part two welcome back. familial cancer genetics cancer genetics 5-10% of all cancer clearly linked...
TRANSCRIPT
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Part Two
Welcome back
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Familial Cancer Genetics
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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
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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)
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Parents
Gametes
At conception
AUTOSOMAL DOMINANT INHERITANCE
AffectedUnaffected
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Cancer
Hereditarygene alteration
1 Somatic mutation
Normal Tissue
Somatic mutation
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Cancer
Hereditarygene alteration
Somatic mutation
Cancer
2 Somatic mutations
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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Parents
Gametes
At conception
AUTOSOMAL DOMINANT INHERITANCE
AffectedUnaffected
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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
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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:
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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:
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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)