Normal cells that form the tissues of our body can be transformed into cancer by mutations within multiple genes that tell the cells how to behave. Mutations can come about in a number of different ways. Small changes in how a gene codes for just one of the amino acids that make up a protein can completely alter the activity of a protein. For example, KRas is a signalling protein with normally undergoes cyclical turning on and off when the cell needs it to help with growth, however a mutated active form a KRas cannot be turned off and goes on to allow cells to grow almost uncontrolled. Larger changes to genes may also occur with whole genes lost or moved around in the DNA. In fact in cancer cells DNA can become very messy!
A very important and well known mutation that was discovered in a leukaemia called chronic myelogenous leukemia (CML) is called the "Philadelphia Chromosome". This occurs when two large structures of DNA called chromosomes (humans have 23 pairs of chromosomes in each cell) swap small pieces; part of chromosome 9 is swapped with part of chromosome 22 making the former longer and the latter shorter. This new chromosome 22 is what is known as the "Philadelphia Chromosome". As a consequence, two genes BCR and ABL, which are not normally associated at the DNA level, become fused together to form the oncogene BCR-ABL. As an oncogene, BCR-ABL is crucial in driving cancer, it is most commonly associated with CML and other leukemias.
Many drugs for treating and managing cancer involve targeting a gene in cancer cells which is either found at a higher level or only slightly modified; because BCR-ABL is a completely different gene that is only found in cancer cells it was an attractive target for drug development. Indeed, an inhibitor of BCR-ABL called Imatinib/Gleevec has been immensely successful in treating CML. A number of patients respond well at first, but their cancer cells acquire a resistance to Imatinib; this occurs because the BCR-ABL protein becomes further mutated. Doctors can switch to using other BCR-ABL inhibitors such as Nilotinib/Tasigna, however some mutations in BCR-ABL also confer resistance to Nilotinib as well.
A recent study in the British Cancer Journal found that mutations in BCR-ABL that become undetectable following treatment with Imatinib, can reemerge years later after treatment is changed to Nilotinib. This occurs in part due to a process called clonal expansion. A mutation which gives a cancer cell a growth or survival advantage compared to other cells within a tumour can be expanded, as these cells take over to form the bulk of the tumour.
It is therefore even more important for doctors to check which mutations of BCR-ABL are present in cancer cells when choosing treatment options, to prevent reemergence of mutations that will make cancer cells resistant.
Parker WT, Yeoman AL, Jamison BA, Yeung DT, Scott HS, Hughes TP, Branford S.
BCR-ABL1 kinase domain mutations may persist at very low levels for many years and lead to subsequent TKI resistance.
Br J Cancer. 2013 Sep 17;109(6):1593-8. doi: 10.1038/bjc.2013.318
Cancer Research UK: Imatinib (Glivec)
Cancer Research UK: Nilotinib (Tasigna)