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PubMed2001

Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways.

BACKGROUND: Ethnicity, when it is used to mean shared genetic inheritance within a group, has become one of the most important factors in determining prostate carcinoma risk. Genetic polymorphisms were hypothesized to be the probable explanation for differences in risk among ethnic groups. The authors evaluated the association between polymorphisms in genes involved in the androgen biosynthesis and metabolism pathway and the risk of prostate carcinoma. METHODS: Two hundred twenty-six patients with the pathologic diagnosis of sporadic prostate tumor and 156 healthy matched (age, ethnic group) male controls from a large epidemiologic cohort were genotyped for previously described polymorphisms in the androgen receptor (AR), 5alpha-reductase type II (SRD5A2), p450c17 (CYP17), and aromatase (CYP19) genes. The different polymorphisms in prostate carcinoma patients also were analyzed according to age of onset, preoperative prostate-specific antigen level, tumor stage, and tumor grade. RESULTS: The distribution of the tetranucleotide simple tandem repeat polymorphism (STRP) in intron 4 of CYP19 was significantly different in control and cancer patients (P = 0.012). The 171 allele and the 187 allele were associated with prostate carcinoma risk (P = 0.05 and P = 0.045, respectively). Conversely, no association was observed between prostate carcinoma risk and the other polymorphisms studied as follow: the CAG repeat in exon 1 of AR, the (TA)n dinucleotide repeat polymorphism in the 3' untranslated region, and the A49T or V89L substitutions in SDR5A2, the single base pair (bp) (a T to C transition) polymorphism that creates an additional Sp1-type (CCACC box) promoter site in CYP17. In prostate carcinoma patients, CAG repeats of AR, and TA repeats of SDR5A2 are associated with age of onset (P = 0.05 and P < 0.001, respectively). CONCLUSIONS: The association between the 171-bp allele of CYP19 and prostate carcinoma risk suggests that aromatase could be used as a new indicator for prostate carcinoma prevention in men of White French ethnogeographic origin. Conversely, it is possible that an individual carries both a high- and a low-risk marker (e.g., CYP17 A2 allele and V89L in SRD5A2) resulting in no overall difference in risk observed across the population. For these reasons, the development of a polygenic model, incorporating multiple loci from the individual genes may maximize the chance of identifying individuals with high-risk genotypes.

Aged↗

PubMed1998

Angiotensin converting enzyme gene polymorphism in coronary artery disease: the Indian scenario.

Angiotensin converting enzyme is a key component of the renin angiotensin system that plays an important role in cardiovascular regulation. It seems to modulate cardiovascular growth by virtue of its role in the conversion of angiotensin I to angiotensin II and degradation of kinins. A deletion polymorphism localized in intron 16 of the human angiotensin converting enzyme gene, corresponding to a 287 bp long Alu repetitive sequence, was found to be associated with increased risk of myocardial infarction in various subgroups, including European, French and Japanese coronary patients. This angiotensin converting enzyme gene I/D polymorphism was examined by the polymerase chain reaction in a cross-sectional study of 201 healthy Indian subjects and 150 patients (angiographically proven cases of coronary artery disease) whose serum angiotensin converting enzyme levels were concomitantly measured. The D/D, I/D and I/I genotypes were found in 20.66%, 46.66% and 32.66% of the Indian coronary heart disease patients and in 23.38%, 49.75% and 26.86% of controls respectively. One of the reasons for not finding an association between the D allele and coronary artery disease in this study could be the ethnic heterogeneity and disease status heterogeneity among the patients and controls. However the phenotypic variance of serum angiotensin converting enzyme levels is strongly influenced by this polymorphism. In the Indian population, the angiotensin converting enzyme gene I/D polymorphism is not associated with risk for coronary artery disease although it is associated with plasma angiotensin converting enzyme activity. Hence the angiotensin converting enzyme gene I/D polymorphism does not seem to be a useful marker for coronary artery disease in the Indian population.

Aged↗

PubMed2002

Endothelial nitric oxide synthase gene and the development of diabetic nephropathy.

