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Papillary serous peritoneal carcinoma (PSPC) is histologically indistinguishable from papillary serous ovarian carcinoma (PSOC) with a similar clinical presentation, yet may differ in its carcinogenesis. The purpose of this study was to determine the incidence of allelic loss and the frequency of p53 mutation by p53 overexpression in PSPC compared to PSOC.An allelotype analysis of 26 patients with PSPC was performed using 39 microsatellite markers from 25 chromosomal arms. Thirty-seven previously studied patients with PSOC served as the comparison. P53 mutations were detected by immunohistochemical protein overexpression.There was significantly less LOH in PSPC than PSOC. Both the number of chromosomes with LOH and the proportion of tumors with allelic loss were less frequent. Significant LOH, defined as/=30% of informative tumors having loss at a chromosome locus, was seen on 4 chromosome arms in PSPC: 12p, 17p, 17q, and 18q, compared to 18 arms in PSOC: 4q, 5q, 6p, 6q, 9p, 9q, 12p, 12q, 13q, 15q, 16q, 17p, 17q, 18q, 19p, 19q, 22q, and Xq (P0.001). The median LOH frequency was higher in PSOC than PSPC, 43% versus 33%, respectively (P = 0.013), and more PSOC tumors had LOH than PSPC tumors, 91% versus 65% (P = 0.042). P53 overexpression was detected in 80% of PSPC tumors.LOH occurs less frequently in PSPC compared to PSOC. Chromosomal regions with high frequencies of LOH common to PSPC and PSOC, such as 12p, 17p, 17q, and 18q, may harbor tumor suppressor genes important in the carcinogenesis of both malignancies and likely include p53.

Retrovirus receptors remain a largely unexplored group of proteins. Of the receptors which allow infection of human and murine cells by various retroviruses, only three have been identified at the molecular level. These receptors include CD4 for human immunodeficiency virus, Rec-1 for murine ecotropic virus, and GLVR1 for gibbon ape leukemia virus. These three proteins show no homology to one another at the DNA or protein level. Therefore, work to date has not shown any general relationship or structural theme shared by retroviral receptors. Genes for two of these receptors (CD4 and Rec-1) and several others which have not yet been cloned have been localized to specific chromosomes. In order to assess the relationship between GLVR1 and other retroviral receptors, we mapped the chromosome location of GLVR1 in human and mouse. GLVR1 was found to map to human chromosome 2q11-q14 by in situ hybridization and somatic-cell hybrid analysis. This location is distinct from those known for receptors for retroviruses infecting human cells. Glvr-1 was then mapped in the mouse by interspecies backcrosses and found to map to chromosome 2 in a region of linkage conservation with human chromosome 2. This mouse chromosome carries Rec-2, the likely receptor for M813, a retrovirus derived from a feral Asian mouse. These data raise the interesting possibility that Rec-2 and Glvr-1 are structurally related.

Background Molecular genetic markers to identify the 13% lymph node-negative mammary carcinomas that are prone to develop metastases would clearly be of considerable value in indicating those cases in need of early aggressive therapy. Methods Representational difference analysis was used in an attempt to identify genetic alterations related to breast cancer metastasis by comparing genomic DNA from microdissected normal cells and from metastatic cells of ductal breast carcinoma patients. Results Representational difference analysis products yielded 10 unique metastasis-associated DNA sequences (MADS), i.e. products apparently lost in metastatic cell DNA. Of these sequences, MADS-IX was found to be lost in the transition from primary to metastasis in two out of five ductal breast carcinoma cases. This sequence was localized on chromosome 10q21 by radiation hybrid mapping and fluorescence in situ hybridization. The PTEN gene, which is also located on chromosome 10q, was detected to be present by PCR in all five cases. On the contrary, a breast carcinoma cell line, HCC-1937, which has homozygous loss of a region encompassing the PTEN gene, showed the presence of MADS-IX. PCR screening of three additional breast carcinoma cell lines with known losses in specific chromosomal regions also showed the presence of MADS-IX. Conclusion These data suggest that MADS-IX possibly is part of a novel candidate metastasis-associated gene located close to the PTEN gene on chromosome 10q. The first set of PCR screening in five patient samples indicates that it could be used as a molecular marker for ductal mammary metastasis.

