Familial cancer

Question 1

What features of a patients cancer suggest it may be familial?

Answer 1

• Many close relatives with the cancer including one first degree relative
• cancers in successive generations (eg grandad, father, son)
• young onset of cancer
• multiple cancers in one patient

Note: some cancers will have their own specific criteria to determine if the cancer is familial eg HNPCC

Question 2

What is the moelcular basis of a familial cancer? (what mutation/where)

Answer 2

In familial cancers people inherit a germline mutation in all of their cells. The majority involve tumour suppressive genes.

Question 3

Why are familial cancers that involve oncogenes rare?

Answer 3

Oncogenes are dominant acting (you only need to have a mutation in one of the alleles to produce the altered function of the oncogene) and so many of these hereditary syndromes are incompatible with life;

Question 4

What must happen to the cells of an individual who has inherited a tumour suppressive mutation in order for them to develop the cancer?

Answer 4

Because tumour suppressor genes are reccessive acting, they require a somatic/aquired mutation to the other normal allele to get total loss of function. (the 2 hit hypothesis).

Question 5

What are two common hereditary syndromes involving tumour suppressor genes in the colon?

Answer 5

Familial bowel cancer syndromes:

1. HNPCC - hereditary non-polyposis colo-rectal cancer syndrome

This is a autosomal dominance inheritance. Causes accelerated progression from adenoma to carcinoma. It is a multisystem disease so not only affects the colon but causes cancer elsewhere aswell. It is due to a mutation in one of 6 mismatch repair genes.

2. FAP - familial adenomatous polyposis syndrome

This is also autosomal dominant inheritance. It causes the colon to be carpeted in polyps in adolescence which will turn into adeno-carcinomas within 20 years. It is due to a inherited mutation of the APC gene.

Note: In both of these cases a “second hit” is required in addition to the germline mutation

Question 6

What are the genes involved in the breast and ovarian cancer syndrome?

Answer 6

BRCA1 and BRCA2.

BRCA proteins are involved in DNA repair. Mutations to these genes is autosomal dominant inheritance and responsible for an increased lifetime risk of breast cancer of 75-85% and increased ovarian cancer between 30-45%.

Alarm bells are early onset breast and menopausal cancer (pre-menopausal) as well as multiple family members.