Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting Normal HER2 and TOP2A Status / 한국유방암학회지

PURPOSE: This study aimed to investigate the clinical significance of chromosome 17 centromere (CEP17) multiplication (increased copy number of CEP17) related to human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) status in patients with invasive breast cancer. METHODS: We constructed tissue microarrays using 594 invasive breast cancer samples and performed single-color silver-enhanced in situ hybridization (SISH) assay for HER2, TOP2A, and CEP17 to assess for copy number aberrations. The association of CEP17 multiplication with patient survival was analyzed according to HER2 and TOP2A status. RESULTS: Among 567 informative cases, HER2 amplification was noted in 22.8%, TOP2A amplification in 8.3% and TOP2A deletion in 11.1%. CEP17 multiplication was identified in 33.2% and was significantly associated with worse overall survival (OS) (p=0.02) and disease-free survival (DFS) (p=0.02). CEP17 multiplication correlated with patient survival in patients with normal TOP2A or non-amplified HER2 status, but the prognostic significance was lost in those with altered TOP2A or amplified HER2. On multivariate analyses, CEP17 multiplication was an independent prognostic factor for poorer OS (p=0.02) and DFS (p=0.01) in patients with normal TOP2A and non-amplified HER2. CONCLUSION: CEP17 multiplication was identified as a promising prognostic marker in patients with invasive breast cancer exhibiting either non-amplified HER2 or normal TOP2A status.

Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting Normal HER2 and TOP2A Status / 한국유방암학회지

PURPOSE: This study aimed to investigate the clinical significance of chromosome 17 centromere (CEP17) multiplication (increased copy number of CEP17) related to human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) status in patients with invasive breast cancer. METHODS: We constructed tissue microarrays using 594 invasive breast cancer samples and performed single-color silver-enhanced in situ hybridization (SISH) assay for HER2, TOP2A, and CEP17 to assess for copy number aberrations. The association of CEP17 multiplication with patient survival was analyzed according to HER2 and TOP2A status. RESULTS: Among 567 informative cases, HER2 amplification was noted in 22.8%, TOP2A amplification in 8.3% and TOP2A deletion in 11.1%. CEP17 multiplication was identified in 33.2% and was significantly associated with worse overall survival (OS) (p=0.02) and disease-free survival (DFS) (p=0.02). CEP17 multiplication correlated with patient survival in patients with normal TOP2A or non-amplified HER2 status, but the prognostic significance was lost in those with altered TOP2A or amplified HER2. On multivariate analyses, CEP17 multiplication was an independent prognostic factor for poorer OS (p=0.02) and DFS (p=0.01) in patients with normal TOP2A and non-amplified HER2. CONCLUSION: CEP17 multiplication was identified as a promising prognostic marker in patients with invasive breast cancer exhibiting either non-amplified HER2 or normal TOP2A status.

HER2-Positive Breast Carcinomas with Co-amplification or Gain of Chromosome 17 Centromere Locus: Report of Three Cases and an Impact on HER2 Testing

Recently we experienced three cases of human epidermal growth factor receptor 2 (HER2)-amplified invasive breast carcinomas associated with co-amplification or gain of chromosome 17 centromere (CEP17) in silver-enhanced in situ hybridization (SISH) analysis. These cases revealed 2+ or 3+ staining for HER2 immunohistochemistry and >6 HER2 copies per cell on SISH analyses. However, the calculated HER2/CEP17 ratios were low (6 per cell vs HER2/CEP17 ratio>2.2). We recommend reporting raw SISH or fluorescence in situ hybridization data, including number of cells counted, average numbers of HER2 and CEP17 signals, and the calculated HER2/CEP17 ratio to prevent underreporting of HER2 amplification.

A Case of 17q22 with Interstitial Deletion

Cases of interstitial deletions of the long arm of chromosome 17 are very rare, with only nine cases ever reported worldwide. We describe a 12-year-old boy with profound developmental delay, microcephaly, facial dysmorphism, contracture of the large joints and bilateral hearing loss. A chromosomal study using a peripheral blood sampled revealed 46,XY,del(17)(q22q23). To our knowledge, he is the first case of interstitial deletion of the long arm of chromosome 17 ever reported in Korea.