A dinucleotide (T-G) repeat sequence was isolated by comparing DNA from metastatic lymph node and matched normal breast samples from a ductal mammary carcinoma patient using representational difference analysis (RDA) method. Our present study used this metastasis associated DNA sequence (MADS) as a diagnostic probe to screen five patient samples by slot blot method. A new approach to isolate single cells by microdissection, namely single cell microdissection (SCM) was developed to obtain homogeneous population of tumor cells (approximately 1000) from matched primary tumors and corresponding positive lymph nodes of five patients. We isolated DNA from these homogeneous tumor cells and used for the RDA and DNA slot blot experiments. The screening of patient samples showed loss of this MADS in the transition from primary to metastasis in four out of five cases (80%) suggesting its possible role in breast metastasis.

Inactivation of the protein product of the wild-type tumour suppressor gene p53 through complexing of the protein with the E6 oncoprotein of human papillomaviruses (HPV) in HPV-infected cells is thought to be important in the aetiology of cervical carcinoma. Mutations of p53 have also been reported in HPV-negative carcinomas, and we now demonstrate loss of heterozygosity (LOH) of chromosome region 17p13 (in which p53 is located) in such tumours. Immunocytochemical staining with monoclonal antimutant-p53 antibody revealed that the carcinomas with LOH on 17p and completely lacking HPV DNA sequences had mutant p53. Thus the LOH had apparently resulted in the loss of the wild-type allele. Consequently, in both HPV-positive and HPV-negative tumours there is loss of function of wild-type p53, in the former because the protein product of the p53 gene complexes with that of the viral E6 gene, in the latter because the protein is altered, presumably as a result of a direct alteration of the p53 gene but possibly because of other post-translational changes. That this mutant allele of the tumour suppressor gene may sometimes behave like an oncogene is suggested by the presence of more than the expected number of copies of the remaining chromosome 17 homologue in some carcinomas.

Colon polyps - a damaged developmental system and a precursor to cancer, R.L. White familial adenomatous polyposis (FAP) and its gene, APC, W. Bodmer mechanisms of APC-driven tumorigenesis -lessons from mouse models, R. Fodde, R. Smits et al molecular pathology of colorectal cancer, F.T. Bosman genetic predictive testing for bowel cancer predisposition - the impact on the individual, P.D. Chapman and J. Burn familial adenomatous polyposis - from bedside to bench and vice versa, G. Griffioen, H.F.A. Vasen et al hereditary nonpolyposis colorectal cancer (HNPCC), H.T. Lynch clinical implications of genetic testing of hereditary nonpolyposis colorectal cancer, H.F.A. Vasen and J. Wijnen commentary on the current role of human genetics in health care, G.J.B. Van Ommen genome-wide allelotyping indicates increased loss of heterozygosity on 9p and 14q in early age of onset colorectal cancer, T.K. Weber, J. Conroy et al population genomics in Sardinia - a novel approach to hunt for genomic combinations underlying complex traits and diseases, M. Siniscalco, R. Robledo et al leber hereditary optic neuropathy (LHON) - a mitochondrial disease with unresolved complexities, L.N. Went comparative genomic hybridization analysis of hepatoblastomas -additional evidence for a genetic link with Wilms tumour and rhabdomyosarcoma, M. Steenman, G. Tomlinson et al the changing challenges of nomenclature, H. Wain, J. White and S. Povey.

Loss of heterozygosity (LOH) involving 3p occurs in many carcinomas but is complicated by the identification of four distinct homozygous deletion regions. One putative target, 3p14.2, contains the common fragile site, FRA3B, a hereditary renal carcinoma-associated 3;8 translocation and the candidate tumor suppressor gene, FHIT. Using a approximately 300 kb comsid/lambda contig, we identified homozygous deletions in cervix, breast, lung and colorectal carcinoma cell lines. The smallest deletion (CC19) was shown not to involve FHIT coding exons and no DNA sequence alterations were present in the transcript. We also detected discontinuous deletions as well as deletions in non-tumor DNAs, suggesting that FHIT is not a selective target. Further, we demonstrate that some reported FHIT aberrations represent normal splicing variation. DNA sequence analysis of 110 kb demonstrated that the region is high in A-T content, LINEs and MER repeats, whereas Alu elements are reduced. We note an intriguing similarity in repeat sequence composition between FRA3B and a 152 kb segment from the Fragile-X region. We also identified similarity between a FRA3B segment and a small polydispersed circular DNA. In contrast to the selective loss of a tumor suppressor gene, we propose an alternative hypothesis, that some putative targets including FRA3B may undergo loss as a consequence of genomic instability. This instability is not due to DNA mismatch repair deficiency, but may correlate in part with p53 inactivation.

