Brain tumours searching for a cause
Sally Smith, B.Sc., M.P.H.
Department of Neurosurgery, RNSH supported by the Andrew Olle Memorial Trust
1
The Andrew Olle Memorial Trust is funding a study of admission with brain tumour in the Northern Sydney Area
Three databases, collated by one manager, unique in Australia, provide a complete record of over 30,000 neurosurgical admissions since 1976 in the Northern Sydney Health Area. Aims of the study are there trends in occurrence of different types of brain tumour, is surgery improving treatment for patients? Are there trends in complications for brain tumour patients? So far, analysis of admissions since 1977 shows all tumours referred here increased from 80 to 220 cases/year; ungradeable astrocytoma decreased from 13.1% to 1.5% due to better imaging, biopsy and pathology methods; oligodendroglioma and lymphoma numbers increased; 2 length of stay & inpatient death rate have fallen markedly.
Database analysis: 3,829 admissions for intracranial tumour in the Northern Sydney Area since 1977
• • • • Benign meningioma: 19% pituitary: 11% acoustic neuroma: 4% others • • • • Malignant malignant astrocytoma & glioblastoma: 25% metastasis (secondary) from cancer in other part of body: 15% juvenile and low-grade astrocytoma: 5% central nervous system lymphoma & tumour seeding on the membranes around the brain: 4% oligodendroglioma: 2% others
3
• •
Andrew Olle study: continuing work
Incidence of brain tumour by postcode: how do our figures compare with Cancer Registry figures for NSW? Are there trends in complications for patients with different tumours? What are the survival times for patients with different tumours?
How do changes in pathology grading schemes affect the incidence of brain tumours? Why are numbers of CNS lymphoma and oligodendroglioma increasing?
4
Inside the Brain
Highly magnified image showing nerve cells (brown, blue), structural glial cells (white), excitatory synapses (messages) in yellow, inhibitory synapses in red.
Illustration from Laboratory for Computational Neuroscience, University of Pittsburgh
5
Inside brain tumours
Grade 3 astrocytoma, shows increased density of cells, cell nuclei ( dark shapes) vary in size, shape, and coarseness. Cell division rate is abnormally high.
6
(West Virginia University radiation oncology)
Inside brain tumours
Brain tumour growth shown by fluorescence imaging:
(Alex C. Stan, Institute of Neuropathology, Hannover Medical School)
7
Hopefully, current research is more directed than this…….
8
Looking for causes in community patterns
Epidemiologists tell us that primary brain cancer is rare WORLDWIDE: 2-8 new cases per 100,000 people per year; In NSW: 5 females and 8 male cases per100,000 people per year; (compare with breast: 90 cases per 100,000 per year, colon: 60 cases per100,000 per year) In NSW: 422 new cases in 1999*; In the N. Sydney databases:102 new cases in 1999.
Primary brain cancer varies by sex, age, ethnicity, country & over time.
There are many types of tumours (World Health Organisation has >120)
Incidence is increasing, but only for people over 65. This may be because of increased investigation and reporting of tumours in elderly patients. DeathsIn NSW: 4 females and 6 males per 100,000 people per year;
307 in 1999* *from NSW Cancer Registry figures
9
Known causes of brain tumours
Ionising radiation (strong x-rays) can cause nerve sheath tumours,
meningiomas and gliomas.
Genetic predisposition (rare):
• people with neurofibromatosis type 1(Von Recklinghausen): about 1 per 4,000 population. Many are affected by benign & malignant tumours. • neurofibromatosis type 2: about 1 per 40,000 population. Most have bilateral acoustic tumours. NF2 gene is a tumour suppressor. • von Hippel-Lindau disease: about 1 per 40,000 population. Most patients have cerebellar haemangioblastoma and may develop other tumours. • other rare syndromes: some cases of glioblastoma, medulloblastoma, ependymoma, etc
10
Suspected causes & investigated causes of brain tumours
• Chemicals: Formaldehyde, vinyl chloride, agricultural chemicals (pesticides), N-nitroso compounds in some high-meat diets. • Infections: viruses in animal studies; other infection: chickenpox, toxoplasma? These agents may rearrange genes. • Occupation: medical & dental, electrical workers, pilots, farmers, potters, oil refinery workers etc. • Trauma has been associated with meningioma. • Drugs & medications: no increased risk has been shown. • Non-ionising Extra Low Frequency EMR, e.g. from mobile phones and antennas, transmission lines, are suspected as tumour promoting -
- but no firm proof of causality has been shown.
11
The most likely explanation of the causes of most brain tumours at present is:
most brain tumours occur as random accidents of nature.
12
Why it’s been hard to find causes for brain tumours strict criteria
Epidemiologists need 7-8 criteria to prove that an factor causes a disease, including:
• there must be a dose/response relationship - the more people are exposed, the more likely they are to acquire the disease; • cause must come before disease. It’s hard to measure exposure to a possible cause & outcome (disease) accurately over time & in geographical location • there needs to be a biologically possible mechanism; • exposure to the causal factor should make people at least 4 times more likely to get the disease; • the same results should be seen many times in independent research studies. 13
Why it’s been hard to find causes for brain tumours - research methods
• Epidemiologic studies have not been very helpful because of the low incidence of brain tumours, lack of agreement on tumour classification / grading and the large variety of tumour types, so studies have been based on small numbers. • A tumour may take years to develop. Case-control studies, based on interviews with patients about their past exposure to suspected causal factors, have not been very helpful because patients diagnosed with brain cancer may not be well enough to participate; and it is not easy to remember your lifetime exposure. • Molecular genetic studies: hope for the future. Much cell biology & molecular research is underway worldwide at present, untangling the biochemistry & relationships between genes &their 14 products.
Molecular genetic studies - looking for causes in the genes
• In normal body tissues, there is a balance between making new cells (mitosis) & destroying unwanted cells (apoptosis) in tissues. • Multitudes of genes on chromosomes in every cell constantly control this process by making proteins which act as machines, messengers, energy suppliers, etc. • Tumours grow when cells’ normal regulation is upset by a complex process of accumulation of damage to many of these genes (called mutations). • Tumour progression from one grade to the next comes with more changes in the genes of tumour cells.
15
Causes in the genes: main culprits - oncogenes
• can be turned on by mutation • they produce growth factors which make tumours grow; • e.g. a vascular growth factor develops a blood supply to feed the tumour, and may also cause swelling round tumour. • Dexamethasone probably works by reducing production of VEGF (vascular endothelial growth factor).
16
Causes in the genes: main culprits - tumour suppressor genes
• Tumour suppressor genes such as TP53 can be turned off by mutation. • Normal function is to start apoptosis after damage to genes in cell’s DNA. • Doesn’t cause brain tumours, but when turned off it can’t start apoptosis, so damaged cells survive and grow. • TP53 has been linked to poor outcome. • The pattern of TP53 mutation in astrocytoma suggests that cancer is caused by internal rather than external factors.
17
One idea: heat shock proteins
• Electromagnetic (non-thermal) radiation such as from mobile phones may have some effect on cells• which might reduce the body’s defences against cancer. • Heat shock proteins are produced as a normal defence to stress like dehydration, salt flux on cells; • chronic overproduction of heat shock proteins starts or promotes tumours, metastases and/or resistance to anticancer drugs • Does repeated exposure to mobile phone radiation cause over-production of heat shock proteins, affecting their normal regulation and promoting cancer?
Ref: Mobile phones, heat shock proteins and cancer. French, PW et al Differentiation 67 pp 93-97
18
19