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At least 199 records · Page 11Linked to original sources
PubMed2005

ERCC1 codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer.

PURPOSE: The aim of our study was to assess whether the polymorphism of the nucleotide excision repair enzyme, excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), had an effect on the tumor response in patients treated with standard chemotherapy regimens for a metastatic colorectal cancer. We have studied the synonymous polymorphism that causes a single nucleotide change C to T at codon 118 converting a codon of common usage (AAC) to a less used codon (AAT), both coding asparagine. This change results in a decreased ERCC1 gene expression, which impairs repair activity. EXPERIMENTAL DESIGN: Ninety-one patients with a median age of 55.1 years treated for a metastatic colorectal cancer were included in our retrospective study. The ERCC1 polymorphism was analyzed in the normal tissue of all patients. RESULTS: Twenty (22%) were homozygous for AAC codon (C/C genotype), 30 were (33%) homozygous for AAT codon (T/T genotype), and 41 (45%) were heterozygous (C/T genotype). The objective response rate to oxaliplatin in combination with 5-fluorouracil (5-FU) was significantly higher in the T/T genotype group compared with the C/T and the C/C genotype groups (61.9%, 42.3%, and 21.4%, respectively; P = 0.018). By contrast, no significant difference was observed when patients were treated with either 5-FU alone (45%, 29.2%, and 33.3%, respectively; P = 0.407) or in combination with irinotecan (46.1%, 25.0%, and 27.3%, respectively; P = 0.305). CONCLUSIONS: Our observations allowed us to define the first useful predictive criterion for oxaliplatin/5-FU response in patients with metastatic colorectal cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Detection of genetic alterations in the human gastric cancer cell lines by two-dimensional analysis of genomic DNA.

We examined genomic DNA from each of three human-derived gastric cancer cell lines, using the technique of restriction landmark genomic scanning (RLGS) which allows monitoring of approximately 2, 000 NotI landmarks. The resulting DNA spots from cancer cell DNA were compared with those in normal mucosa or gastric primary tumor. In all, 9 intense spots were detected from two of the three cancer cell lines. Two highly intensified spots were common in the two cancer cell lines and proven to be originated from DNA region containing the human c-myc proto-oncogene on chromosome 8. The degree of amplification of c-myc DNA was similar to each other and was estimated to be 60-fold as compared to those from normal mucosa DNA. On the basis of chromosome-assigned RLGS (CA-RLGS), other spots were assigned to each chromosome, such as one on chromosome 8, two each from chromosome 20, and three on one of chromosome 9-12. The remaining spot seems to be due to demethylation of a repetitive element. Twenty-four spot that were lost due to either homozygous deletion or methylation on corresponding NotI cleavage sites were commonly observed in all cancer cells. These spots were also assigned to each chromosome: one each from chromosome 2, 6, 7, 13, 14, 16, and 20, two each from chromosome 3 and 5, and nine from chromosome 9-12 by CA-RLGS. Many of the multi-copy spots corresponding to ribosomal RNA genes were greatly decreased due mainly to methylation on CpG islands along with minor rDNA variants, indicating that only minor rRNA genes may be silenced in these cancer cells. These results show that the present alterations detected by RLGS might be useful for identification of candidate genes inactivated or expressed unexpectedly in tumor development and tumor progression in the stomach.

Base Sequence↗
PubMed2006

The mismatch repair gene hPMS2 is mutated in primary breast cancer.