BACKGROUND: Endothelial nitric oxide synthase gene and the development of diabetic nephropathy BACKGROUND: Intron 4 insertion/deletion polymorphism of the constitutive endothelial nitric oxide synthase (ecNOS) gene may be related to diabetic nephropathy. METHODS: A case-control study was performed in three groups of Japanese patients with Type 2 diabetes mellitus, which including 123 patients with advanced diabetic nephropathy, 107 patients with overt proteinuria and normal serum creatinine level, and a control group of 203 patients with normal renal function despite having diabetes for over 10 years. Additionally, logistic regression analysis was used to assess the findings. RESULTS: When we examined the a-deletion/b-insertion in intron 4 of ecNOS gene, the genotype and allele frequencies were not significantly different between the patients with advanced diabetic nephropathy (a/a 2.4, a/b 21.9, b/b 75.5, 'a' 13.4, 'b' 86.6%), the patients with overt proteinuria (a/a 2.8, a/b 15.8, b/b 81.4, 'a' 10.7, 'b' 89.3%) and the control group (a/a 1.4, a/b 21.6, b/b 76.8, 'a' 12.8, 'b' 87.7%). Logistic regression analysis showed that the ecNOS intron4 a-allele frequency was not the related to nephropathy (P = 0.88). CONCLUSION: We conclude that there is no association of the ecNOS gene polymorphism with the development of diabetic nephropathy in Japanese patients with type 2 diabetes.

Albuminuria↗

PubMed2003

Association study between the fibronectin gene and schizophrenia.

Fibronectin is one of the cell adhesion proteins. Adhesion molecules play an important role in neural and synaptic genesis, and their dysfunction may result in neurodevelopmental abnormalities, which have been assumed to be a factor in the pathogenesis of schizophrenia. To examine the possible involvement of fibronectin in the etiology of schizophrenia, we analyzed six polymorphisms, located in introns 2, 21, 24, and 26, and exons 20 and 28, in the human fibronectin gene (FN1) of schizophrenic patients in the Japanese population (n = 104) and age-and gender-matched controls (n = 104). No significant positive association was observed between either of the polymorphisms and schizophrenia, nor was an association found between either of the polymorphisms and any subtypes of schizophrenia. These data did not provide evidence for a contribution of the FN1 gene to susceptibility to schizophrenia.

Adult↗

PubMed1999

Gene structure and polymorphism of an invertebrate nitric oxide synthase gene.

Nitric oxide synthases (NOSs) are ubiquitous in living organisms. However, little is known about the evolution of this large gene family. The first inducible NOS to be described from an invertebrate regulates malaria parasite (Plasmodium spp.) development in the mosquito Anopheles stephensi. This single copy gene shows the highest homology to the vertebrate neuronal isoforms, followed by decreasing homology to endothelial and inducible isoforms. The open reading frame of 1247 amino acids is encoded by 19 exons, which span approximately 33 kilobases. More than 50% of the mosquito exons, distributed around the putative heme, calmodulin, and FAD/NADPH cofactor-binding domains, are conserved with those of the three human genes. Repetitive elements identified within the larger introns include a polymorphic dinucleotide repeat, two tandem repeats, and a putative miniature inverted repeat transposable element. Sequence analysis and primer extension indicate that the upstream promoter is 'TATA-less' with multiple transcription start sites within approximately 250 base pairs of the initiation methionine. Transcription factor binding sites in the 5'-flanking sequence demonstrate a bipartite distribution of lipopolysaccharide- and inflammatory cytokine-responsive elements that is strikingly similar to that described for vertebrate inducible NOS gene promoters.

Animals↗

PubMed1993

Detection of a CA repeat polymorphism in the rat class I alcohol dehydrogenase gene.

Differences in the amount of alcohol dehydrogenase (ADH) expressed in liver could play a role in altering ethanol metabolic rates and thus influence alcohol consumption. There is an alternating purine-pyrimidine repeat length polymorphism in the first intron of mouse Adh-1. Mouse strains that lack 101 basepairs of this 288 basepairs alternating sequence express only half as much ADH mRNA and have lower ADH-A2 activity, suggesting that this alternating sequence might modify transcription of the gene. The rat class I ADH gene also has a CA repeat in the first intron. A polymerase chain reaction (PCR) method was used to amplify the CA repeat region in different rat lines to determine whether this CA repeat is polymorphic in the rat and if so, if different length repeats correlate with the drinking behavior of rats selectively bred for high [preferring (P); high alcohol drinking (HAD); Alko, Alcohol (AA) lines] and low [non-preferring (NP); low alcohol drinking (LAD); Alko, Non-Alcohol (ANA) rat lines] alcohol drinking. A CA repeat polymorphism was detected in rat class I ADH of these different rat lines, but there was no difference in the length of the repeat between the high and low drinking rats in each line. Liver ADH activity was also not significantly different between two rat lines that have different CA repeat lengths. Thus, there is CA repeat length polymorphism in the first intron of rat class I ADH, which may be useful in genomic mapping, but it is not associated with differences in ADH activity or drinking behavior in these rat lines.

