THE HINDU
New Delhi, December 3, 2013
People attend a free screening camp for oral cancer and lung
check-up in Hyderabad. File photo: K. Ramesh Babu
A team of Indian scientists has identified new genes and new
biological pathways that are specific to driving oral cancer associated
predominantly with smokeless tobacco consumption in India. Further detailed
study on these discoveries may lead to finding better therapies for oral
cancer, the researchers point out. The findings have been published on Monday
in the journal Nature Communications.
The Indian group is part of the International Cancer Genome
Consortium (ICGC), an initiative started in 2009, to understand the genomic
basis of 50 different types of cancer with clinical and societal importance
around the globe.
The Indian component is being conducted collaboratively by the
National Institute of Biomedical Genomics (NIBMG), Kalyani, West Bengal, and the
Tata Memorial Centre (TMC), Mumbai. This is the first set of results to come
out of the India Project, which has been noted as an important contribution to
cancer genomics.
Oral cancer is the eighth most common cancer worldwide and is the
leading cancer among males in India. Unlike in the West, where 65 per cent of
oral cancers are tongue cancer, in India, oral cancer predominantly (60 per
cent) is of the lining of the mouth, lower gum and other mucosal regions of the
oral cavity, termed the Oral Squamous Cell Carcinoma of the gingivo-buccal
region (OSCC-GB). Tobacco chewing is a major cause of OSCC-GB, which accounts
for over half of the oral cancers in India.
Cancer is known to be associated with changes in the DNA
contained in the cells of the tumour tissues. However, these genetic changes —
triggered by lifestyle or other environmental factors such as exposure to
tobacco, chemicals and radiation — occur only in non-reproductive cells and are
called somatic alterations. But, as Dr. Partha Majumder of the NIBMG, who led
the research, explains, most somatic alterations do not cause the abnormal
growth, which results in cancer. Gene alterations that do provide this growth
advantage to cancerous cells over normal cells are called driver mutations.
Though past studies have identified several genes associated with oral cancer,
these have not been systematically catalogued. More pertinently, as the paper
says, “Oral cavity comprises sub-sites with distinct biological features. It is
therefore likely that genes driving cancers in these sub-sites may be
different.”
The study included 110 subjects suffering from OSCC-GB, about
half of who were between the age of 40 and 50, and nearly all were tobacco
users. Eighty-eight per cent of the patients were male and 94 per cent were in
advanced stages of cancer. Fifty patients, who had not undergone any treatment,
were identified for investigation into the genetics of OSCC-GB and the data on
the remaining 60 were used to test the validity of the discoveries.
Using the technique of massively-parallel DNA sequencing, blood
and tumour DNA of each patient were screened for all genes — about 20,000 — in
the human genome. On an average, 85 somatic alterations were found on each
patient. But, as mentioned above, only some of these are potential drivers.
The study found 10 significantly mutated genes that were
associated with OSCC-GB. These are TP53, FAT1, CASP8, NOTCH1, HRAS, USP9X,
MLL4, UNC13C, ARID2 and TRPM3. Of these, the first five have been implicated
earlier in the cancer called, the Head and Neck Squamous Cell Carcinoma
(HNSCC), of which OSCC-GB is a subtype. The remaining five are new, which seem
to be specific to OSCC-GB. These new genes were found to be altered in 10-22
per cent of the patients.
Any alteration in a ‘tumour suppressor gene’ means that it cannot
perform its normal function of tumour suppression, which can lead to cancer.
Sixty-two per cent of patients exhibited mutations in TP53, a very important
tumour suppresser gene. In fact, four of the five genes identified earlier are
tumour suppresser genes, according to Dr. Majumder.
While MLL4 acts in concert with TP53, and increases its
expression, both MLL4 and ARID2 are involved in regulating key biological
processes in the cell, such as programmed cell death, inefficiency of which can
cause cancer. The authors note that TRPM3 may also be indirectly involved in
tumour suppression. “Overall,” says the paper, “tumour suppresser genes,
compared with oncogenes [cancer causing genes], are predominantly involved in
oral cancer; this fact may have therapeutic implications.”
The remaining two new genes — UNC13C and TRPM3 — are involved in
biochemical pathways associated with neurotransmitter release and, according to
the authors, alterations in these could be related to predisposition to tobacco
addiction, which enhances the risk of oral cancer.
“The characterisation of a large sample of the OSCC-GB subtype
provides a unique contribution to the literature on characterisation of
HNSCCs,” Dr. Carolyn Hutter of the National Human Genome Research Institute
(NHGRI), USA, observed in an e-mail message.
Posted By:
Rajni Jaiswal (Faculty)
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