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Low levels of ATM in breast cancer patients with clinical radiosensitivity.

Fang Z, Kozlov S, McKay MJ, Woods R, Birrell G, Sprung CN, Murrell DF, Wangoo K, Teng L, Kearsley JH, Lavin MF, Graham PH, Clarke RA - Genome Integr (2010)

Bottom Line: Adjuvant radiotherapy for cancer can result in severe adverse side effects for normal tissues.In this respect, individuals with anomalies of the ATM (ataxia telangiectasia) protein/gene are of particular interest as they may be at risk of both breast cancer and clinical radiosensitivity.The association of specific ATM gene mutations with these pathologies has been well documented, however, there is uncertainty regarding pathological thresholds for the ATM protein.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Radiation Oncology, St George Clinical School of Medicine University of NSW, St George Hospital, Kogarah, NSW 2217, Australia. r.clarke@unsw.edu.au.

ABSTRACT

Background and purpose: Adjuvant radiotherapy for cancer can result in severe adverse side effects for normal tissues. In this respect, individuals with anomalies of the ATM (ataxia telangiectasia) protein/gene are of particular interest as they may be at risk of both breast cancer and clinical radiosensitivity. The association of specific ATM gene mutations with these pathologies has been well documented, however, there is uncertainty regarding pathological thresholds for the ATM protein.

Results: Semi-quantitative immuno-blotting provided a reliable and reproducible method to compare levels of the ATM protein for a rare cohort of 20 cancer patients selected on the basis of their severe adverse normal tissue reactions to radiotherapy. We found that 4/12 (33%) of the breast cancer patients with severe adverse normal tissue reactions following radiotherapy had ATM protein levels < 55% compared to the mean for non-reactor controls.

Conclusions: ATM mutations are generally considered low risk alleles for breast cancer and clinical radiosensitivity. From results reported here we propose a tentative ATM protein threshold of ~55% for high-risk of clinical radiosensitivity for breast cancer patients.

No MeSH data available.


Related in: MedlinePlus

Scatterplot showing the level of the ATM protein for LCLs established for the following population groups. Breast cancer patients with no adverse reaction to radiotherapy referred to as non-reactor controls (NRC); Women with SLE; Cancer patients with severe acute normal tissue reactions to radiotherapy (RS-acute); Patients with severe acute and late reactions (RS-A/L); Patients with only severe late reactions (RS-Late); Obligate A-T heterozygotes (ATH - Note: the 4 highest expressing ATH carry  mutations); A-T patients (A-T). ATM protein densities were plotted as a percentage of the level of the ‘highest ATM expresser’.
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Figure 2: Scatterplot showing the level of the ATM protein for LCLs established for the following population groups. Breast cancer patients with no adverse reaction to radiotherapy referred to as non-reactor controls (NRC); Women with SLE; Cancer patients with severe acute normal tissue reactions to radiotherapy (RS-acute); Patients with severe acute and late reactions (RS-A/L); Patients with only severe late reactions (RS-Late); Obligate A-T heterozygotes (ATH - Note: the 4 highest expressing ATH carry mutations); A-T patients (A-T). ATM protein densities were plotted as a percentage of the level of the ‘highest ATM expresser’.

Mentions: We determined ATM protein levels from LCLs established from patients: 52 individuals in total. We referred to the individual with the highest level of ATM protein in cell extracts as the 'highest expresser'. The highest expresser was subsequently included as a reference lane in repeat immunoblots (Fig. 1A lane 8, Fig. 1B lanes 1 & 8, Fig. 1C lanes 7 & 8). At least two different cell extracts were analysed and averaged as a percentage of the highest expresser using scatter plots (Fig. 2). The 14 breast cancer patients which had no adverse reaction to radiotherapy, referred to here as 'non-reactor controls' (NRC see Fig. 2), had a mean level of the ATM protein of 84% compared with the highest expresser (range 63% - 100%). For the 2 A-T cell lines we observed no ATM expression [25]. For the 4 obligate A-T heterozygotes (ATH) with mutations the ATM protein levels were > 55% (range 56% - 84%) compared to the mean for non-reactor controls (Fig. 2). Unexpectedly, ATH5ABR, the A-T heterozygote control with a missense mutation (see below) was the lowest expresser of all obligate heterozygotes with an ATM protein level ~14% compared to the highest expresser and ~17% compared with the mean for non-reactor controls (Fig. 2 and see also Fig. 1A lane 10). Women with SLE (Fig. 2) had ATM levels > 70% compared with the highest expresser and a mean ATM protein level (87%) comparable to the mean for non-reactor controls (84%) (Fig. 2).


