Genetic Damage Caused by ALU Repeats in Breast Cancer

11051 Background: A serious complication associated with breast cancer treatment is the increased risk for development of therapy-related acute myeloid leukemia (t-AML). To evaluate and possibly identify patients (pts) at high risk for development of t-AML, the Southwest Oncology Group asked whether dose-intensive adjuvant regimens for high risk breast cancer pts induced genetic damage to hematopoietic stem cells (HSC), defined by the emergence of clonal hematopoiesis, an early marker of HSC damage. Methods: 274 pts consented to the clonal hematopoiesis study objective of S0012, a randomized clinical trial of standard doxorubicin and cyclophosphamide followed by weekly paclitaxel (arm 1, 129 pts) vs. weekly doxorubicin and daily oral cyclophosphamide plus G-CSF followed by weekly paclitaxel (arm 2, 145 pts) as neoadjuvant therapy for inflammatory and locally advanced breast cancer. Two different clonality assays were used: the HUMARA (HUMan Androgen Receptor) Assay to estimate the incidence of early genetic damage by clonal proliferation and microsatellite instability (MSI) testing at 5 loci (Bat 26, Bat 40, APC, Mfd, D2S123), common ‘hotspots‘ in t-AML, to screen for loss of heterozygosity or defective DNA mismatch repair mechanisms. Blood samples were evaluated prior to treatment and at 6 and 12 mos post-surgery for emergence of clonal hematopoiesis. Results: Of the 274 pts enrolled, follow-up clonal hematopoiesis samples were available for 195 pts; 96 pts on arm 1 and 99 pts on arm 2. Both HUMARA and MSI results were negative for clonal hematopoiesis in 96% of samples analyzed. In 14 cases, the HUMARA assay suggested that a clonal population was present, but MSI analysis was negative. No cases were HUMARA+/MSI+. With a median follow-up of 19.6 mos, only one pt has developed t-AML 3 yr 5 mos post randomization. Her clonal hematopoiesis test samples at 6 and 12 mos following treatment were negative. Conclusions: Clonal hematopoiesis assays performed within the first year following neoadjuvant therapy and surgery on S0012 failed to identify an emerging clonal HSC population. Longer clinical follow-up will be necessary to define the positive predictive value of detecting clonal hematopoiesis in the 14 HUMARA+/MSI- cases as a harbinger of t-AML. No significant financial relationships to disclose.

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The relationship between genetic damage from polycyclic aromatic hydrocarbons in breast tissue and breast cancer

Carcinogenesis ◽

10.1093/carcin/21.7.1281 ◽

2000 ◽

Vol 21 (7) ◽

pp. 1281-1289 ◽

Cited By ~ 118

Author(s):

Andrew Rundle ◽

Deliang Tang ◽

Hanina Hibshoosh ◽

Allison Estabrook ◽

Freya Schnabel ◽

...

Keyword(s):

Breast Cancer ◽

Polycyclic Aromatic Hydrocarbons ◽

Aromatic Hydrocarbons ◽

Breast Tissue ◽

Genetic Damage ◽

Polycyclic Aromatic ◽

The Relationship

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Acute Myeloblastic Leukemia after Adjuvant Chemotherapy with Melphalan in Breast Cancer. Case Report with Cytogenetic Analysis

Tumori Journal ◽

10.1177/030089168306900206 ◽

1983 ◽

Vol 69 (2) ◽

pp. 117-122 ◽

Cited By ~ 2

Author(s):

Stefania Gori ◽

Emilio Donti ◽

Giovanna Venti ◽

Cristina Mecucci ◽

Lucio Crinò ◽

...

Keyword(s):

Breast Cancer ◽

Cytogenetic Analysis ◽

Alkylating Agents ◽

Breast Cancer Case ◽

Underlying Disease ◽

Lymphocytic Leukemia ◽

Cancer Case ◽

Genetic Damage ◽

History Of ◽

Group A

Therapy of solid and hematologic tumors with alkylating agents appears to increase the frequency of acute non-lymphocytic leukemia (ANLL), as indicated by the cases reported in the literature. The carcinogenetic mechanism of alkylating agents seems related to their ability to damage DNA, and this is supported by the findings of multiple cytogenetic abnormalities in these patients. We report a case of ANLL secondary to therapy with melphalan, which was utilized on an adjuvant basis for breast cancer. ANLL developed 24 months after chemotherapy was discontinued. Results of the cytogenetic analysis in our patient showed multiple rearrangements and marker chromosomes. Among these was a large metacentric chromosome, identified in 6 of 8 karyotypes, in the size range of group A, which probably resulted from a translocation t(7;14) (7qter→7p11::14p11-→14qter). The natural history of the underlying disease and of the ANLL in our patient and data from chromosomal analysis seem to confirm the hypothesis that alkylating agents are potentially leukemogenic in man, probably through genetic damage. This possibility should be considered when such cytotoxic drugs are used in an adjuvant setting.

