Common mutations

Question 1

Gastric cancers

Answer 1

Intestinal-type gastric cancers are associated with increased signalling through the Wnt pathway, which is caused by LOF mutations of APC and GOF mutations of β-catenin. As such, individuals carrying germline APC mutations are more at risk of these forms of cancers

Question 2

Gastrointestinal stromal tumours

Answer 2

Most cases (>90%) are sporadic, caused by sporadic GOF mutations of receptor tyrosine kinases such as KIT (85%) and closely related PDGRA (8%), which is thought to be in same signalling pathway – Tyrosine kinase inhibitors are effective treatments

Question 3

Hepatocellular carcinoma

Answer 3

• Activating β-catenin mutations are identified in up to 40% of persons with HCC. These tumours are more likely to be unrelated to HBV and to demonstrate genetic instability
• Inactivation of p53 is present in up to 60% of HCC cases. These tumours are strongly associated with aflatoxin

Question 4

Acute lymphoblastic leukaemia

Answer 4

The t(12;21) translocation results in creation of the TEL-AML fusion gene which is associated with 30% of cases

Question 5

Acute premyelocytic leukaemia

Answer 5

Acute premyelocytic leukaemia is characterised by translocation of the retinoic acid receptor (RAR) on chromosome 17 to 15. RAR disruption blocks maturation and promyelocytes (blasts) accumulation

Question 6

Chyronic lymphocytic leukaemia

Answer 6

• CLL is commonly associated with chromosomal abnormalities including deletions on chromosome 11q (18%), 13q14 (50%) and 17p (7%), as well as trisomy chromosome 12
• Around 50% of cases are also associated with somatic hypermutation of the Ig heavy chain (IgVH), which is associated with slower disease progression and better prognosis
• There is also associated expression of zeta-associated protein 70 (ZAP70) (suggests IgVH -ve thus poor prognosis), and expression of CD38 (suggests IgVH -ve thus poor prognosis) and CD49d (also associated with poor prognosis)

Question 7

Chronic myeloid leukaemia

Answer 7

Over 80% of patients with CML have the Philadelphia chromosome, formed from the translocation of long arm fragments between chromosome 9 and 22, resulting in the formation of the oncogenic fusion protein BCR-ABL which has persistently activated ABL tyrosine kinase activity, promoting uncontrolled cell proliferation

Question 8

Follicular lymphoma (form of non-Hodgkin’s lymphoma)

Answer 8

• It generally arises from germinal centre B-cells and is heavily associated with a chromosomal translocation that juxtaposes the IGH locus from chromosome 14 next to the BCL2 locus on chromosome 18 (found in 90% of cases)
• This leads to overexpression of BCL2, which antagonises apoptosis and promotes survival of germinal centre cells

Question 9

Diffuse large B-cell lymphoma

Answer 9

• Mutations in BCL6 are implicated. It can either be translocations that have common breakpoints in the BCL6 gene. Alternatively, there can be acquired mutations in the BCL6 promoter genes. These mutations are most likely attributed to somatic hypermutation
• BCL6 normally represses expression of factors that promote germinal centre B-cell differentiation, growth arrest and apoptosis

Question 10

Burkitt lymphoma

Answer 10

• Burkitt’s lymphoma is heavily associated with the c-MYC gene translocation on chromosome 8
• c-MYC is a leucine zipper transcription factor that affects different pathways regulating cell cycle, growth, adhesion, differentiation, and apoptosis
• The most common translocation occurs between chromosome 8 and 14 (~80%), placing c-MYC gene into the Ig heavy chain locus, where it becomes juxtaposed to more transcriptionally-active Ig promoters

Question 11

Wilm’s tumour

Answer 11

One of the commonly implicated genes in Wilm’s tumour (WT1, on chromosome 11) encodes a transcription repression factor downregulating IGF-II. However, it is most likely that a 2-hit hypothesis is present in pathogenesis of Wilm’s tumours; whereby genetic predisposition is the first hit (e.g. inactivates one copy of a tumour suppressor gene), and a second hit (e.g. sporadic mutation) is required for second hit before tumourigenesis occurs

Question 12

Neuroblastoma

Answer 12

• Germline mutations in the anaplastic lymphoma kinase (ALK) and PHOX2B gene have recently been implicated in the familial and sporadic form of the disease
• V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) is also implicated in the pathogenesis of the condition, and amplification of MYCN is associated with poor prognosis

Question 13

Renal cell carcinoma

Answer 13

• Tumour suppressor VHL protein is commonly mutated (60-70% of RCC patients), most often associated with clear cell carcinomas
• In 98% of cases of clear cell carcinoma (regardless of whether sporadic or familial), there is deletion of sequence on short arm of chromosome 3, which harbours the VHL gene. The other non-deleted allele of the VHL gene shows somatic mutations or hypermethylation-induced inactivation in up to 80% of clear cell tumours
• VHL seems to code for protein that forms part of the ubiquitin ligase complex whose function is to target protein for destruction. One important protein it targets for destruction is the HIF protein, whose downstream targets include regulators of angiogenesis and genes that promote cell growth. HIF may also contribute to the signalling pathway of the oncogene MYC