Possible Molecular Basis to Associations Between Alzheimer's Disease, Glioblastoma and Lung Cancer Identified

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Highlights:

• Alzheimer's disease (AD), lung cancer (LC) and glioblastoma (GBM, a brain cancer) continue to be major health concerns globally and are associated with increased mortality and morbidity.
• Alzheimer's disease is associated with an increased risk of glioblastoma but a reduced risk of lung cancer.
• Current study suggests a possible genetic basis to these varying associations and hopes to gain insight into these conditions that may help spur newer and more effective treatments.

There may be a genetic connection to explain the direct and inverse risk association between Alzheimer's disease with glioblastoma and lung cancer respectively, according to a recent study published in Nature.

Why Look Into Molecular Processes Underlying AD, GBM and LC

As stated earlier, Alzheimer's disease, lung cancer and glioblastoma continue to pose major health challenges worldwide to the healthcare community with not many effective treatments currently available.

‘Genetic changes occurring in Alzheimer�s disease, glioblastoma and lung cancer, when analyzed in conjunction, throw up new insights and as yet unexplored treatment options for future research.’

Various reasons put forth for direct and inverse comorbidities between diseases include environmental influences, lifestyle or drug treatments.

The current research team believes that a molecular basis might be able to explain these varying associations, at least partly, and offer more information to fuel further research into developing newer and better treatments.

Transcriptomic Meta-analyses of Genes in these Three Conditions and Results

To validate their hypotheses, the research team embarked on a transcriptomic meta-analyses (an analysis that studies the combined data and statistics available from multiple studies) of these 3 conditions.

In general, genes are said to be up-regulated when their expression is increased from normal levels and down-regulated when the expression is reduced. Both these situations are referred to as deregulation (or disordered regulation).

The interesting and most notable molecular observations were as follows.

AD and LC

• A significant proportion of genes were deregulated in opposite directions (for example up-regulated in AD but down-regulated in LC) in Alzheimer's disease and lung cancer.
• Overall, 395 biological processes were significantly deregulated in AD and/or LC. Among these 92 processes were common to both diseases.
• Of the 92 common pathways, 21 processes were up-regulated in AD and down-regulated in LC, while 71 processes were down-regulated in AD and up-regulated in LC.
• The pathways in which the genes were up-regulated in AD and down-regulated in LC were those present in immune and inflammatory responses.
• The genes that were down-regulated in AD and up-regulated in LC included processes were related to synaptic transmission.

AD and GBM

• In contrast, a significant number of genes were deregulated in the same direction in Alzheimer's disease (for example up-regulated or down-regulated in both conditions).
• Overall, more than 300 genes were deregulated; not all were common to both.
• Of the deregulated genes, 8 genes were up-regulated in both AD and GBM, and 14 were down-regulated in both conditions.
• The up-regulated genes were related to the immune system function and the down-regulated ones were associated with synaptic transmission.
• Interestingly, 10 genes that were deregulated in opposite directions in AD and GBM, were also deregulated in lung cancer, suggesting a possible molecular link to these 3 conditions.

GBM and LC

• Among the 70 pathways found to be up-regulated in GBM and the 177 processes up-regulated in LC, 43 were increased in both GBM and LC. Most of these functions are related to the cell cycle, for instance "DNA repair" or "mitosis".
• The 5 processes deregulated in opposite directions between the two cancer types (GBM+/LC−) are related to the immune function.

AD, GBM and LC

• Overall, 198 genes were significantly deregulated in the three diseases. Among these, 112 had a similar pattern of deregulation in AD and GBM but demonstrated the opposite pattern in LC.
• A comparison of the genes and processes deregulated in AD, GBM and/or LC indicated "oxidative phosphorylation" to be down-regulated in AD and GBM, and up-regulated in LC, pointing to potential metabolic differences between these two types of cancer.
• Interestingly, 10 of the 11 processes down-regulated in AD and up-regulated in GBM were also up-regulated in LC. The large majority of these were related to the cell cycle, a central activity in tumorigenesis.

Possible Reasons For Inverse Link Between AD And LC

Genes down-regulated in AD but up-regulated in LC are those involved in mitochondrial function. The following mechanisms aim to explain how AD patients may have reduced LC risk.

• In AD, oxidative phosphorylation is dampened; it has been shown that oxidative phosphorylation is critical for lung carcinoma growth.
• Decreased glutathione levels seen in AD increases chemotherapy sensitivity in LC.
• Genes up-regulated in AD cause cell cycle arrest and limit cell proliferation pathways involved in LC, reducing lung cancer growth.
• Protein folding and proteasome inhibition in AD decrease cell migration and cause cell death in LC.

Possible Reasons For Direct Link Between AD and GBM

• Diminished oxidative phosphorylation in both conditions may play a role in their pathogenesis. Studies have shown that methylene can be used to treat both AD and GBM.
• Persistent activation of immune system may play a role in both diseases as well. Many studies have shown an association between immune dysfunction and cancer as well as AD.

In conclusion, the study opens up possible genetic factors linking AD, LC and GBM. Some of the insights gained in this study may help in exploring newer treatment options for these conditions, for example, combinations of proteasome and chaperone inhibitors, oxidative phosphorylation or TCA cycle inhibitors and anti-oxidants for LC treatment.

Source: Medindia

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