Mismatch repair (MMR) genes play a fundamental role in the correction of replication errors and their mutation leads to cancer development. In the present study we have analyzed the hPMS2 MMR gene for mutation using 20 primary breast cancers and seven breast tissues obtained from areas adjacent to breast cancer. For this purpose we have used cDNA sequence analysis and Western blotting using the specific antibody against the amino-terminal domain E-19. In primary breast cancers we found that the hPMS2 gene had 9 missense mutations [codons: 513 (by change of Ser x Asp) in 14 tumors, 520 (Ala x Val) in 8 tumors, 573 (by change of Thr x Ser in 19 tumors), 578 (by change of Arg x Leu in 9 tumors), 587 (by change of Ser x Asp in 7 tumors), 590 (by change of Ile x Leu in 12 tumors), 598 (by change of Gln x His in 5 tumors), 601 (by change of Ser x Leu in 13 tumors), 608 (by change of Ala x Ser in 9 tumors. Nine out of 20 breast cancers had a non-sense mutation in nucleotide 1862 by changing Adenine by Thymine (AAG x TAG), which corresponded with a change in codon 613 by a change of Lys by stop codon. This non-sense mutation is responsible for the premature truncation of the protein hPMS2, which is reflected in the Western blotting by two bands, one corresponding with the wild-type form (100 kDa) and a lower one (75 kDa) corresponding with the truncated form of the hPMS2 MMR protein. This truncated protein and the mutations in the hPMS2 gene were also detected in two samples of normal-appearing tissue adjacent to their corresponding cancerous lesion. Altogether the present report demonstrates that primary breast cancers harbor mutations in this MMR gene and that normal-appearing breast tissue adjacent to the primary lesion also harbors the same mutations before the neoplastic process is manifested.

Adenosine Triphosphatases↗
PubMed1997

Quantitative polymerase chain reaction-based homogeneous assay with fluorogenic probes to measure c-erbB-2 oncogene amplification.

We describe a PCR-based assay for determining c-erbB-2 oncogene amplification in breast cancer in which we use the TaqMan system. Two fluorogenic probes anneal to the target between primers for c-erbB-2 and beta-globin genes and contain both a reporter dye (6-carboxy-fluorescein) and a quencher dye (6-carboxy-tetramethyl-rhodamine). During the extension phase of the PCR cycle, the 5'-->3' exonuclease activity of Taq polymerase cleaves the hybridized fluorogenic probe, resulting in an increase of fluorescence emission of the reporter dye that is quantitative for the amount of PCR product and, under appropriate conditions, for the amount of template. Assay performance showed adequate precision and a lower detection limit and good correlation with the results obtained in the same samples by a competitive PCR assay (n = 25, r = 0.94, P < 0.01). This homogeneous assay is time-saving, avoids usually cumbersome postamplification procedures (that can be additional sources of inaccuracy and contamination), and seems suitable for determination of c-erbB-2 oncogene amplification in tumor specimens.

Base Sequence↗
PubMedDate not supplied

Hypermethylation of HpaII recognition sequences within the 5' coding region of the estrogen receptor gene is not associated with estrogen receptor negativity in primary breast tumours.

Estrogen receptor negative tumours are unable to respond to antiestrogen therapy. The underlying molecular mechanisms of estrogen receptor negativity are poorly understood. Cytosine mechylation is one of the mechanisms of gene control and previous studies, particularly on breast tumour derived cell lines have suggested that hypermethylation of HpaII recognition sequences within the 5' coding region of estrogen receptor may be responsible for gene inactivity. This study has examined the methylation status of HpaII recognition sequences in estrogen receptor positive and negative breast tumours taking into account a polymorphic HpaII site in the 5' coding region of the estrogen receptor gene. It is concluded that hypermethylation of one or more of the 4 or 5 HpaII recognition sequences in the 5' coding region of estrogen receptor is not associated with ER negativity in primary breast tumours.

Adenocarcinoma↗
PubMed1990

[Nuclear DNA content in tumors of the colon and rectum. Relationship between ploidy and site of the neoplasm].

The DNA distribution pattern was determined 30 colo-rectal carcinomas. The DNA content in individual cells was measured according to a cytophotometric method based on light transmission measurement of Feulgen-stained nuclei. The DNA non diploid carcinomas were significantly more common from the left (descending and sigmoid) colon and rectum (P = 0.0002). No relationship existed between DNA pattern and age, sex, Dukes' stage, tumor grade.

Adenocarcinoma↗
PubMed1996

An integrated microsatellite length analysis using an automated fluorescent DNA sequencer.