Evidence is presented for the occurrence of a unique opiate alkaloid-selective, opioid peptide-insensitive binding site in N18TG2 mouse neuroblastoma cells and in late passage hybrid F-11 cells, derived from N18TG2 neuroblastoma cells and rat dorsal root ganglion cells. Those cells lacked classical opioid peptide-sensitive receptor subtypes, but contained [3H]morphine and [3H]diprenorphine binding sites with affinity for certain opiate alkaloids but not for any endogenously occurring opioid peptide or peptide analog tested, including D-ala2-D-leu5-enkephalin (DADLE), D-Ala2,N-Me-Phe4,Gly5-ol (DAGO) and dynorphin A(1-17). The binding site differed from hitherto described mu, delta and kappa neuronal opioid receptors not only on the basis of peptide insensitivity, but also on the basis of selectivity and affinities of alkaloids. Saturation experiments with [3H]morphine indicated the presence of a single site with Kd = 49 nM and Bmax = 1510 fmol/mg protein. This novel binding site was not present in F-11 hybrid cells at early passage. Instead the hybrid cells contained conventional opioid receptors (predominantly delta and also mu) capable of binding DADLE and other peptides as well as opiate alkaloids. With additional passage (cell divisions) of the hybrid cells, during which a limited change occurred in mouse chromosome number, the peptide-insensitive binding appeared and the opioid peptide-binding (delta and mu) receptors were lost reciprocally. Thus, expression of the peptide-insensitive binding normally may be repressed when conventional opioid receptors are expressed. The peptide-insensitive opiate binding site described here appears to correspond to the mu 3 receptor subtype, recently identified pharmacologically and functionally in several cell types of the immune system.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies with cell hybrids of normal diploid cells fused with tumorigenic D98AH2 (D98) cells had implicated human chromosome 11 of a normal cell as carrying tumorigenicity suppressing information. The cervical carcinoma-derived D98 (HeLa) cells contain two copies of chromosome 11. In this study, analysis of restriction fragment length polymorphism of DNA from D98 cells digested with one of nine restriction endonucleases and hybridized with five DNA probes for highly polymorphic regions on the short arm of chromosome 11 detected no heterozygosity at the insulin (INS), Harvey murine sarcoma virus 1 (HRAS1), and the β-globin cluster (HBBC) regions. The low probability of an individual being homozygous at all these loci suggests that the Nos. 11 of the D98 cells are both copies of only one of the original homologs, or at least of the short arm segment examined. This indicates that the D98 cells could express altered or lost genes associated with tumorigenicity, even if such changes were recessive. In tumorigenically suppressed hybrids the Nos. 11 of the normal cell could then be complementing this genetic defect of the D98 cells.

Mouse A9 cells, deficient in hypoxanthine phosphoribosyltransferase (EC 2.4.2.8), were fused with normal chick erythrocytes and selected in hypoxanthine-aminopterin-thymidine medium for cells with hypoxanthine phosphoribosyltransferase activity. Recovered hybrid cells produced the chick hypoxanthine phosphoribosyltransferase exclusively, as demonstrated by electrophoretic mobility and immunoprecipitation tests, even though no chick chromosomes or chick cell-surface antigens could be identified in the hybrids. Surprisingly, the expression of the chick hypoxanthine phosphoribosyl-transferase activity in the mouse/chick hybrids required the presence of aminopterin in the growth medium; in its absence, enzyme synthesis decreased markedly. Because of the rapid and reversible modulation of hypoxanthine phosphoribosyltransferase activity, the hybrid cells could proliferate equally well in media containing hypoxanthine-aminopterin-thymidine or 8-azaguanine. Cellular selection was definitely ruled out as a possible cause. These results confirm previous reports that specific genetic information can be selectively transferred from one cell to another of a distant species. Furthermore, they demonstrate that an avian gene, whose activity is normally expressed constitutively, can become facultative when integrated into a mammalian cell. This seems to be the first instance where heterologous gene activity has been shown to be reversibly modulated in hybrid cells.

