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Patterns of chromosomal instability in breast cancer
Vol. 201, No. 3S, September 2005
Multi-Disciplinary Session I
However, in an evaluation of never and ever smokers there were a significantly greater association with pancreatic cancer in never smokers and the MnSOD –102 genotype (C⬎T).
Genotype
MnSOD–9 T/T T/C C/C MnSOD–102 C/C C/T T/T Never smoke MnSOD–102 C/C C/T T/T
Cases (%)
Controls (%)
p Value
77 (31) 120 (48) 55 (22)
91 (29) 153 (49) 68 (22)
0.15
78 (71) 23 (21) 9 (8)
124 (72) 39 (23) 9 (5)
1.022
20 (77) 12 (32) 5 (14)
58 (77) 13 (17) 4 (5)
0.038
S43
RESULTS: The mean DNA content index of basal-like tumors was similar to that of IA tumors (1.61 vs.1.58, p⫽0.87). Basal-like IB tumors had a higher mean FLOH (34.4% in basal-like vs. 15% in IA, 6.7% in IIA, and 14.3% in IIB, p⫽0.0013) and a higher mean whole chromosome loss (WCL) than other tumors (mean WCL 2.86 vs. 0.88, 0.75, and 0.67 for IA, IIA, and IIB, respectively; p ⫽ 0.01). CONCLUSIONS: Basal-like tumors have significantly more partial and whole chromosome loss than other subclasses, yet also have increased DNA content, likely through duplication of remaining isochromosomes. These results suggest that basal-like tumors have both profound double-strand break repair defects and also unique chromosome segregation defects.
Placental gene transfer of IGF-1 corrects placental insufficiency
CONCLUSIONS: Subjects with the loss of the promoter function of the MnSOD gene have a significantly greater risk of pancreatic adenocarcinoma when not exposed to cigarette smoke. Further genegene and gene exposure evaluation is needed in predicting pancreatic carcinogenesis.
Patterns of chromosomal instability in breast cancer Sharon B Chang MD, Xin Lu PhD, Ruth Gomes BS, J Dirk Iglehart MD, Andrea Richardson MD, PhD, Zhigang C Wang MD, PhD Dana-Farber Cancer Institute, Boston, MA INTRODUCTION: Chromosomal instability may contribute to breast cancer progression and heterogeneity. Gene-expression profiling clustered breast tumors into subclasses IA, predominantly HER2-positive; IB, ER-negative/HER2-negative “basal-like”; IIA, low-grade ER-positive; and IIB, high-grade ER-positive. We hypothesized that chromosomal instability differs among these subclasses, and assessed tumor ploidy and frequency of allelic imbalance. METHODS: 40 breast tumor samples representing all four subclasses were analyzed. Ploidy/DNA content was measured by nuclear staining and quantitative image analysis of tissue sections. For loss of heterozygosity (LOH) analysis, allelotyping of DNA from tumor and matched normal tissue samples was performed on Affymetrix HuSNP 1.5K arrays. LOH was determined using dChip, and the fractional LOH (FLOH), or proportion of LOH calls per total number of informative calls, was calculated. Statistical analysis was performed using ANOVA.
Ursula F Harkness MD, Jignesh Parvadia MD, Sachin Vaikunth MD, Marwan Marwan MD, Arturo Maldonado MD, Eva Uzvolgyi PhD, Barbara Kalinowska, Datis Alaee, Timothy Crombleholme MD, FACS Cincinnati Children’s Hospital Medical Center, Cincinnati, OH INTRODUCTION: Our goal was to examine the effect of adenoviral mediated placental gene transfer of insulin-like growth factor-1 (IGF-1) on growth in rats with placental insufficiency. METHODS: Bilateral uterine artery ligation was performed in time-mated Sprague-Dawley rats on day 18 of a 22 day gestation. Intraplacental gene transfer of Ad-IGF-1 (1x10∧9 PFU, n⫽11) or Ad-LacZ (5x10∧8 PFU, n⫽10) was performed. Pups (n⫽9) from a sham operated rat served as controls. Postnatally, each litter was randomly reduced to 8 to assure uniformity of litter size. Pups were weighed weekly for 7 weeks. RESULTS: No maternal or fetal losses occurred. The growth curves of the three treatment groups were significantly different (repeated measures, p⫽0.001). The growth pattern of Ad-LacZ treated animals was significantly different from that of the control pups (p⬍0.001). In contrast, Ad-IGF-1 treatment corrected pup growth to that of controls (p⫽0.340). Pups of animals who underwent uterine artery ligation/LacZ injection weighed significantly less than sham operated controls each week between 1 week of age (11.9 ⫹/1.97 gms vs 16.0 ⫹/- 0.58 gms, P⬍0.001)and 6 weeks (172.1 ⫹/16.4 gms vs 203.4 ⫹/- 30.6 gms, P⫽0.048). In another group of animals, repeated measures analysis showed sexual dimorphism in post-natal growth patterns (p⫽0.002). CONCLUSIONS: Adenoviral mediated over-expression of IGF-1 corrects growth restriction due to placental insufficiency. Ongoing studies of this treatment option consider sexual dimorphism and pup position in the uterine horn. Placental gene therapy is an innovative strategy which may prove useful in treating intrauterine growth restriction.
