Familial Cancers

Familial Cancers

Key Issues • Mutations inherited through germ cells are responsible for about 5% of all cancers. • Two genetic (rate limiting) mutations are required for tumour development. • Germ-line mutations in tumour suppressors can be: – recessive – dominant negative

• Sporadic cancers can be caused by acquired mutations in the same genes.

Key issues • In a single gene, germ- line mutations can occur in different loci in different families. • Germ-line mutations cause cancers in selected cell types. • Defective DNA repair results in increased cancer risk in some inherited syndromes.

The Incidence of familial cancers Familial Involvement

% of all cancers

Examples

None (Sporadic)

> 90

All types of cancer

Involved

5-10

Colorectal, breast, retinoblastoma, Wilm’s (kidney)

Well-defined

0.1

Retinoblastoma, Wilm’s

Familial Cancers are “rare” • Despite rarity of familial cancers, information obtained from their study has taught us about the cellular and molecular biology of sporadic cancers. • Rb tumour suppressor was identified by its defective function in familial retinoblastoma. • Now known to be a negative regulator of proliferation in may cell types • Rb mutations can occur in several sporadic cancers – Eg. Bladder cancer, some skin cancers

Condition

Gene

Chrom.

Cancer

Function

Retinoblastoma

Rb

13q

Eye

Proliferation control

Wilm’s tumour

WT1

11p

Kidney

Transcription

Familial Adenomatous polyposis APC coli

5q

Colon

Cell recognition

HNPCC

MSH2, MLH1

2p 3p

Colon

DNA mismatch repair

Breast Cancer

BRCA1 BRCA2

17q 13q

Breast DNA repair Breast male and female Transcription?

Li-Fraumeni

P53

17q

Breast +others

Transcription

Neurofibromatosis 1

NF1

17q

Neurosarcoma

Signal transduction

Multiple Endocrine Neoplasia type 1

MEN1

11q

Parathyroid, pancreas, Not known anterior pituitary

Familial Melanoma

INK4A

9p

Skin

Proliferation control

Xeroderma Pigmentosum

XP (A-F)

Several

Skin

Excision repair

Ataxia telangeictasia

ATM

11q

Leukaemias, lymphomas

DNA repair

Bloom’s syndrome

BLM

15q

Leukaemias, lymphomas

DNA repair

“Two hits”

Strong family link •

Rare cancers occurring in childhood with high frequency – inactivation of both alleles. In TSGs.

•

Most cancers are associated with age (need to accumulate multiple hits over a lifetime).

•

Childhood cancer indicates fewer changes are required.

•

This is the case for retinoblastoma which follows the two hit model. – Each allele inactivated independently.

Strong family link •

Retinoblastoma occurs in bilateral and unilateral forms – 90% of bilateral cases before age 2 – Unilateral cases by 4yrs old

•

Unilateral cases are due to the strong family link – The first mutation is already inherited

•

Familial cases are also characterised by multiple tumours in the same eye (clonal origin of cancer) each with a different type of second RB mutation.

•

In unilateral cases the first hit is acquired

Rb • Rb was localised to chromosome13q14 by means of karyotype markers • Familial RB cells were compared to normal cells from same patient – number of markers lost in 13q14 region (including esterase D gene). • Rb families were compares each with s slightly different deletion of chromosome 13q14 • Several families had also lost esterase D gene allowing precise localisation of Rb.

Wilm’s tumour • Commonest abdominal tumour in children with similar genetics to retinoblastoma. • Familial and sporadic forms. • Unilateral and bilateral forms requiring two hits for tumour formation. • WT1 located on 11p13 and gene encodes for a 49kDa DNA binding transcription factor expressed only in kidney cells (also maybe the gonads) • WTI mutations can be dominant negative – Similar to P53 gene

Wilm’s tumour • Down stream targets of WT1 – – – –

Insulin like growth factor (IGF-II) Epidermal growth factor (EGFi) Platelet derived growth factor (PDGF) Transforming growth factor-β (TGF-β )

• Inhibition of the transcription of these growth factors is a way in which cell growth can be suppressed.

Weaker Family Link •

Cancers in this category involve genes implicated directly in the carcinogenesis process.

•

Kindreds in the category have an elevated risk of developing one of several types of distinct cancer.

•

Genes involved often regulate a pathway common to many cell types: – Proliferation – Signal transduction

•

Multiple endocrine neoplasia, Neurofibromatosis are examples of weak family link inherited conditions.

Li-Fraumeni Syndrome • Due to germ-line mutations in the P53 gene causing breast and sarcomas but not other cancer types. • P53 has many function in cell cycle regulation and cell death (apoptosis) – Raises question as to why so few cancer types are seen in Li-Fraumeni syndrome.

• The pattern of P53 mutations in Li-Fraumeni is different to the pattern of mutations in somatic cells (sporadic cancers).

Connection with sporadic cancers •

•

•

Mutations in Rb are responsible for inherited and sporadic forms of retinoblastoma. Same is true for APC in colorectal cancer. In other examples the picture is more complex.

Familial Cancer Gene

Altered in Sporadic Cancers

Retina

RB

Yes

Colon

APC

Yes

HNPCC

13% of cases

Breast

BRCA1, BRCA2

No

Melanoma

INK4

Yes

Summary • Familial cancers are responsible for a minority of all cancers. • Types of tumours associated with familial involvement. • Strong family vs weak family link. • Specific examples – Retinoblastoma – Li-Fraumeni Syndrome – Wilm’s tumour

• Inherited cancers has taught us about the genetics of sporadic cancers.