In the KOP translocation, t(X;14)(q13;q32), virtually the entire long arm of the X has been translocated to the end of the long arm of chromosome 14. Meiotic secondary nondisjunction in a female balanced carrier of the translocation has led to a son with two der(14) or 14-X chromosomes. The normal X chromosome is late replicating in the mother. One of the two 14-X chromosomes is late replicating in the son, with heavy terminal labeling of all but the centromeric end of the chromosome. This suggests that genetic inactivation has spread from the Xq segment of the translocation chromosome to at least two thirds of the segment derived from chromosome 14, and that the remaining proximal segment of chromosome 14 is possibly still genetically active. These findings provide an explanation for the phenotype: Klinefelter syndrome plus a few mild malformations that are sometimes seen in this syndrome but are also seen in duplication of the proximal portion of chromosome 14. Although the proband has a duplication of virtually an entire chromosome 14, 14(pter leads to q32), the phenotypic effect of the autosomal duplication has been mostly nullified by the spread of inactivation.

The sex distribution of 1421 induced abortuses and 2986 newborn infants was correlated with maternal contraceptive histories. Sex of abortuses was determined by chromosome and sex chromatin analyses. No statistically significant differences (P Greater Than 10) were found between the sex ratios either of the fetuses or of the infants of women who used hormonal (oral) contraceptives as compared to those of noncontraceptive controls nor between the induced and newborn series. Also, no correlation was found between sex of the conceptus and total duration of oral contraceptive use, or interval between termination of contraceptive use and conception. Therefore, if the use of low dose oral hormonal contraceptives has an effect on the sex of subsequent offspring, it is likely to be small since the 95% confidence interval for the sex ratios for the oral contraceptive groups divided by the sex ratios of the noncontraceptive group (odds ratio) are 0.80 to 1.22 for induced abortions, and 0.82 to 1.10 for newborns. These conclusions are not in agreement with some earlier reports, generally of small samples, but they are consistent with the results of Rothman and Liess (1976) from a sample of 6109 infants born to oral contraceptive users.The sex distribution of 1421 induced abortuses and 2986 newborn infants was correlated with maternal contraceptive histories. Sex of abortuses was determined by chromosome and sex chromatin analyses. No statistically significant differences were found between sex ratios either of the fetuses or of the infants of women who had used hormonal (oral) contraceptives as compared to those of noncontraceptive controls, nor between the induced and newborn series. Also, no correlation was found between sex of the conceptus and total duration of oral contraceptive use, or interval between termination of contraceptive use and conception. Therefore, if the use of low dose oral hormonal contraceptives has an effect on the sex of subsequent offspring, it is likely to be small since the 95% confidence interval for the sex ratios for the oral contraceptive groups divided by the sex ratios of the noncontraceptive group (odds ratio) are 0.80 to 1.22 for induced abortions, and 0.82 to 1.10 for newborns. These conclusions are not in agreement with some earlier reports, generally of small samples, but they are consistent with the results of Rothman and Liess (1976) from a sample of 6109 infants born to oral contraceptive users.

Biochemical analysis of macromolecular constituents of somatic cells in culture frequently requires the production of large quantities of cells from small initial populations, often a laborious and expensive procedure. Here we show that nude mice, because of their genetic immune deficiency, provide a relatively simple and reliable means of growing large quantities of cells irrespective of the species or tissue of origin. Most established animal cell lines are capable of growing as large tumors in these athymic mice. The passage of mammalian cells in nude mice does not cause either the loss or modification of specific biochemical, chromosomal, antigenic or other cellular markers, nor the induction of malignant transformation of the host cells. Tumors formed by the injected cells grow as localized, encapsulated masses, and host cell admixture due to elements of the vascular system in the tumor is variable but not extensive. Pure cultures of the original cell type can easily be recovered from the tumors if they are derived from previously established cell lines. The use of nude mice for large scale growth of animal cells is particularly advantageous for cell lines which are not adapted to mass suspension culture for highly differentiated functional tumor cells which cannot be grown in vitro.