Multi-Disciplinary Session I
However, in an evaluation of never and ever smokers there were a significantly greater association with pancreatic cancer in never smokers and the MnSOD –102 genotype (C⬎T).
Genotype
MnSOD–9 T/T T/C C/C MnSOD–102 C/C C/T T/T Never smoke MnSOD–102 C/C C/T T/T
Cases (%)
Controls (%)
p Value
77 (31) 120 (48) 55 (22)
91 (29) 153 (49) 68 (22)
0.15
78 (71) 23 (21) 9 (8)
124 (72) 39 (23) 9 (5)
1.022
20 (77) 12 (32) 5 (14)
58 (77) 13 (17) 4 (5)
0.038
S43
RESULTS: The mean DNA content index of basal-like tumors was similar to that of IA tumors (1.61 vs.1.58, p⫽0.87). Basal-like IB tumors had a higher mean FLOH (34.4% in basal-like vs. 15% in IA, 6.7% in IIA, and 14.3% in IIB, p⫽0.0013) and a higher mean whole chromosome loss (WCL) than other tumors (mean WCL 2.86 vs. 0.88, 0.75, and 0.67 for IA, IIA, and IIB, respectively; p ⫽ 0.01). CONCLUSIONS: Basal-like tumors have significantly more partial and whole chromosome loss than other subclasses, yet also have increased DNA content, likely through duplication of remaining isochromosomes. These results suggest that basal-like tumors have both profound double-strand break repair defects and also unique chromosome segregation defects.
Placental gene transfer of IGF-1 corrects placental insufficiency
CONCLUSIONS: Subjects with the loss of the promoter function of the MnSOD gene have a significantly greater risk of pancreatic adenocarcinoma when not exposed to cigarette smoke. Further genegene and gene exposure evaluation is needed in predicting pancreatic carcinogenesis.
Patterns of chromosomal instability in breast cancer Sharon B Chang MD, Xin Lu PhD, Ruth Gomes BS, J Dirk Iglehart MD, Andrea Richardson MD, PhD, Zhigang C Wang MD, PhD Dana-Farber Cancer Institute, Boston, MA INTRODUCTION: Chromosomal instability may contribute to breast cancer progression and heterogeneity. Gene-expression profiling clustered breast tumors into subclasses IA, predominantly HER2-positive; IB, ER-negative/HER2-negative “basal-like”; IIA, low-grade ER-positive; and IIB, high-grade ER-positive. We hypothesized that chromosomal instability differs among these subclasses, and assessed tumor ploidy and frequency of allelic imbalance. METHODS: 40 breast tumor samples representing all four subclasses were analyzed. Ploidy/DNA content was measured by nuclear staining and quantitative image analysis of tissue sections. For loss of heterozygosity (LOH) analysis, allelotyping of DNA from tumor and matched normal tissue samples was performed on Affymetrix HuSNP 1.5K arrays. LOH was determined using dChip, and the fractional LOH (FLOH), or proportion of LOH calls per total number of informative calls, was calculated. Statistical analysis was performed using ANOVA.
Ursula F Harkness MD, Jignesh Parvadia MD, Sachin Vaikunth MD, Marwan Marwan MD, Arturo Maldonado MD, Eva Uzvolgyi PhD, Barbara Kalinowska, Datis Alaee, Timothy Crombleholme MD, FACS Cincinnati Children’s Hospital Medical Center, Cincinnati, OH INTRODUCTION: Our goal was to examine the effect of adenoviral mediated placental gene transfer of insulin-like growth factor-1 (IGF-1) on growth in rats with placental insufficiency. METHODS: Bilateral uterine artery ligation was performed in time-mated Sprague-Dawley rats on day 18 of a 22 day gestation. Intraplacental gene transfer of Ad-IGF-1 (1x10∧9 PFU, n⫽11) or Ad-LacZ (5x10∧8 PFU, n⫽10) was performed. Pups (n⫽9) from a sham operated rat served as controls. Postnatally, each litter was randomly reduced to 8 to assure uniformity of litter size. Pups were weighed weekly for 7 weeks. RESULTS: No maternal or fetal losses occurred. The growth curves of the three treatment groups were significantly different (repeated measures, p⫽0.001). The growth pattern of Ad-LacZ treated animals was significantly different from that of the control pups (p⬍0.001). In contrast, Ad-IGF-1 treatment corrected pup growth to that of controls (p⫽0.340). Pups of animals who underwent uterine artery ligation/LacZ injection weighed significantly less than sham operated controls each week between 1 week of age (11.9 ⫹/1.97 gms vs 16.0 ⫹/- 0.58 gms, P⬍0.001)and 6 weeks (172.1 ⫹/16.4 gms vs 203.4 ⫹/- 30.6 gms, P⫽0.048). In another group of animals, repeated measures analysis showed sexual dimorphism in post-natal growth patterns (p⫽0.002). CONCLUSIONS: Adenoviral mediated over-expression of IGF-1 corrects growth restriction due to placental insufficiency. Ongoing studies of this treatment option consider sexual dimorphism and pup position in the uterine horn. Placental gene therapy is an innovative strategy which may prove useful in treating intrauterine growth restriction.