Two Cases of Acute Leukemic Transformation with a Chromosome 17 Abnormality and p53 Overexpression Evolving from Essential Thrombocythemia / 대한혈액학회지

Essential thrombocythemia (ET) is a clonalmyeloproliferative disorder that can rarely transform into acute leukemia in 1~5% of cases. A recent study has found that a significant proportion of leukemic cases from ET were associated with a cytogenetic abnormality (17p deletion). Herein, we report two cases of acute myeloid leukemic transformations harboring a 17p abnormality from a series of 119 ET patients. The first case, a 48-year-old female, developed acute myeloid leukemia with maturation (AML-M2) accompanying myelodysplasia was diagnosed 6.1 years after the initial diagnosis of ET. She was treated with hydroxyurea. Her karyotype showed a monosomy 17. The second case, a 61-year-old male, developed acute megakaryoblastic leukemia (AML-M7) with a very complex hyperdiploidy including addition of 17p13 that developed 6.5 years after the initial diagnosis. He was treated with hydroxyurea and anagrelide. The immunohistochemistry showed p53 overexpression in both cases. Our cases support the specificity of chromosome 17 abnormality and p53 overexpression in acute leukemic transformation from ET.

Loss of Heterozygosity Analysis of Chromosome 17p13.1-13.3 and Its Correlation with Clinical Outcome in Medulloblastomas / 대한소아혈액종양학회지

PURPOSE: Cytogenetic studies molecular genetic studies, including loss of heterozygosity (LOH) studies, have shown that deletions on the short arm of chromosome 17 (17p) distal to TP53 locus are the most common genetic events in medulloblastoma, and that these occur in 30 to 50% of medulloblastomas. We examined the occurrences and frequencies of allelic deletions on chromosome 17p13.1-13.3 by LOH analysis to investigate the possible involvement of 17p13.1-13.3 in medulloblastoma development. We also performed survival analysis to determine whether LOH analysis of 17p13.1-13.3 can be used to predict prognosis in medulloblastoma. METHOD: LOH was analyzed by polymerase chain reaction (PCR) on chromosome 17p13.1-13.3 using 3 microsatellite markers, TP53 on 17p13.1, D17S796 on 17p13.1-13.2 and D17S1574 on 17p13.3, in 17 medulloblastoma DNAs extracted from archival tissue specimens (cases 1~15) or fresh frozen tissue specimens (cases 16 and 17). RESULTS: Allelic deletions were detected in 5 of 17 informative cases (29%) on TP53, 8 of 17 informative cases (47%) on D17S796, and 4 of 17 informative cases (24%) on D17S1574. Overall, 9 of 17 cases (53%) showed LOH on chromosome 17p13.1-13.3. The 5-year progression free survival (PFS) and 5-year overall survival (OS) rates were identical (59%). The 5-year PFS for 9 medulloblastoma patients with LOH on 17p13.1-13.3 was 56%, and the 5-year PFS for 8 medulloblastoma patients without LOH on 17p13.1-13.3 was 63%. In our survival analysis, we did not find a significant association between survival and LOH on 17p13.1-13.3. CONCLUSION: Our results support the notion that deletions of chromosome 17p13.1-13.3 may be involved in the pathogenesis of medulloblastoma. From survival analysis, we conclude that LOH on chromosome 17p13.1-13.3 may not be a significant predictor of prognosis in medulloblastoma.

A Case of de novo Interstitial Deletion of 17 Chromosome

This is the first reported case of a unique interstitial deletion involving the long arm of chromosome 17 in a Korean male infant born to parents with normal karyotype. The patient presented with multiple congenital malformations suggestive of chromosomal anomaly including round face, upslanted palpebral fissure, hypertelorism, posteriorly rotated low set ear, micrognathia, microcephaly, finger- like thumb, bilateral hearing loss, cryptorchidism, and severe developmental delay found upon outpatient follow-ups. A table of comparison is shown in between our case with previously reported 3 cases by Park, et al.(1992), Dallapiccola, et al.(1993), and Khalifa, et al.(1993).