Analyzing microsatellite instability (MI) in malignant tumors is thought to be useful for screening cancer patients to identify those patients with a higher risk of developing second malignant tumors. In this paper, we report a new, accurate, and efficient method of detecting MI using an automated fluorescent DNA sequencer and a computer that automatically calculates the size, height, and area of each fluorescent product, making it possible to assess MI more accurately and more rapidly. The primers for amplification of each microsatellite locus are labeled by two different fluorescent dyes, rox (red) and fam (blue). The rox-labeled primer was used for the tumor, whereas the fam-labeled primer was used for the corresponding normal tissue. Two amplified products from both the tumor and the normal tissue were co-loaded into a single lane of the sequencing gel and were analyzed. MI could be detected based on the presence of different waving patterns. Furthermore, several loci could also be analyzed simultaneously for MI in a single lane. Using this method, we examined the frequency of MI in gastric cancer. The results showed that 5 of 22 (22.7 %) gastric cancers were MI-positive, which corresponds to the findings of previous reports that used the radioisotopic method. The improved method may open up the possibility of performing routine examination of MI in many cancer patients and offers hope for the potential clinical application of Ml analysis as a follow-up evaluation of cancer patients.

Chromosome Aberrations↗
PubMed2001

Expression profile of nine novel genes differentially expressed in hepatitis B virus-associated hepatocellular carcinomas.

Chronic hepatitis B virus (HBV) infection is known to be one of the major causes in the development of hepatocellular carcinoma (HCC), although the biomolecular mechanism(s) involved remain unclear. To identify the cellular gene(s) involved in HBV-associated hepatocarcinogenesis, we used the mRNA differential display method and examined three paired tumor and nontumor tissues, all of which had chromosomally integrated HBV-DNA through chronic infection. Using 240 different combinations of three one-base anchored oligo-dT primers and 80 arbitrary 13-mers, genes decreased or increased in expression more than twofold between each tumor tissue and its paired nontumor tissue were identified. Twenty-nine known genes and four novel genes were differentially over-expressed in the HCC tumor tissues. In contrast, 27 known genes and five novel genes were under-expressed in those tumor tissues. The nucleotide sequences of the nine novel gene fragments were determined and their expression patterns were examined in 40 HCC samples. HA61T2, PT18, HG63T1, and HG57T1 were preferentially over-expressed in 32 cases (80%, P<0.001), 24 cases (60%), 23 cases (57.5%) and 22 cases (55%) of the 40 tumor tissues, respectively. There was an increased frequency of HG57T1 over-expression in HCC patients with HBV-positive serology and low serum alpha-feto protein (AFP) levels (P<0.05). DNT10, PT8, PT19, ENT25 and HA6T4 were under-expressed in 26 cases (65%), 23 cases (57.5%), 21 cases (53%), 20 cases (50%) and 18 cases (45%) of the 40 tumor samples, respectively. There was a strong correlation of DNT10 under-expression with high serum AFP level in HCC patients, irrespective of HBV serology (P<0.01). HA6T4 was preferentially under-expressed in HCC tumors in patients with HBV-positive serology and high serum AFP levels (P<0.05). Thus, the functional analyses of the known and novel genes identified in this study should prove valuable to further understand the mechanism(s) of hepatocarcinogenesis.

Base Sequence↗
PubMed1994

Allelotype of uterine cancer by analysis of RFLP and microsatellite polymorphisms: frequent loss of heterozygosity on chromosome arms 3p, 9q, 10q, and 17p.

Cancers in which mutations have been identified in putative tumor suppressor genes, such as the TP53 gene, the retinoblastoma (RBI) gene, the adenomatous polyposis coli (APC) gene, and the Wilms tumor (WTI) gene, frequently show loss of the corresponding allele on the homologous chromosome. To identify locations of tumor suppressor genes involved in uterine cancer, we examined loss of heterozygosity (LOH) by using genomic probes detecting RFLPs in 35 uterine cancers at 29 loci throughout the genome, and with highly informative microsatellite markers in 21 uterine cancers at nine putative or known tumor suppressor gene loci. High frequencies of allelic loss found at loci on 3p (71%), 9q (38%), 10q (35%), and 17p (35%) suggest that tumor suppressor genes involved in uterine carcinogenesis exist in these regions. There were no significant differences in frequencies of LOH between cancers of the uterine cervix and cancers of the uterine endometrium at any of the loci tested.

Adenocarcinoma↗
PubMed1990

Newly established human retinoblastoma cell lines exhibit an "immortalized" but not an invasive phenotype in vitro.