Alcohol Dehydrogenase↗

PubMed2001

Seven single nucleotide substitutions in human Fc(gamma) receptor IIB gene.

Variation screening for the immunoglobulin G Fc receptor IIB (Fc(gamma)RIIB) gene was performed with the genomic DNA from 100 healthy Japanese subjects. We identified 3 non-synonymous and 2 synonymous substitutions and 2 single-nucleotide polymorphisms in an intron region. These substitutions were found to be located in the ligand-binding domain and the intron, which might alter the function of Fc(gamma)RIIb.

Amino Acid Motifs↗

PubMed2004

Two distinct compound heterozygous constellations (R277X/IVS34-1G>C and R277X/R1511X) in the thyroglobulin (TG) gene in affected individuals of a Brazilian kindred with congenital goiter and defective TG synthesis.

In this study, we have extended our initial molecular studies of a nonconsanguineous family with two affected siblings and one of their nephews with congenital goiter, hypothyroidism, and marked impairment of thyroglobulin synthesis. Genomic DNA sequencing revealed that the index patient (affected nephew) was heterozygous for a single base change of a cytosine to a thymine at nucleotide 886 in exon 7 (886C>T, mother's mutation) in one allele and for a novel guanine to cytosine transversion at position -1 of the splice acceptor site in intron 34 (IVS34-1G>C, father's mutation) in the other allele. The two affected siblings inherited the 886C>T mutation from their mother and a previously reported cytosine to thymine transition at nucleotide 4588 in exon 22 from their father (4588C>T). The 886C>T and 4588C>T substitutions resulted in premature stop codons at amino acids 277 (R277X) and 1511 (R1511X), respectively. In vitro transcription analysis showed that the exon 35 is skipped entirely when the IVS34-1G>C mutation is present, whereas the wild-type allele is correctly spliced. SSCP (exon 7 and 35) and restriction analysis (exon 22) using Taq I indicated that the two affected siblings, the affected nephew, his mother, and his unaffected brother were all heterozygous for the R277X mutation. The two affected siblings, their father, and three unaffected siblings were all heterozygous for the R1511X mutation, whereas the affected nephew and his father were heterozygous for the IVS34-1G>C mutation. Moreover, in this kindred, we have characterized polymorphisms (insertion/deletion, microsatellite, and single nucleotide polymorphism) located within introns 18 and 29 and exon 44 that are associated with the described mutations. Haplotype analysis with these polymorphic markers in two unrelated Brazilian families (present family studied and previously reported family) harboring the R277X mutation suggests a founder effect for the R277X mutation. In conclusion, the affected individuals of this family are either compound heterozygous for R277X/IVS34-1G>C or R277X/R1511X. This observation further supports that thyroglobulin gene mutations display significant intraallelic heterogeneity.

Amino Acid Sequence↗

PubMed2001

Genomic structure of human alpha-pix, and variable deletions in a poly (T) tract in gastric cancer tissue.

PAK-interacting exchange factor (PIX) has been reported to mediate the recruitment of PAK into focal adhesions and activate Rac, thus creating a feedback loop that stimulate PAK and other targets. This pathway is thought to be related to cellular changes, such as transformation and migration, that are often encountered in cancer cells. Here, we report the genomic structure of alpha-PIX, one of the PAK- interacting exchange factors, including the identification of the promoter region, which consisted 772 amino acids in 22 exons, spanning about 100 kb on genome of X chromosome. All splice sites conformed to the GT-AT rule. To investigate the role of alpha-PIX in carcinogenesis, we screened 60 cases of gastric cancer for mutations and polymorphisms using an intron-primer that covered all the exons, but no mutations or polymorphisms were found in the coding region. However an 18 bp repeat of thymidine tract was present in 50 bp downstream from exon 12 and the deletion of variable numbers of mononucleotide repeats was observed in seven out of the 60 gastric cancer tissue specimens that were examined. These seven cases all exhibited a mutator phenotype, suggesting that the deletions are passenger mutations. Thus our results revealed that alpha-PIX probably does not play any primary role in human gastric carcinogenesis.

