Biomedical subjects

Susanne Popp

Publications and source records attributed to Susanne Popp.

8 recordsLinked to original sources

PubMed2005

Telomere-dependent chromosomal instability.

Telomeres are specialized DNA-protein structures at the ends of the linear chromosomes. In mammalian cells, they are composed of multifold hexameric TTAGGG repeats and a number of associated proteins. The double-stranded telomeric DNA ends in a 3' single stranded overhang of 150 to 300 base pair (bp) which is believed to be required for a higher order structure (reviewed in (Blackburn, 2001)). One important model is that the telomeres form loop structures, the T-loops, and by invasion of the 3' overhang into the duplex region of the double stranded part protect the DNA against degradation and hinder the cellular machinery to recognize the ends as broken DNA, thus providing chromosomal integrity (Griffith et al, 1999). If telomeres become critically short they loose their capping function, become sticky, and are prone to illegitimate chromosome end-to-end fusions. The resulting dicentric chromosomes are highly unusable and because of bridge-fusion-breakage cycles they give rise to chromosomal translocations, deletions, and amplifications. Thus, critically short telomeres are thought to be responsible for the onset of genomic instability. In addition, we provide evidence that in a length-independent manner telomeres can confer to genomic instability by forming telomericaggregates which through chromosomal dys-locations contribute to chromosomal aberrations.

Animals↗

PubMed2005

Intratumoral genomic heterogeneity in advanced head and neck cancer detected by comparative genomic hybridization.

OBJECTIVES: Little is known about the extent of intratumoral genetic heterogeneity in head and neck squamous cell carcinoma (HNSCC). MATERIAL: Therefore, we examined 79 stage III and IV primary HNSCCs and matched lymph node metastases for over- and underrepresentation of specific chromosome regions by comparative genomic hybridization. RESULTS: The overall ratio of gains and losses was higher in metastases (M) than in primary (P) tumors (4/1 vs. 2.5/1). Gains of 3q (78.1% P vs. 87.5% M) and 11q (78.1% P vs. 62.5% M), and deletions of 3p (43.8% P vs. 34.4% M) and 9p (31.3% P vs. 15.6% M) were most frequently detected. The highest rate of intratumoral discordance was observed for primary tumors and corresponding metastases (32.8%) compared to matched pairs of 2 metastases (26.5%), and of 2 anatomically distinct sides of 1 primary tumor (24.3%). Furthermore, the discordance rate was dependent on the primary tumor site (oral cavity 49.2%, oropharynx 31%, hypopharynx 30.3% and larynx 27.3%). In some tumors, the extent of genomic discordance argues against a monoclonal origin. CONCLUSION: We demonstrate a high individual variation of intratumoral genomic heterogeneity depending on the localization and selection of matched pairs. These findings are of specific importance in view of establishing prognostic markers.

Aged↗

PubMed2003

Breast cancer in young women (< or = 35 years): Genomic aberrations detected by comparative genomic hybridization.

Sporadic breast cancer in young women is different from the one in older patients regarding pathological features and aggressiveness of the tumors, but the spectrum of genetic alterations are largely unknown. We used comparative genomic hybridization (CGH) to analyze DNA copy number changes in 88 tumor samples from women </=35 years of age. Findings were compared to histopathological data including tumor type, grading, lymph nodes and metastasis. Genomic gains clustered to chromosome arms 1q (64.8%), 8q (61.4%), 17q (50.0%), 20q (33.0%), 3q (20.5%), 1p (17.0%), 5p (17.0%) and 15q (17%). Losses were commonly located on 8p (19.3 %), 11q (11.4%), 16q (11.4%), 17p (11.4%) and 18q (10.2%). A comparison with published CGH data from breast carcinomas of similar type and grade showed the following differences: (1) gains were much more frequent than losses, and (2) losses on 8p22-p23 were more prevalent in patients with positive lymph node metastasis (p = 0.02), and Grade III tumors were associated with gains on the long arm of chromosome 8 (p = 0.01). Therefore, alterations in these genomic regions may be responsible for the reduced survival of patients with early onset breast cancer.

Adult↗

PubMed2003

Intratumoral genomic heterogeneity in advanced head and neck cancer detected by comparative genomic hybridization.

Little is known about the extent of intratumoral genetic heterogeneity in head and neck squamous cell carcinoma (HNSCC). We therefore examined 79 stage III and IV primary HNSCCs (P) and matched lymph node metastases (M) for over- and underrepresentation of specific chromosome regions by comparative genomic hybridization (CGH). The overall ratio of gains and losses was higher in metastases than in primary tumors (4/1 vs. 2.5/1). Gains of 3q (78.1% P vs. 87.5% M) and 11q (78.1% P vs. 62.5% M) and deletions of 3p (43.8% P vs. 34.4% M) and 9p (31.3% P vs. 15.6% M) were most frequently detected. The highest rate of intratumoral discordance was observed for primary tumors and corresponding metastases (32.8%) compared with matched pairs of two metastases (26.5%) and of two anatomically distinct sides of one primary tumor (24.3%). Furthermore, the discordance rate was dependent on the primary tumor site (oral cavity 49.2%, oropharynx 31%, hypopharynx 30.3%, and larynx 27.3%). In some tumors, the extent of genomic discordance argues against a monoclonal origin. In conclusion, we found a high individual variation of intratumoral genomic heterogeneity depending on the localization and selection of matched pairs. These findings are of specific importance in view of establishing prognostic markers.