Retinoblastoma (RB), an intraocular childhood tumor occurring in a hereditary (mostly bilateral) or non-hereditary (unilateral) form, is associated with the inactivation of both alleles of a putative tumor suppressor gene (RB-I) located on chromosome 13q14. Both the process of RB development and the biological characteristics of RB cells are as yet poorly understood. We have established 7 new RBL lines (RBL13, RBL14, RBL18 and RBL30, derived from unilateral RB; and RBL7, RBL15 and RBL20, derived from bilateral RB). Southern blot analyses of restriction fragment length polymorphisms in DNA samples from 6 cell lines revealed loss of constitutional heterozygosity at one or several polymorphic loci on chromosome 13 in 4 cases. Gross deletions involving the RB-I locus and amplification of the N-myc gene were not detected in any of the RBL lines. The phenotypic properties of the RBL lines were analyzed in comparison with cells from the original RB tumors, with 4 RB lines established by others (RB383, RB355, RB247C3 and Y79) and with the adenovirus-EIA-transformed human retinoblast line HER-Xhol-CC2. It was found that RB tumors consist of phenotypically heterogeneous cell subpopulations with varying nutrient requirements and differentiation potential in vitro. All cell lines showed the typical characteristics of established ("immortalized") cells. In some cases, cells from original RB tumors or cell lines were able to form colonies when cell aggregates of 2-10 cells were suspended in semi-solid agar medium; however, anchorage-independent colonies never developed from single cells. Cell lines RBL13, RBL18, RB247C3, RB355, RB383 and Y79 were tested for invasion into embryonic chick heart fragments in vitro and found to be non-invasive. None of the RBL or RB lines were tumorigenic in nu/nu (T-) mice. Y79 cells (propagated in culture for many years) exhibited properties distinctly different from those of the other cell lines, and thus cannot be considered phenotypically representative of RB cells.

Animals↗
PubMed1982

The adenovirus type 12 - mouse cell system: permissivity and analysis of integration patterns of viral DNA in tumor cells.

The integration patterns of persisting adenovirus type 12 (Ad12) DNA were analyzed in two Ad12-induced tumors of Balb/c and CBA/J mice and in one tumor cell line derived from an Ad12-induced retinoblastoma of C3H origin. In all three tumors the Ad12 genome was integrated colinearly and various copy numbers of viral DNA were found. Analysis of the Ad12 integration patterns revealed relatively simple offsize band patterns regardless of Ad12 copy numbers. The degree of methylation at the 5'-CCGG-3' sites in the inserted Ad12 genome was determined using the isoschizomeric restriction endonuclease pair HpaII and MspI. Methylation was rather incomplete in the primary tumor tissues but almost complete in the retinoblastoma line carried in culture for many passages. The levels of expression of the viral genome in the Balb/c tumor and in the retinoblastoma line were determined by in vitro translation of RNA isolated from these cells and selected with appropriate restriction endonuclease fragments of Ad12 DNA. In both instances the 59 K, 19 K, and 17 K proteins of the E1b region were expressed. Proteins of the E1a region appeared very faint in the size class between 22 K and 42 K. The permissivity of Ad12 and the replication of Ad12 DNA in mouse cells were investigated by blotting restricted DNA from cells soon after, and a long time after, infection and by hybridization with 32P-labeled Ad12 DNA. Neither primary mouse kidney cells nor the established L929 mouse cell line supported viral DNA replication. These results raise the question to what extent host cell factors determine Ad12 DNA replication in mammalian cells.

Adenoviruses, Human↗
PubMed1986

A new site of integration for mouse mammary tumor virus proviral DNA common to BALB/cf(C3H) mammary and kidney adenocarcinomas.