Clinical, Electrophysiological and Pathological Characteristics in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) with Chromosome 17p11.2-p12 Deletion

BACKGROUND: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. A 1.5-Mb deletion in chromosome 17p11.2- p12 is present in the majority but not all cases of HNPP. The aim of the present study was to evaluate the clinical, electrophysiological and morphological aspects of HNPP patients associated with chromosome 17p11.2-p12 deletion. METHODS: To detect the presence of the deletion, the DNA of the patients was analyzed with pVAW409R3 (D17S122). An electrophysiological study was done in all patients. Sural nerve biopsy with teasing was done in three patients. RESULTS: DNA analysis and electrophysiological tests revealed the deletion in 8 families and 16 patients. Nerve conduction studies demonstrated diffuse mild to moderate slowing of nerve conduction velocities especially worse over the common entrapment sites, regardless of clinical manifestations. The long duration of compound muscle and nerve action potentials without conduction blocks or dispersion is characteristic of patients with HNPP. The tomacula of myelin sheaths was found on sural nerve teasing. CONCLUSIONS: We report the clinical, electrophysiological and morphological aspects of the Korean HNPP patients associated with chromosome 17p11.2-p12 deletion. (J Korean Neurol Assoc 19(3):251~259, 2001)

Intraoperative Electrophysiological Monitoring during Microvascular Decompression for Hemifacial Spasm and Surgical Outcome

BACKGROUND: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. A 1.5-Mb deletion in chromosome 17p11.2- p12 is present in the majority but not all cases of HNPP. The aim of the present study was to evaluate the clinical, electrophysiological and morphological aspects of HNPP patients associated with chromosome 17p11.2-p12 deletion. METHODS: To detect the presence of the deletion, the DNA of the patients was analyzed with pVAW409R3 (D17S122). An electrophysiological study was done in all patients. Sural nerve biopsy with teasing was done in three patients. RESULTS: DNA analysis and electrophysiological tests revealed the deletion in 8 families and 16 patients. Nerve conduction studies demonstrated diffuse mild to moderate slowing of nerve conduction velocities especially worse over the common entrapment sites, regardless of clinical manifestations. The long duration of compound muscle and nerve action potentials without conduction blocks or dispersion is characteristic of patients with HNPP. The tomacula of myelin sheaths was found on sural nerve teasing. CONCLUSIONS: We report the clinical, electrophysiological and morphological aspects of the Korean HNPP patients associated with chromosome 17p11.2-p12 deletion. (J Korean Neurol Assoc 19(3):251~259, 2001)

Numerical Chromosome 17 Aberrations in Tumor Tissue, Tumor-adjacent Mucosa and Normal Bladder Mucosa of the Patients with Bladder Cancer Detected by in situ Hybridization / 대한비뇨기과학회지

PURPOSE: The purpose of this study is to obtain informations about the accumulation of genetic alterations during the urothelial tumorigenetic processes and to define the efficiency of the polysomy of chrosome 17 as a biomarker to predict the risk of tumor recurrences by observing the differences of numerical aberrations of chromosome 17 in tumor tissue, tumor adjacent mucosa and normal bladder mucosa of the patients with bladder cancer. MATERIALS AND METHODS: In 20 patients with the superficial transitional cell carcinoma of the bladder, tumor tissue, mucosa adjacent to the tumor and normal mucosa distant from the tumor were biopsied. The obtained specimen were probed for numerical chromosome aberrations by nonisotopic, in situ hybridization using chrosome-specific centromeric DNA probes for chrosome 17. Normal bladder mucosa obtained from 9 patients with benign prostate hyperplasia were used as controls. Data obtained from the study were analysed according to the grade of tumor and recurrence status. RESULTS: Frequency of numerical aberrations of chromosome 17 and average polysomy counts were 75%, 8.2% in cancer tissue, 40%, 4.5% in tumor adjacent mucosa and 35%, 4.2% in normal mucosa distant from tumor, which were all significantly higher than control(0%, 2.0%). Cancer tissue showed significantly higher polysomy counts in accordance with high grade(100% vs. 61.5%) and recurrence(100% vs. 54.5%) compared to low grade and no recurrence. CONCLUSIONS: In patients with bladder cancer, tumor adjacent mucosa and endoscopically normal looking mucosa showed higher rate of numerical aberrations of chromosome 17. As cancer tissue showed different polysomy status in accordance with high grade and frequent recurrences, in situ hybridization to detect numerical aberrations of chromosome 17 may be used as a good prognostic marker for bladder cancer.

