0430 - Familial Neoplasia

Question 1

How can a common genetic defect present with multiple phenotypes in a situation of familial neoplasia? What is the syndrome?

Answer 1

While some genes are associated with particular cancers, others, such as P53 are associated with a loss of genome protection. Mutations in P53 therefore make the individual more vulnerable to the ‘second hit’ that causes cancer.
This syndrome is Li Fraumeni Syndrome, involving a heterozygous, germline P53 deletion.

Question 2

Name two tumour suppressor genes that are commonly mutated to cause cancer. What cancers is it associated with, and how does it work?

Answer 2

Mutations in the TSG’s BRCA 1 and 2 are associated with breast, ovarian, and prostate cancer.
One mutation is inherited via the germline, the second is acquired, generally due to deletion or epigenetic changes.

Question 3

What is CDKN2A and how does it associate with cancer?

Answer 3

Tumour suppressor gene on 9p21.
Homozygously deleted in cancers of lung, breast, brain, bone, skin, bladder, kidney, ovary and lymphomas.
No relationship between phenotype and genotype.
Also associated with Li-Fraumeni syndrome, melanoma, and multiple other cancers.

Question 4

What cancers are associated with Li Fraumeni syndrome?

Answer 4

Breast cancer, osteosarcoma, soft fissue sarcomas, brain tumours, leukaemias.

Question 5

What genes are associated with Li-Fraumeni syndrome?

Answer 5

CHEK2 and P53, both tumour suppressor genes.

Question 6

How is Li Fraumeni Syndrome inherited?

Answer 6

Autosomal Dominant.