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The relationship between genetic damage from polycyclic aromatic hydrocarbons in breast tissue and breast cancer

Carcinogenesis ◽

10.1093/carcin/21.5.281 ◽

2000 ◽

Vol 21 (7) ◽

pp. 1281-1289 ◽

Cited By ~ 9

Author(s):

Andrew Rundle ◽

Deliang Tang ◽

Hanina Hibshoosh ◽

Allison Estabrook ◽

Freya Schnabel ◽

...

Keyword(s):

Breast Cancer ◽

Polycyclic Aromatic Hydrocarbons ◽

Aromatic Hydrocarbons ◽

Breast Tissue ◽

Genetic Damage ◽

Polycyclic Aromatic ◽

The Relationship

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Clonal Hematopoiesis as a Marker of Genetic Damage Following Adjuvant Chemotherapy for Breast Cancer: Pilot Study to Evaluate Incidence

10.21236/ada378125 ◽

1999 ◽

Author(s):

Charles A. Coltman ◽

Jr.

Keyword(s):

Breast Cancer ◽

Pilot Study ◽

Adjuvant Chemotherapy ◽

Genetic Damage ◽

Clonal Hematopoiesis

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Virus-Like Particles in a Human Breast Cancer: Structural Similarity to Previously Reported Particles

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100072332 ◽

1973 ◽

Vol 31 ◽

pp. 378-379

Author(s):

G. Kasnic ◽

S. E. Stewart ◽

C. Urbanski

Keyword(s):

Breast Cancer ◽

Biological Activity ◽

Human Breast Cancer ◽

Osteogenic Sarcoma ◽

Human Tumor ◽

Structural Similarity ◽

Cell Tumor ◽

Human Breast ◽

Human Tumor Cell ◽

Type Particle

We have reported the maturation of an intracisternal A-type particle in murine plasma cell tumor cultures and three human tumor cell cultures (rhabdomyosarcoma, lung adenocarcinoma, and osteogenic sarcoma) after IUDR-DMSO activation. In all of these studies the A-type particle seems to develop into a form with an electron dense nucleoid, presumably mature, which is also intracisternal. A similar intracisternal A-type particle has been described in leukemic guinea pigs. Although no biological activity has yet been demonstrated for these particles, on morphologic grounds, and by the manner in which they develop within the cell, they may represent members of the same family of viruses.

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Further Ultrastructural Observations on Metastatic Nodules of Human Breast Cancer

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010010086x ◽

1968 ◽

Vol 26 ◽

pp. 224-225

Author(s):

John L. Swedo ◽

R. W. Talley ◽

John H. L. Watson

Keyword(s):

Breast Cancer ◽

Human Breast Cancer ◽

Estrogen Therapy ◽

Specimen Preparation ◽

Human Breast ◽

Autophagic Vacuoles ◽

Previous Communication ◽

Linear Profiles ◽

Metastatic Nodule

Since the report, which described the ultrastructure of a metastatic nodule of human breast cancer after estrogen therapy, additional ultrastructural observations, including some which are correlative with pertinent findings in the literature concerning mycoplasmas, have been recorded concerning the same subject. Specimen preparation was identical to that in.The mitochondria possessed few cristae, and were deteriorated and vacuolated. They often contained particulates and fibrous structures, sometimes arranged in spindle-shaped bundles, Fig. 1. Another apparent aberration was the occurrence, Fig. 2 (arrows) of linear profiles of what seems to be SER, which lie between layers of RER, and are often recognizably continuous with them.It was noted that the structure of the round bodies, interpreted as within autophagic vacuoles in the previous communication, and of vesicular bodies, described morphologically closely resembled those of some mycoplasmas. Specifically, they simulated or reflected the various stages of replication reported for mycoplasmas grown on solid nutrient. Based on this observation, they are referred to here as “mycoplasma-like” structures, in anticipation of confirmatory evidence from investigations now in progress.

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