovascular, and musculoskeletal systems).