Alleles↗

PubMed2005

Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype.

BACKGROUND: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the same CF transmembrane conductance regulator (CFTR) genotype, is variable and must therefore be influenced by secondary genetic factors as well as environmental factors. Possible candidate genes that modulate the CF lung phenotype may include proinflammatory cytokines. One such protein is tumour necrosis factor alpha (TNFalpha), a member of the immune system. METHODS: Three polymorphic loci in the promoter (-851c/t, -308g/a, -238g/a) and one polymorphic locus in intron 1 (+691g ins/del) of the TNFalpha gene were typed by a single nucleotide primer extension assay in CF patients and healthy controls. Spirometric data and first age of infection with Pseudomonas aeruginosa were collected retrospectively from patients' medical records. RESULTS: An association was found between the TNFalpha +691g ins/del polymorphic locus and severity of CF lung disease. Patients heterozygous for +691g ins and +691g del were more likely to have better pulmonary function (mean (SD) forced expiratory volume in 1 second (FEV1) 79.7 (12.8)% predicted) than patients homozygous for +691g ins (mean (SD) FEV1 67.5 (23.0)% predicted; p = 0.008, mean difference 12.2%, 95% CI 3.5 to 21.0). Also, patients heterozygous for +691g ins and +691g del were more likely to have an older first age of infection with P aeruginosa (mean (SD) 11.4 (6.0) years) than patients homozygous for +691g ins (mean (SD) 8.3 (4.6) years; p = 0.018, mean difference 3.1 years, 95% CI 0.5 to 5.6). An association was also found with the -851c/t polymorphic locus. In the group of patients with more severe FEV1% predicted, a higher proportion of patients were homozygous for the -851c allele than in the other group of patients (p = 0.04, likelihood ratio chi2, odds ratio = 2.4). CONCLUSION: TNFalpha polymorphisms are associated with the severity of CF lung disease in Czech and Belgian patients with CF.

Adolescent↗

PubMed1995

Distribution of an NcoI polymorphism in the lymphotoxin alpha gene in Dutch patients with inflamatory bowel diseases.

An NcoI restriction fragment length polymorphism in the first intron of the lymphotoxin alpha gene was investigated in 35 patients with Crohn's disease, 40 patients with ulcerative colitis, and 30 unrelated healthy controls, all of Dutch origin. The results showed that no significant differences existed in the genotype frequencies of the NcoI polymorphism in the first intron of the LT alpha gene between ulcerative colitis patients or Crohn's disease patients and the healthy controls. The study indicates that the NcoI polymorphism in the LT alpha gene can not be used as a genetic marker for the predisposition to inflammatory bowel diseases. However, since this polymorphism may control the production of tumor necrosis factor, study of this and other related tumor necrosis factor gene polymorphisms may be used as markers to identify patient subgroups and to define patient heterogeneity. Further studies are being carried out on other polymorphisms and on the relevance of LT alpha and TNF alpha haplotypes.

Alleles↗

PubMed1997

Plasticity of the mitochondrial genome in Podospora. Polymorphism for 15 optional sequences: group-I, group-II introns, intronic ORFs and an intergenic region.

The mitochondrial chromosome of 15 Podospora anserina and one Podospora comata wild-type strains have been extensively examined for the presence of optional elements and for sequence divergence. Among the P. anserina strains, nine optional sequences were found. By comparing P. anserina with the closely related and weakly interfertile P. comata species, six additional optional sequences were detected. These optional elements correspond to mitochondrial introns belonging to different groups and subgroups (11 cases), intronic open reading frames (two cases), a complex insert and an intergenic region. Although difficult to explain, the distribution of optional mitochondrial sequences among the 15 wild-type isolates of P. anserina is far from random.

