Familial and Hereditary Cancer

Question 1

How much of cancer has a hereditary basis?

Answer 1

5-10% of all cancer

Question 2

Why is the study of inherited cancer syndromes useful for the study of sporadic cancers?

Answer 2

The processes which occur in hereditary cancer are often the same as those which occur in sporadic cancer allowing us to gain insight into important mechanisms for tumour development
However hereditary cancers are often due to single highly penetrant mutations which will only cause a small proportion of cancers

Question 3

Is smoking likely to be due to nature or nurture?

Answer 3

There is a behavioural relationship where if both parents smoke then there is a 25% chance you will smoke going down to 11 if only one parent smokes and 4.3 if two parents smoke
However there may be mild genetic component with CYP2A6 variants (involved in the rate of nicotine metabolism) influences the risk of smoking

Question 4

How common is familial and hereditary cancer?

Answer 4

Familial cancer accounts for 30% of cancers while hereditary cancer accounts for 15% of all cancer

Question 5

What is inherited cancer?

Answer 5

This refers to cancer susceptibility which is being genetically inherited in a Mendelian fashion
Within this category are genes of variable penetrance
Highly penetrant genes are usually rare but may be concentrated in particular groups or families because of consanguinity or founder effects
These may contribute 5-10% of all cancers

Question 6

What is familial cancer?

Answer 6

This refers to cancer which is clustered in families and by implication suggests that both genetics and environmental factors play a role
This may contribute 10-30% of overall cancer

Question 7

What are cancer syndromes?

Answer 7

Many hereditary cancer syndromes and their causative genes have been identified
Most hereditary syndromes appear to be due to the inheritance of a mutant tumour suppressor gene, as both copies of the gene are required to be inactivated therefore dependent on the 2nd hit to the wild type allele
While inherited cancer follows an autosomal dominant Mendelian pattern of inheritance, tumour suppressor genes actually act recessively at the cellular level

Question 8

How are inherited cancers recognized?

Answer 8

There is recognition of individuals with an inherited susceptibility to cancer usually relies on taking a careful family history to document the presence or absence of other family members with similar or related cancers
The malignancies which develop in susceptible individuals are often the same as those which occur in the population in general
The genes responsible for the hereditary forms of prostate, lung, pancreatic and testicular cancer are yet to be found

Question 9

What are the features of an inherited cancer syndrome?

Answer 9

Several close family members with a common cancer
Several close relatives with related cancers
Two family members with the same rare cancer
Early age at diagnosis
Bilateral tumours in paired organs
Synchronous or successive tumours
Tumours in two different organ systems in one individual
Presentation of cancer in the less usually affected sex

Question 10

What are the features of inherited breast cancer?

Answer 10

Several close family members with breast cancer
Age of onset is younger
Bilateral involvement is common
Presence of associated tumours at other sites (especially ovarian
cancer) in affected individuals in some families
Male breast cancer

Question 11

What are the high penetrance genes for risk of breast cancer?

Answer 11

BRCA1, BRCA2, TP53

Question 12

What are the moderate penetrance genes for the risk of breast cancer?>

Answer 12

ATM, BRIP1, CHEK2, PALB2

Question 13

What are the low penetrance genes for risk of breast cancer?

Answer 13

FGFR2, TNRC9/TOX3,

MAP3K1, LSP1, CASP8

Question 14

What is Familial adenomatous polyposis (FAP)?

Answer 14

This is a condition inherited in an autosomal dominant fashion which makes up approx.. 1% of colorectal cancer
Begin to grow benign polyps (adenomas) at age 10-15, the
colon becomes carpeted with hundreds or thousands of
polyps in 20’s and 30’s
The polyps are not all malignant, but one or more of them is
likely to evolve into an invasive carcinoma

Question 15

What is the Adenomatous Polyposis Coli gene (APC)?

Answer 15

Accounts for 80% of FAP, tumours lacking APC mutations often have
inactivating mutations in β-catenin
Mutations are mainly nonsense or truncating frameshifts, located in the
5’ end of the gene
Acts as classical (gate keeper) tumour suppressor gene, with
inactivation of both alleles required
An attenuated form of FAP, with and 3’ mutations in APC

Question 16

What is Hereditary nonpolyposis colon

cancer (HNPCC)?

Answer 16

Inherited as autosomal dominant condition
Early age of onset (< 45 years, which is 20 years less than sporadic
cases)
Predominantly right side of proximal colon
No preceding phase of polyposis
Causes between 2-4% of colon cancer

Question 17

What are the Amsterdam criteria for determining if a colorectal cancer is due to an inherited syndrome?

Answer 17

At least 3 relatives with: colorectal, endometrial, stomach, ovary, ureter or
renal-pelvis, brain, small bowel, hepatobiliary tract, or skin
Histologically confirmed
One must be first degree relative of the other two
At least 2 successive generations affected
One or more cancers diagnosed before age 50
FAP excluded

Question 18

What makes Li-Fraumeni

Syndrome unusual?

Answer 18

several kinds of cancer are 
involved (sarcoma, breast, 
brain, leukemia, adrenal cortex)
cancer often occurs at a young 
age, and
cancer often occurs several 
times throughout the life of an 
affected person.

Question 19

What is Retinoblastoma?

Answer 19

A rare cancer which develops in the cells of the retina
Accounts for ~ 3/100 cancers occurring in children < 15 years
Children present with an abnormal appearance of the pupil which
reflects light as a white reflex

Question 20

What is the retinoblastoma gene?

Answer 20

RB was discovered because some families appeared to have a high
rate of bilateral retinoblastomas.
However, spontaneous retinoblastomas develop in some individuals,
usually unilateral.
This phenotype is caused by inheriting one defective (but recessive)
allele of RB.
Individuals with one defective allele require one additional hit to remove
the remaining allele (the only functional copy).

Question 21

How are cancer families managed?

Answer 21

If a high risk personal or family history is identified genetic counselling will be offered this may be followed by genetic testing and if the individual is a confirmed mutation carrier close relatives will also be offered the counselling and cancer prevention strategies may be put into place

Question 22

What have been the Lessons learned from genetic testing for

BRCA1/2?

Answer 22

Identifying those with gene mutations helps to evaluate the risks and
options for choosing screening or surgery.
Prophylactic procedures reduces the risk of developing breast and
ovarian cancer. The earlier the procedure is performed, the greater
the benefit.
Communication of risks and options is best provided through genetic
services.
New options for fertility preservation, and new targeted treatments

Question 23

What are the potential options for an identified BRCA1/2 gene carrier?

Answer 23

Increased screening/surveillance
Prophylatic surgery
Chemoprevention
Lifestyle changes