Polysomy of Chromosome 17 Predicting Treatment Failure in Head and Neck Squamous Cell Carcinomas / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: The two major biologically distinct patterns of treatment failure following definitive therapy for the patients with head and neck squamous cell carcinoma are the recurrence of primary tumor and the development of second primary tumor. The purpose of this study is to determine whether the polysomy of chromosome 17 has prognostic significance and is associated with the pattern of treatment failure. MATERIAL AND METHODS: We performed nonfluorescent, nonisotopic, in situ hybridization using chromosome-specific centrometric DNA probe for chromosome 17 on formalin-fixed, paraffin-embedded specimens from the tumor tissue and the resection margins of 42 head and neck squamous cell carcinomas were treated with definitive local therapy. RESULTS: In the tumor tissue, the polysomy of chromosome 17 was a significant predictor for recurrence and treatment failure. In the resection margins, the polysomy of chromosome 17 also showed a predictive significance for the treatment failure. Although there was a chromosomal change in the resection margins believed to be negative on light microscopy, it was also related to the treatment failure. CONCLUSION: The polysomy of chromosome 17 may be a valuable marker for identifying individuals who have the high risk of developing recurrence and treatment failure.

Loss of Heterozygosity Studies on Chromosome 9, 22 and 17p in 12 Various Pediatric Brain Tumors / 대한소아혈액종양학회지

PURPOSE: The normal function of tumor suppressor genes is thought to be related to their ability to regulate cell proliferation and the loss of such function presumably leads to malignant transformation by releasing the transformed cells from growth regulation. One approach to identify these tumor suppressor genes is by loss of heterozygosity (LOH) studies. The rationale of these studies is that the mutation of one allelic copy of a tumor suppressor gene followed by the loss of the remaining wild type allele will result in the total loss of the function of the tumor suppressor gene. Chromosomal loci with frequent LOH in malignant tumors is likely to contain tumor suppressor genes. We want to identify deletions of putative tumor suppressor gene loci in pediatric brain tumors by polymerase chain reaction (PCR)-based LOH studies using microsatellite polymorphic markers of chromosome 9, 22 and 17p as most frequent cytogenetic abnormalities involve chromosome 17p, 22 and 9 in pediatric brain tumors. MATERIAL AND METHOD: Blood and tumor samples were obtained from 12 pediatric brain tumor patients who were operated at Texas Children's Cancer Center from April 1996 to January 1997. The 12 tumors consist of 5 cases of medulloblastomas, 4 cases of juvenile pilocytic astrocytomas, and 1 case each of ependymoma, atypical teratoid rhabdoid tumor and desmoplastic infantile ganglioglioma. Genomic DNA extracted from blood and tumor tissues were amplified by PCR using [gamma-32P]ATP endlabeled primer pairs for the microsatellite polymorphic markers on chromosome 9, 22 and 17p which were D9S171, D9S169, D9S168, D9S165, D9S156, D9S110, D9S146, D9S971, D9S757,D9S176, D9S2105, D9S177, D9S2127, D9S1849, D9S1817, D22S303, D22S33, D22S315, D22S275, D22S299, D22S301, TOP1P2, PDGFB, D22S274, D22S304, D17S1866, D17S1810, D17S796, D17S1566 and D17S1574. The PCR products were separated by electrophoresis in a denaturing 6% polyacrylamide gel and exposed on X-ray films to analyze LOH. RESULTS: 1) There was no evidence of LOH on chromosome 9 in all 12 pediatric brain tumors. 2) Among 12 pediatric brain tumors, only one allelic loss on chromosome 22 (D22S274 : 22q13.31-22q13.33) was observed in an atypical teratoid rhabdoid tumor. 3) LOH for loci on chromosome 17p were detected in 6 cases (50%) of 12 various pediatric brain tumors including 4 cases of medulloblastomas and 1 case each of ependymoma and atypical teratoid rhabdoid tumor. Among 5 cases of medulloblastomas, 4 cases(80%) showed LOH on at least one of 5 markers of chromosome 17p. 4) There was no allelic loss on chromosome 9, 22 and 17p in juvenile pilocytic astrocytomas. CONCLUSION: Our data indicate that there may be a putative tumor suppressor gene located on chromosome 22q13.3 associated with tumorigenesis of atypical teratoid rhabdoid tumor, and other putative tumor suppressor genes located on chromosome 17p13.1-17p13.3 associated with tumorigenesis of medulloblastoma, ependymoma and atypical teratoid rhabdoid tumor. But we need to collect more pediatric brain tumor samples to be studied and allelotype the suggested LOH region in detail.