Ascomycota↗

PubMed1995

Locus-specific amplification of HLA class I genes from genomic DNA: locus-specific sequences in the first and third introns of HLA-A, -B, and -C alleles.

We have identified locus-specific sequences in the first and third introns flanking the polymorphic second and third exons of HLA class I genes. PCR primers derived from these conserved sequences produced DNA fragments of the expected sizes for each of the HLA-A, -B, and -C loci in the amplification of genomic DNA. PCR products generated using each of the locus-specific sets of primers displayed exquisite locus specificity, as assessed by hybridization with oligonucleotide probes specific for ten classical and non-classical HLA class I genes. Amplification with these primer sets was effective and specific for the HLA alleles tested under the given PCR conditions. When hybridized with oligonucleotides derived from shared polymorphic sequence motifs, reaction patterns of PCR products from each locus were precisely as expected from published or database sequences. Chemiluminescent signals generated from digoxygenin-ddUTP-labeled probes were even for all samples and as strong as those obtained in MHC class II typing. These locus-specific primer sets derived from intron sequences provide an effective means to amplify genomic DNA which will facilitate PCR-based HLA class I typing methods. This will also allow HLA class I typing to be conducted with greater precision, at lower cost, and faster than previously described class I typing methodologies.

Alleles↗

PubMed1999

Physical mapping of the serotonin 5-HT(7) receptor gene (HTR7) to chromosome 10 and pseudogene (HTR7P) to chromosome 12, and testing of linkage disequilibrium between HTR7 and autistic disorder.

The gene encoding the serotonin 5-HT(7) receptor (HTR7) has been considered as a candidate locus in several neuropsychiatric disorders, based on pharmacological evidence and ligand-binding studies. After determining over 3 kb of previously unpublished sequence from introns 1 and 2 of HTR7, a single base (C/T) polymorphism in the second intron of HTR7 was found. Allele-specific PCR was used to genotype the HTR7 marker in 53 trios consisting of subjects with autistic disorder and both parents. Using the transmission disequilibrium test (TDT), no evidence of preferential transmission of either allele was found (TDT chi(2) = 0.252, p = 0.602). Sequence data obtained from both intron 1 and intron 2 of HTR7, and from the 5-HT(7) pseudogene (HTR7P), was used to confirm localization of HTR7 to 10q23 and HTR7P to 12p13 using radiation hybrid analyses.

Autistic Disorder↗

PubMed2005

Association of a CAV-1 haplotype to familial aggressive prostate cancer.

BACKGROUND: Multiple lines of evidence have implicated the CAV-1 gene in prostate cancer progression. CAV-1 is located within the prostate cancer aggressiveness locus at 7q31-33, and was identified as being overexpressed in prostate tumors. Mutation screening was performed as well as a case-control study to examine if polymorphisms in CAV-1 are associated with prostate cancer aggressiveness in a German population. METHODS: We sequenced the CAV-1 promoter region and its open reading frame in prostate cancer families with linkage to chromosome 7q31-33. Additionally, 105 unrelated familial prostate cancer probands, 190 sporadic cases, and 191 controls were genotyped at four intronic single nucleotide polymorphisms. Resulting haplotypes were tested for association using age at diagnosis, tumor grade, TNM stage, and follow up information to stratify for aggressive disease. RESULTS: No mutation was found in the CAV-1 coding region or in the promoter. One of the 11 observed haplotypes showed an increased frequency in cases with high tumor stage (P = 0.03). CONCLUSIONS: This is the first report providing evidence for CAV-1 being involved in predisposition to aggressive prostate cancer. The association of a potential risk haplotype agrees well with a role of CAV-1 in tumor progression but needs further confirmation.

Adult↗

PubMed2002

Genetic variation in the apolipoprotein D gene among African blacks and its significance in lipid metabolism.