Chromosome studies of cultured cells derived from endometrial biopsies obtained from 56 healthy women undergoing normal menstrual cycles and two women in the menopause and from five decidual biopsies revealed that 85.0% of the total cells counted (3602) had the modal chromosome number, 11.9% were hypomodal and 3.1% were hypermodal. These results varied only very slightly from counts of cells of chromosomally normal embryos cultured under identical conditions. This distribution of the counts and the fact that karyotype analyses of 608 cells revealed random losses (or, very rarely, gains) of chromosomes in cells from 61 of the 63 cases studied strongly suggest that most of the aneuploid cells result from technical artifacts. Therefore, it is concluded that, in contrast to several older reports but in agreement with some recent reports, the vast majority of endometrial and decidual cells possess a full chromosome complement, even after several cell divisions in vitro.

This simple and reliable 10-min procedure for producing uniformly and intensely stained, as well as fade-resistant, chromosome and sex-chromatin preparations uses pinacyanol chloride as the dye. Slides are extracted in 5 N HC1 at 20-23 C for 2 min, washed in running tap water for 2 min, stained in 0.25% pinacyanol chloride solution (made up in 70% methanol) for 45 sec, differentiated in Wright's buffer solution (pH 6.4-6.5) for 45 sec, washed in running tap water for 5 sec, dehydrated in 2 changes, 1 min each, of absolute tertiary butanol, cleared in 3 changes of xylene, a minimum of 30 sec each, and mounted in a neutral synthetic resin such as Permount.

The deoxyribonucleic acid (DNA) content of Feulgen-stained interphase nuclei from human amnion epithelium and liver parenchyma as well as the DNA content of their sex chromatin or heterochromatic bodies was determined histophotometrically. In female nuclei the ratio between the nuclear DNA content and that of their sex chromatin or heterochromatic bodies remains constant irrespective of the polyploid state of the nucleus. Thus, in polyploid nuclei the heterochromatic bodies double their DNA content with each duplication of the diploid nuclear DNA content. Therefore, it is assumed that the large or multiple heterochromatic bodies of female polyploid nuclei are conjugated or multiple sex chromatin bodies. Some male diploid nuclei show a distinct heterochromatic body whose DNA content is about one-half that of a sex chromatin. About one-half of the polyploid male nuclei have heterochromatic bodies whose DNA content is approximately one-half of those of female nuclei of the corresponding polyploid class. This would indicate that in male diploid nuclei the single X chromosome sometimes leaves a heterochromatic rest one-half the size of a sex chromatin and in polyploid male nuclei the two or more X's may leave larger heterochromatic bodies. However, many male nuclei, even when polyploid, do not have distinct heterochromatic bodies. Possibly the heterochromatic portions of the X's have failed to join and form a sex chromatin-like body; or the Y inhibits the X from leaving a heterochromatic rest. The proposal of other authors that the sex chromatin is derived from but one of the X chromosomes of the female nucleus, the X in the male leaving no heterochromatic rest, is also considered. The DNA content does not vary significantly between nuclei with and without sex chromatin or heterochromatic bodies. It remains clear that female nuclei with abnormally large or multiple sex chromatin bodies and male nuclei with large distinct heterochromatic bodies are always polyploid.

The aim of this study is to determine why, in contrast to expectations based on the Lyon hypothesis, a variable number of nuclei of cells from mammalian females are sex chromatin negative. The frequency of sex chromatin positive nuclei was determined in cell cultures of varying cell densities. The cells were derived from seven chromosomally normal human female embryos, one newborn female with an extra E group chromosome and two normal male embryos. In all cultures of females the frequency of sex chromatin positive nuclei increased linearly from about 35% to 60% at cell densities of less than one cell per 0.01 mm2 of culture surface to 90% to 100% at densities of 20 to 125 cells per 0.01 mm2. This frequency-to-density relationship was independent of the mitotic rate and the rate at which cell density increased. When large variations in cell density were produced intentionally on the same glass coverslip, sex chromatin frequency was related to the density of cells in any one area of a coverslip and seemed to be largely independent of the cell density in other parts of the coverslip. The frequency of sex-chromatin-like bodies of male cultures remained very low at all cell densities. These and other preliminary observations described suggest that, in the nucleus of the female, sex chromatin formation resulting from the condensation of an X chromosome at interphase is not directly related to the mitotic cycle but may be related to the metabolic state of the cell.