Aged↗

PubMed2003

A new case of an interstitial deletion (4)(q25q27) characterised by molecular cytogenetic techniques and review of the literature.

UNLABELLED: Interstitial deletions of the long arm of chromosome 4 involving the region 4q25-q27 are rare. Clinical features of patients carrying such a deletion include craniofacial and skeletal anomalies, malformations of the eye, cardiac abnormalities, congenital hypotonia, and developmental retardation. Here we report a new case of a de novo interstitial deletion 4(q25q27) in a girl with congenital malformations and findings of Rieger syndrome. The abnormal chromosome 4 was characterised by G-banding and molecular cytogenetic methods including comparative genomic hybridisation and two-colour fluorescent in situ hybridisation with band-specific probes. CONCLUSION: this report highlights the importance of high quality banding and fluorescent in situ hybridisation analyses to screen for subtle chromosome 4q25-q27 aberrations in patients with clinical features of Rieger syndrome.

Abnormalities, Multiple↗

PubMed2003

Multicolor chromosomal bar coding characterizes a de novo interstitial deletion (5)(q33.3q35.2) in a child with multiple congenital malformations.

We describe a boy with multiple congenital anomalies including a complex heart defect, club feet, adducted thumbs, and facial dysmorphic features. He died at the age of 2 months following cardiac surgery. G-banding analysis identified an abnormal chromosome 5q suspected to be an interstitial deletion (5)(q33q35). Breakpoints of the deleted segment were confirmed as del(5)(q33.3q35) by multicolor fluorescence in situ hybridization (FISH) using two sets of combinatorially labeled band specific YAC clones. Findings are discussed in view of previously published cases.

Abnormalities, Multiple↗

PubMed2002

Study of 30 patients with unexplained developmental delay and dysmorphic features or congenital abnormalities using conventional cytogenetics and multiplex FISH telomere (M-TEL) integrity assay.

Cryptic subtelomeric chromosome rearrangements are a major cause of mild to severe mental retardation pointing out the necessity of sensitive screening techniques to detect such aberrations among affected patients. In this prospective study a group of 30 patients with unexplained developmental retardation and dysmorphic features or congenital abnormalities were analysed using the recently published multiplex FISH telomere (M-TEL) integrity assay in combination with conventional G-banding analysis. The patients were selected by one or more of the following criteria defined by de Vries et al.: (a) family history with two or more affected individuals, (b) prenatal onset growth retardation, (c) postnatal growth abnormalities, (d) facial dysmorphic features, (e) non-facial dysmorphism and congenital abnormalities. In addition, we included two patients who met these criteria and revealed questionable chromosome regions requiring further clarification. In four patients (13.3%) cryptic chromosome aberrations were successfully determined by the M-TEL integrity assay and in two patients with abnormal chromosome regions intrachromosomal aberrations were characterized by targetted FISH experiments. Our results accentuate the requirement of strict selection criteria prior to patient testing with the M-TEL integrity assay. Another essential precondition is high-quality banding analysis to identify structural abnormal chromosomes. The detection of familial balanced translocation carriers in 50% of the cases emphasizes the significance of such an integrated approach for genetic counselling and prenatal diagnosis.

Abnormalities, Multiple↗

PubMed2002

UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas.

Two developmentally highly divergent nonmelanoma skin cancers, the epidermal squamous cell carcinomas (SCC) and the neuroendocrine Merkel cell carcinomas (MCC), occur late in life at sun-exposed body sites. To determine whether these similarities may indicate common genetic alterations, we studied the genetic profile of 10 MCCs and analyzed 6 derived cell lines and 5 skin SCC lines by comparative genomic hybridization (CGH) and molecular genetic analyses. Although the MCCs were highly divergent-only 3 of the 10 tumors exhibited common gains and losses-they shared gain of 8q21-q22 and loss of 4p15-pter with the genetically much more homogeneous SCC lines. In addition, 2 of 5 SCC and 2 of 6 MCC lines exhibited UV-B-type-specific mutations in the p53 tumor-suppressor gene and a high frequency (9/11) of CC-->TT double base changes in codon 27 of the Harvey (Ha)-ras gene. Since 45% of the tumor lines were homozygous for this nucleotide substitution compared to 14% of the controls and in 1 MCC patient the wild-type allele was lost in the tumor, this novel polymorphism may contribute to tumor development. On the other hand, loss of 3p, characteristic for SCCs, was rare in MCCs. Although in 2 of 3 SCC lines 3p loss was correlated with reduced expression of the FHIT (fragile histidine triad) gene, the potential tumor suppressor mapped to 3p14.2 and 2 MCC lines with normal 3p showed aberrant or no FHIT transcripts. Taken together, in addition to the common UV-B-specific mutations in the p53 and Ha-ras gene, MCCs and SCCs also share chromosomal imbalances that may point to a common environmental-derived (e.g., UV-A) oxidative damage.

Aged↗