The BALB/cf/Cd substrain of mice, developed by inbreeding and selection, shows a 70% incidence of spontaneous kidney adenocarcinomas. Initially foster-nursed on C3H mothers, these mice no longer produce mammary tumors, but there is evidence that mouse mammary tumor virus (MMTV) is involved in the formation of these renal carcinomas. We identified a chromosomal region called int-41, representing a locus interrupted by the integration of an exogenous MMTV provirus in a BALB/c mammary tumor. We found a DNA rearrangement and transcriptional activation in the domain specified by the int-41 probe in one primary kidney adenocarcinoma. A 5.2-kb int-41 specific mRNA was detected in the kidney tumor cell line established from a transplantable renal adenocarcinoma. This mRNA hybridized with MMTV and int-41 specific probes suggesting that it is a hybrid molecule composed of MMTV-LTR sequences covalently linked to host cell RNA. This mRNA was strongly stimulated by the presence of glucocorticoid hormone in the culture medium. Our data are compatible with the hypothesis that the int-41 chromosomal domain is involved in the neoplastic transformation of epithelial cells from different organs.

Adenocarcinoma↗
PubMed2003

The presence of high-risk HPV combined with specific p53 and p16INK4a expression patterns points to high-risk HPV as the main causative agent for adenocarcinoma in situ and adenocarcinoma of the cervix.

Adenocarcinoma in situ (ACIS) and adenocarcinoma (AdCA) of the cervix are frequently missed in population-based screening programmes. Adding high-risk HPV (hrHPV) testing to cervical cancer screening might improve the detection rate of ACIS and AdCA. Since the exact proportion of AdCAs of the cervix that can be attributed to hrHPV infection is still a matter of debate, a comprehensive study was performed of hrHPV presence in ACIS and AdCA of the cervix. Archival formalin-fixed specimens of indisputable ACIS (n=65) and AdCA (n=77) of the cervix were tested for hrHPV DNA by GP5+/6+ PCR-enzyme immunoassay (EIA) and type-specific E7 PCR for 14 hrHPV types. Further immunostaining for p16INK4A and p53 was performed to assess alternative pathways of carcinogenesis potentially unrelated to HPV. hrHPV DNA was found in all (100%) ACISs and 72 (94%) cervical AdCAs, whereas none of 20 endometrial AdCAs scored hrHPV-positive. HPV 18 was most prevalent and found as single or multiple infection in 68% of ACISs and 55% of cervical AdCAs. Diffuse immunostaining for p16INK4a, a potential marker of hrHPV E7 function, was significantly more frequent in hrHPV-positive cervical AdCAs (19/20; 95%) than in those without hrHPV (1/5; 20%; p<0.001). Immunostaining for p53, pointing to stabilized wild-type or mutant p53 protein, was significantly more frequent in hrHPV cervical AdCAs negative for hrHPV (p=0.01). No difference in p16INK4a and p53 immunostaining was found between hrHPV-negative cervical AdCAs and endometrial AdCAs. Hence, only a minority of cervical AdCAs displayed absence of HPV DNA and immunostaining profiles suggestive of an aetiology independent of HPV. Since all ACISs and nearly all cervical AdCAs were hrHPV-positive, the incorporation of hrHPV testing in cervical cancer screening programmes is likely to decrease markedly the incidence of cervical AdCA.

Adenocarcinoma↗
PubMed1997

Squamous cell carcinoma of the endometrium with human papillomavirus type 31 and without tumor suppressor gene p53 mutation.

Primary squamous cell carcinoma of the endometrium (ESCC) is extremely rare. There has been no report of human papillomavirus (HPV) detected in ESCC. A 64-year-old Japanese female underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and dissection of the pelvic, para-aortic, and bilateral inguinal lymph nodes. The tumor was confined to the endometrium, without invasion of myometrium or cervix. The endometrium was seen to be replaced by moderately differentiated squamous cell carcinoma, without any adenocarcinomatous element. Polymerase chain reaction amplification produced a 244- to 256-bp DNA fragment from the L1 region of the HPV genome. The amplification products were restricted, and the restricted fragment length polymorphism patterns were analyzed. The squamous cell carcinoma DNA was amplified for each exon, 5 through 8, of the p53 gene. The amplification products were used in single-stranded conformation polymorphism analysis. The tumor described showed the presence of HPV DNA. This amplified fragment was further purified by extraction from agarose gel, and the DNA was sequenced. Comparison of the fragment DNA sequence with known PV sequences showed that it had been amplified from HPV type 31. This is the first detection of HPV DNA in ESCC. Despite previous reports, HPV cannot not be excluded as a possible factor in the development of the malignancy.

Carcinoma, Squamous Cell↗