Die zellkerne in den Zellen der Septen und groszelligen Inseln der menschlichen Placenta enthalten in Praparaten, die von mannlichen Feten und Neugeborenen stammen, in 73% Sex-Chromatin. Die Septen und die groszelligen Inseln sind dadurch eindeutig als Bestandteile der Placenta materna gekennzeichnet. Fur die groszelligen Inseln sollte deshalb der alte richtige Name Deciduainseln verwendet werden.

IN previous reports from this laboratory it was noted that two or more sex chromatin bodies are present in some female nuclei, particularly in those from amnion epithelium1–3. Barr and Moore4 found multiple sex chromatin in some nuclei from malignant tumours and suggested that this is due to hyper-ploidy. Myers5 described multiple sex chromatin in teratomas. Atkin6 found that 7 out of 65 malignant tumours from females had two sex chromatin-like bodies per nucleus. He assumed that these nuclei were tetraploid and confirmed this with the aid of chromosome counts and estimations of deoxyribonucleic acid. It was of interest to determine if in non-pathological tissue the female nuclei in which we had found more than one sex chromatin body were of a polyploid nature and whether the occasional sex chromatin-like structure in male nuclei could be correlated with polyploidy.

Presumptive monosomy for chromosome 21 was found in a male child with multiple malformations and severe psychomotor retardation. Chromosome analyses of cells from blood and skin samples were performed at intervals during the first few years of his life. In preparations stained with nonbanding as well as quinacrine, Giemsa, and reverse acridine orange banding techniques, only one No. 21 chromosome could be detected with no apparent abnormalities of the other chromosomes. The proband’s phenotypically normal father, paternal grandfather, brother, and paternal aunt have a deletion for a short segment of the long arm of a G-group chromosome. Genetic-marker studies allow the exclusion of a number of blood groups as being associated with No. 21. There is inconclusive evidence suggesting that expression of the Duffy blood group, which has been mapped to chromosome 1, may be influenced by genetic information on chromosome 21. This family is of potential value for further gene-mapping studies.

Excerpt In the last two decades the rapid growth of human genetics has put a burden on its nomenclature. The burden has been particularly heavy in cytogenetics because the field is a hybrid of clas...

The locations of the genes for fibronectin (FN) on chromosomes of human germ line and somatic cells were determined by in situ molecular hybridization with two 3H-labeled DNA probes, one for the region encoding the cell attachment domain of human FN, the other for the 3’ noncoding and part of the coding region. Pachytene chromosomes of two males and lymphocyte chromosomes of one of these males and a female were used. Two regions of hybridization on pachytene and somatic chromosome 2 (p14→p16 and q34→q36) were found, but not in all individuals. A third region of hybridization was found at 11q12.1→ql3.5 in meiotic, but not with significant frequency in somatic chromosomes. It is not clear if these differences between meiotic and somatic chromosomes, and the large differences between individuals at some of the other hybridization sites, resulted solely from technical factors. The differences between the findings in meiotic and somatic preparations might be due to the presence of four strands in pachytene chromosomes versus only one per somatic chromatid. Individual differences in DNA sequences in the chromosome segment containing the gene, differences in gene locations among individuals, or between meiotic and mitotic chromosomes might account for the other findings. The results confirm some of the earlier studies with cell hybrids that mapped FN genes to chromosomes 2 or 11. The combined findings suggest that some of these loci may be coding for the plasma form of FN and others for the cellular form. The expression of the different FN types by differentiated cells might then depend on the loci that are activated.

Overlapping deletions in chromosome 7 of the mouse are responsible for activity deficiencies of various liver-specific enzymes, including tyrosine aminotransferase (TAT). In an effort to elucidate the nature and type of action of the deleted genes, somatic cell hybridization experiments were carried out. Enzyme-deficient liver cells of homozygous mutant mice or normal liver cells of control newborn mice were hybridized with 2S Faza rat hepatoma cells and the hybrid cell colonies were analyzed for TAT activity, The results show the presence of inducible mouse TAT activity in mutant-2S Faza hybrid cells, thereby excluding the possibility that the structural gene for TAT is included in the gene sequences deleted in the mutants. Furthermore, determinations of mouse glucose-6-phosphate isomerase 1 as a marker eliminate chromosome 7 as the possible carrier of the TAT structural gene, which therefore appears to map on a different chromosome. The deletions interfering with normal enzyme activities apparently include genes other than the respective structural genes, namely those with essential functions in controlling the expression of the differentiated state of the liver cell.