Part Two

Welcome back

Familial Cancer Genetics

Cancer Genetics• 5-10% of all cancer clearly linked to an inherited gene

alteration

• If cancer seen at younger ages (before 50) possible that inherited genes increased susceptibility

• Some genetic conditions increase someone’s risk of getting several different types of cancer at young age (eg. Li-Fraumeni syndrome, MEN 1)

• Some gene alterations lead to uncontrolled cell growth:– tumour suppressor genes– oncogenes– DNA repair genes

Breast Cancer• BRCA 1 & BRCA 2 testing may be available for people at

high risk, but others genes known to be involved

• If gene alteration found, woman at up to 80% lifetime risk of developing breast cancer

• Carry risk of other cancers; ovary (BRCA 1 = 44%, BRCA 2 = 27%), and a slightly increased risk prostate, pancreas and some other cancers

• Dominantly inherited through families (ie. only one copy of the altered gene needed for it to have effect)

Parents

Gametes

At conception

AUTOSOMAL DOMINANT INHERITANCE

AffectedUnaffected

Cancer

Hereditarygene alteration

1 Somatic mutation

Normal Tissue

Somatic mutation

Cancer

Hereditarygene alteration

Somatic mutation

Cancer

2 Somatic mutations

What would indicate that a woman is at higher risk of developing breast/ovarian

cancer?

Relative with male breast

cancer

Relative with bilateral breast

cancer

2+ relatives on the same side of the family affected

by breast cancer (especially if affected at younger ages)

2+ relatives with ovarian cancer

Relative with breast cancer before the age of 40

Breast Cancer ReferralNumber of Relatives Age at diagnosis Refer to Genetics

1 (first degree) > 40 years No

1 (first degree) < 40 years Yes

1 (first degree) bilateral Primary <50 years Yes

1 Male (first degree) Any age Yes

≥ 2 (one first degree) average <60 years Yes

FH with Jewish ancestry Yes

Strong FH on paternal side Yes

Tumour associations - ovary, endometrium, prostate, bowel

Yes

Case 1

Breast cancer

46Kay

65

76

49 51 53 55

70

Reassure and explain population risk. Advise on symptom awareness and to report any changes in family history

Low risk – manage in primary care

• Older age of onset

• Different sides of the family

Ovarian CancerNumber of Relatives Age at diagnosis Refer to Genetics

1 fdr no other FH of cancer Any age No

2 fdr Any age Yes

1fdr and 1sdr Any age Yes

1fdr or sdr with ovarian and 1 fdr or sdr with breast or colorectal cancer (at least 1 fdr)

Any age Yes

Case 2Refer – high risk

• Young age onset

• Equal transmission through men

• Multiple tumours in one individual

• Breast and ovarian cancer

32Janet

48 breast cancer 56 ovarian cancer

42

Breast cancer

Ovarian cancer

Colorectal Cancer Familial Adenomatous Polyposis (FAP)

Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Other cancers associated with HNPCC – endometrial, stomach, ovarian

Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk

Bowel CancerNumber of relatives Age at diagnosis Refer to Genetics

1 fdr >50 years No

1 fdr < 50 years Yes

2 fdr (includes both parents) Any age Yes

1fdr and 1 sdr Any age Yes

3+ relatives Any age Yes

FH of known hereditary colorectal cancer syndrome(e.g. HNPCC, FAP)

Any age Yes

HNPCC related cancers include endometrial, gastric, ovarian, pancreatic and urothelial

Case 3

73

32Peter

75

60’s

78

73

4377

35 died in war

68

Colorectal cancer

Refer – moderate risk Young age of onset (under 45)

Case 4

80 75

6955

784842George

49

4230Martin

39Polyps

Colorectal cancer

Endometrial cancer

Refer – High risk

Young age of onset,

Endometrial and Bowel

Two generations, Polyps

Referral for family history of cancer• Young age at onset,

• Pattern of similar tumours on one side of the family (or multiple primaries in one individual)

• Use national/local guidelines e.g. NICE familial breast cancer

• Remember ethnicity e.g. – Chinese, Indian, Ashkenazi Jewish ancestry

• If in doubt - Contact the Clinical Genetic Service

Patient Information

• Detailed information of affected family members required

• Patient will receive information regarding level of risk and options

• Will not necessarily mean a genetic test

Parents

Gametes

At conception

AUTOSOMAL DOMINANT INHERITANCE

AffectedUnaffected

Familial Hypercholesterolaemia• If fulfil Simon Broome criteria, refer to

specialist lipidologist• Where Genetic testing is not available,

cascade testing for family members by fasting lipid profile

• Children tested below 10 years• Boys have lower cholesterol during puberty

Heart UK Definition using Simon Broome Register

Total Cholesterol LDL Cholesterol

Adult >7.5mmol/l >4.9mmol/l

Child < 16 >6.7mmol/l >4.0mmol/l

PLUSb) Tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 2nd degree relative (grandparent, uncle, aunt)ORc) DNA-based evidence of an LDL receptor mutation or familial defective apo B-100

Definite Familial Hypercholesterolaemia:

Heart UK Definition using Simon Broome Register

PLUS• d) Family history of myocardial infarction: below age of 50

in 2nd degree relative or below age 60 in 1st degree relative

Or • e) Family history of raised cholesterols:

– >7.5 mmol/l in adult 1st or 2nd degree relative or– > 6.7 mmol/l in child or sibling under 16

Total Cholesterol LDL Cholesterol

Adult >7.5mmol/l >4.9mmol/l

Child < 16 >6.7mmol/l >4.0mmol/l

Possible Familial Hypercholesterolaemia:

Daughter Daughter Son Son

Parents

Gametes

At conception

X-LINKED INHERITANCE WHERE THE MOTHER IS A CARRIERFather Mother

X Y XX

(Carrier) (Affected)

(Carrier)(Unaffected)