1. Part Two Welcome back

2. Familial Cancer Genetics

3. 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

4. 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)

5. Parents Gametes At conception AUTOSOMAL DOMINANT INHERITANCE Affected Unaffected

6. Cancer Hereditary gene alteration 1 Somatic mutation Normal Tissue Somatic mutation

7. Cancer Hereditary gene alteration Somatic mutation Cancer 2 Somatic mutations

8. 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

9. Breast Cancer Referral Number of RelativesAge at diagnosisRefer to Genetics 1 (first degree)> 40 yearsNo 1 (first degree)< 40 yearsYes 1 (first degree) bilateralPrimary <50 yearsYes 1 Male (first degree)Any ageYes ≥ 2 (one first degree) average <60 yearsYes FH with Jewish ancestryYes Strong FH on paternal sideYes Tumour associations - ovary, endometrium, prostate, bowel Yes

10. Case 1 Breast cancer 46 Kay 65 76 4951 5355 70 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

11. Ovarian Cancer Number of RelativesAge at diagnosisRefer to Genetics 1 fdr no other FH of cancerAny ageNo 2 fdrAny ageYes 1fdr and 1sdrAny ageYes 1fdr or sdr with ovarian and 1 fdr or sdr with breast or colorectal cancer (at least 1 fdr) Any ageYes

12. Case 2 Refer – high risk Young age onset Equal transmission through men Multiple tumours in one individual Breast and ovarian cancer32Janet 48 breast cancer 48 breast cancer 56 ovarian cancer 42 Breast cancer Ovarian cancer

13. Colorectal Cancer Familial Adenomatous Polyposis (FAP) Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Other cancers associated with HNPCC – endometrial, stomach, ovarian Supporting Genetics Education for Health www.geneticseducation.nhs.uk

14. Bowel Cancer Number of relativesAge at diagnosisRefer to Genetics 1 fdr>50 yearsNo 1 fdr< 50 yearsYes 2 fdr (includes both parents)Any ageYes 1fdr and 1 sdrAny ageYes 3+ relativesAny ageYes FH of known hereditary colorectal cancer syndrome (e.g. HNPCC, FAP) Any ageYes HNPCC related cancers include endometrial, gastric, ovarian, pancreatic and urothelial

15. Case 3 73 32 Peter 75 60’s 78 73 43 77 35 died in war 68 Colorectal cancer Refer – moderate risk Young age of onset (under 45)

16. Case 4 8075 69 55 7848 42 George 49 42 30 Martin 39 Polyps Colorectal cancer Endometrial cancer Refer – High risk Young age of onset, Endometrial and Bowel Two generations, Polyps

17. 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

18. 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

19. Parents Gametes At conception AUTOSOMAL DOMINANT INHERITANCE Affected Unaffected

20. 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

21. Heart UK Definition using Simon Broome Register Total CholesterolLDL Cholesterol Adult>7.5mmol/l>4.9mmol/l Child < 16>6.7mmol/l>4.0mmol/l PLUS b) Tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 2nd degree relative (grandparent, uncle, aunt) OR c) DNA-based evidence of an LDL receptor mutation or familial defective apo B-100 Definite Familial Hypercholesterolaemia:

22. 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 CholesterolLDL Cholesterol Adult>7.5mmol/l>4.9mmol/l Child < 16>6.7mmol/l>4.0mmol/l Possible Familial Hypercholesterolaemia:

23. Daughter Son Parents Gametes At conception X-LINKED INHERITANCE WHERE THE MOTHER IS A CARRIER FatherMother XYXX (Carrier) (Affected) (Carrier) (Unaffected)