Apolipoprotein D (APOD, gene; apoD, protein) is a plasma high-density lipoprotein (HDL)-associated glycoprotein, with a putative role in the cholesterol (CHOL) transport pathway. An apoD protein polymorphism has been previously reported by us. The cathodically shifted pattern seen on isoelectric focusing gels, controlled by the APOD*2 allele, was found to be unique to populations of African ancestry. To characterize the molecular basis of the protein polymorphism and to identify new mutations, we used a combination of SSCP, DHPLC and DNA sequencing techniques to screen the entire coding region of the APOD gene. We identified three distinct missense mutations, including Phe36Val, Tyr108Cys, and Thr158Lys with frequencies ranging from 2.1 to 2.8% in 722 African blacks from Nigeria. In addition, a common 8 bp deletion polymorphism was observed in intron 1 with a carrier frequency of 30.1%. The missense mutation, Thr158Lys correlated with the APOD*2 allele of the protein polymorphism. None of the 454 Caucasians screened for these polymorphisms showed any variation. We also determined the effect of these polymorphisms on plasma lipid levels in the African black population by generalized linear model (GLM). The Val36 allele was associated with significantly decreased HDL3-C (P=0.027) and apoA-I (P=0.030) levels among females. The Lys158 allele was associated with significantly increased Lp(a) (P=0.018) and triglyceride (P=0.017) levels, among females and males, respectively. In addition, males heterozygous for both intron 1 and codon 108 polymorphisms showed significantly increased HDL-C (P=0.011), HDL3-C (P=0.041), HDL2-C (P=0.009), apoA-I (P=0.005) and decreased LDL-C (P=0.025) levels. The results of our study show that the APOD gene harbors several polymorphisms, which are unique to African populations. Further study of these polymorphisms may help to characterize the role of apoD in lipid metabolism, and in cardiovascular disease among African populations.

Adult↗

PubMed1993

Two new mutations detected by single-strand conformation polymorphism analysis in cystic fibrosis from Russia.

Single-strand conformation polymorphism (SSCP) analysis followed by direct sequencing of exons containing ATP-binding domains of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was performed on 80 Russian DNA samples. Two new alterations--S1196X (exon 19) and W1282R (exon 20)--and two novel polymorphisms--1525-61 (intron 9) and 1716+12 T-C (intron 10)--were identified. Mutation S1196X changes a TCA codon to TGA and destroys an EcoRI site. Alteration W1282R results from a T-to-C change at position 3976. It was found in one Russian patient and creates an AciI site; however, it is unclear whether this is a disease-causing mutation or a polymorphism. Polymorphism 1525-61 results from an A-to-G change. Alteration 1716+12 T-C was found in a Moldovian patient and creates a new MaeII site. It is not known whether this alteration affects the splicing of the mRNA. The previously described A4002G polymorphism was encountered in approximately 9% of Russian CF chromosomes. In addition, we have found the previously described 3732delA mutation in 7 CF chromosomes, making it the second (after delta F508) most frequent mutation in the Russian population.

Cystic Fibrosis↗

PubMed2003

Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer.

Germline mutations in the BHD gene cause the dominantly inherited cancer susceptibility disorder, Birt-Hogg-Dubé (BHD) syndrome. Individuals with BHD are reported to have an increased risk of renal cell carcinoma (RCC) and of colorectal polyps and cancer. The BHD gene maps to 17p11.2, and to investigate whether somatic inactivation of the BHD gene region is implicated in the pathogenesis of sporadic RCC and colorectal cancer (CRC), we performed mutation analysis in 30 RCC primary tumours and cell lines, and 35 CRCs and cell lines. A somatic missense mutation (Ala444Ser) with loss of the wild type allele (consistent with a two hit mechanism of tumorigenesis) was detected in a primary clear cell RCC, and a further missense mutation (Ala238Val) was identified in a clear cell RCC cell line for which matched normal DNA was not available. A somatic missense substitution (Arg392Gly) was identified in a primary CRC, and the same change was detected in three RCCs (all oncocytomas) for which matched normal DNA was not available. A germline Arg320Gln missense variant detected in a primary CRC was not detected in 40 control individuals or in a further 159 familial and sporadic CRC cases. However, AA homozygotes for an intronic single nucleotide polymorphism (c.1517+6 G-->A) were under-represented in familial cases compared with controls (p = 0.03). For some tumour suppressor genes, epigenetic silencing is a more common mechanism of inactivation than somatic mutations. However, we did not detect evidence of epigenetic silencing of BHD in 19 CRC and RCC cell lines, and BHD promoter region hypermethylation was not detected in 20 primary RCCs. These findings suggest that BHD inactivation occurs in a subset of clear cell RCC and CRC.

Aged↗