Revealed… 12 cancers that ARE inherited – and how the ‘Angelina Jolie gene’ could also trigger stomach and prostate tumors

It has long been recognized that part of the risk a person will develop cancer, is a genetic one.Mutations hidden within our DNA, and passed through the generations, are very important in some tumors, yet less so in others.But now, a new study has shed light on which forms of the disease can be blamed on genetics.Scientists at Washington University have identified 12 cancers triggered by inherited mutations.They are ovarian, stomach, breast, prostate, two types of lung disease, glioma, head and neck, endometrial, kidney, glioblastoma and acute myeloid leukaemia.Furthermore, the researchers analysed the role the BRCA gene mutations – dubbed the ‘Angelina Jolie gene’ -have in cancers other than ovarian and breast.The BRCA1 and BRCA2 mutations are most commonly associated with breast and ovarian cancer.

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Their role in the diseases has been highlighted by the plight of Hollywood star, Jolie, after she revealed she was found the carry the mutation.The mother-of-six opted to have a double mastectomy and have her ovaries removed, as a preventative measure after doctors warned she faced an 87 per cent chance of developing breast cancer – eight times the chance for an average woman.Surprisingly, the Washington scientists discovered the mutations also play a key role in stomach and prostate cancers, and could influence other forms of the disease.The discovery has implications for improving the accuracy of existing genetic tests for cancer risks, scientists said.It may also lead to the expansion of available tests to include a wider variety of tumors.Study author Dr Li Ding said: ‘In general we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution.‘But this is the first time on a large scale that we’ve been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility.’The scientists analysed genetic information from more than 4,000 cancer cases included in The Cancer Genome Atlas Project.Previous genomic studies of cancer compared sequencing from patients’ healthy tissue as well as their tumors.Those studies uncovered genetic mutations present in the tumors and helped researchers identify important genes that could play a role in cancer.But that research doesn’t distinguish between inherited mutations that are present at birth – or mutations acquired over a person’s life.
The new study sought to ‘tease out’ cancer’s inherited components.To do so, the scientists added analysis of the sequencing data from the patients’ normal cells that contain ‘germline’ information.A person’s germline is the genetic information inherited from both parents.By looking at this layer of information, scientists were able to look at a genetic baseline of a patient’s genesat birth – and reveal whether cancer-associated mutations were already present.The scientists looked for rare germline mutations in genes known to be associated with cancer.If one copy of one of the genes from one parent was already mutated at birth, the second normal copy fromthe other parent can often ‘compensate’ for the defect.However, people with such mutations are more susceptible to a ‘second hit’ – meaning that as they age, they have a higher risk of developing mutations in the remaining copy of the gene.Dr Ding said: ‘We looked for germline mutations in the tumor.‘But it was not enough for the mutations simply to be present; they needed to be enriched in the tumor – present at higher frequency.

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If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer.’Of the 114 genes already known to be associated with cancer, the scientists found rare germline mutations in all 12 cancer types.The scientists focused on a type of mutation called a truncation – as most truncated genes can’t function.The study found that 19 per cent of ovarian cancers carry rare germline truncation.
On the other hand, only four per cent of acute myeloid leukemia cases carried those truncations.Furthermore, they found that 11 per cent of the stomach cancer cases include the truncations – which was a surprise because the number is similar to the percentage for breast cancer.Dr Ding said: ‘We also found a significant number of germline truncations in the BRCA1 and BRCA2 genes present in tumour types other than breast cancer, including stomach and prostate cancers, for example.‘This suggests we should pay attention to the potential involvement of these two genes in other cancer types.‘Of the patients with BRCA1 truncations in the germline, 90 per cent have this BRCA1 truncation enriched in the tumour, regardless of the cancer type.’Genetic testing for BRCA1 and BRCA2 genes in women at risk of breast cancer has proven to be ‘extremely useful’ in prevention efforts.But genetic testing can also reveal many other genetic mutations that have unknown consequences – which means their cancer risk can’t be predicted.That’s why the scientists investigated 68 germline non-truncation mutations of unknown significance in theBRCA1 gene.They tested how well the BRCA1 protein could perform DNA-repair functions – and found that six of the mutations behaved like truncations, disabling the gene completely.Those same mutations were also found in the tumors – which means they may play a role in cancer.Dr Ding said: ‘It is important to be able to show that these six mutations of unknown clinical significance are, in fact, loss-of-function mutations.’The scientists said more information is needed to confirm these results before patients should use them to make healthcare decisions.

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