Part Two Welcome back
Apr 01, 2015
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)