Low levels of ATM in breast cancer patients with clinical radiosensitivity.

Fang Z, Kozlov S, McKay MJ, Woods R, Birrell G, Sprung CN, Murrell DF, Wangoo K, Teng L, Kearsley JH, Lavin MF, Graham PH, Clarke RA - Genome Integr (2010)

Scatterplot showing the level of the ATM protein for LCLs established for the following population groups. Breast cancer patients with no adverse reaction to radiotherapy referred to as non-reactor controls (NRC); Women with SLE; Cancer patients with severe acute normal tissue reactions to radiotherapy (RS-acute); Patients with severe acute and late reactions (RS-A/L); Patients with only severe late reactions (RS-Late); Obligate A-T heterozygotes (ATH - Note: the 4 highest expressing ATH carry  mutations); A-T patients (A-T). ATM protein densities were plotted as a percentage of the level of the ‘highest ATM expresser’.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2914013&req=5

Figure 2: Scatterplot showing the level of the ATM protein for LCLs established for the following population groups. Breast cancer patients with no adverse reaction to radiotherapy referred to as non-reactor controls (NRC); Women with SLE; Cancer patients with severe acute normal tissue reactions to radiotherapy (RS-acute); Patients with severe acute and late reactions (RS-A/L); Patients with only severe late reactions (RS-Late); Obligate A-T heterozygotes (ATH - Note: the 4 highest expressing ATH carry mutations); A-T patients (A-T). ATM protein densities were plotted as a percentage of the level of the ‘highest ATM expresser’.
Mentions: We determined ATM protein levels from LCLs established from patients: 52 individuals in total. We referred to the individual with the highest level of ATM protein in cell extracts as the 'highest expresser'. The highest expresser was subsequently included as a reference lane in repeat immunoblots (Fig. 1A lane 8, Fig. 1B lanes 1 & 8, Fig. 1C lanes 7 & 8). At least two different cell extracts were analysed and averaged as a percentage of the highest expresser using scatter plots (Fig. 2). The 14 breast cancer patients which had no adverse reaction to radiotherapy, referred to here as 'non-reactor controls' (NRC see Fig. 2), had a mean level of the ATM protein of 84% compared with the highest expresser (range 63% - 100%). For the 2 A-T cell lines we observed no ATM expression [25]. For the 4 obligate A-T heterozygotes (ATH) with mutations the ATM protein levels were > 55% (range 56% - 84%) compared to the mean for non-reactor controls (Fig. 2). Unexpectedly, ATH5ABR, the A-T heterozygote control with a missense mutation (see below) was the lowest expresser of all obligate heterozygotes with an ATM protein level ~14% compared to the highest expresser and ~17% compared with the mean for non-reactor controls (Fig. 2 and see also Fig. 1A lane 10). Women with SLE (Fig. 2) had ATM levels > 70% compared with the highest expresser and a mean ATM protein level (87%) comparable to the mean for non-reactor controls (84%) (Fig. 2).

Bottom Line: Adjuvant radiotherapy for cancer can result in severe adverse side effects for normal tissues.In this respect, individuals with anomalies of the ATM (ataxia telangiectasia) protein/gene are of particular interest as they may be at risk of both breast cancer and clinical radiosensitivity.The association of specific ATM gene mutations with these pathologies has been well documented, however, there is uncertainty regarding pathological thresholds for the ATM protein.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Radiation Oncology, St George Clinical School of Medicine University of NSW, St George Hospital, Kogarah, NSW 2217, Australia. r.clarke@unsw.edu.au.

ABSTRACT

Background and purpose: Adjuvant radiotherapy for cancer can result in severe adverse side effects for normal tissues. In this respect, individuals with anomalies of the ATM (ataxia telangiectasia) protein/gene are of particular interest as they may be at risk of both breast cancer and clinical radiosensitivity. The association of specific ATM gene mutations with these pathologies has been well documented, however, there is uncertainty regarding pathological thresholds for the ATM protein.

Results: Semi-quantitative immuno-blotting provided a reliable and reproducible method to compare levels of the ATM protein for a rare cohort of 20 cancer patients selected on the basis of their severe adverse normal tissue reactions to radiotherapy. We found that 4/12 (33%) of the breast cancer patients with severe adverse normal tissue reactions following radiotherapy had ATM protein levels < 55% compared to the mean for non-reactor controls.

Conclusions: ATM mutations are generally considered low risk alleles for breast cancer and clinical radiosensitivity. From results reported here we propose a tentative ATM protein threshold of ~55% for high-risk of clinical radiosensitivity for breast cancer patients.

No MeSH data available.


Related in: MedlinePlus