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Cancer Genetics for Primary Care Sara Levene Registered Genetic Counsellor Proportion of cancer that is inherited Inherited susceptibility to cancer: ‘genetic’ Single genes Family history of cancer: ‘familial’ ?multi-factorial origins Population risk: Breast cancer 1:10 Ovarian cancer 1:100 Colorectal cancer 1:25 - 35 No family history of Cancer: ‘sporadic’ ?multi-factorial origins To make a long story short: All cancer is genetic Cancer is rarely inherited Sporadic cancer 2 normal genes 1 normal gene 1 mutated gene hormones viruses chemicals radiation 2 mutated genes cancer Spontaneous mutations Inherited cancer 1 normal gene 1 mutated gene hormones viruses chemicals radiation 2 mutated genes Spontaneous mutations cancer Inherited Mutations and Cancer • Inherited mutations relating to cancer do not cause cancer • Mutations are often found in genes that are ‘tumour suppressors’ • Mutations mean that protection from cancer is lost or reduced • Mutations lead to increased susceptibility to certain types of cancer Autosomal dominant inheritance mother child father child Each child has 50:50 chance of inheriting the altered gene. Genetic testing Cancer Genes Mendelian Inheritance (AD) • In the last 10 years several genes relating to specific cancer syndromes have been identified • There are more cancer genes waiting to be ‘discovered’ • It is difficult to locate the exact mutation in a cancer gene for a particular family Cancer Genes Multi-factorial Inheritance • More recently the search for other AD genes has led to the discovery of some ‘lower risk’ genes eg. CHEK2 – found in ~2% cases ca br – est doubles risk of ca br • ? Liability/threshold model with several similar genes (+ env factors) • This research is not yet applicable to clinical practice Genetic Testing • Technically difficult • Can only be offered to high risk families • Can only search small number of high risk dominant genes • Can take more than a year to search for the mutation in a family • Often cannot locate the mutation for a family (?unknown genes) Searching for the faulty gene cgattgagg cgattgagg cgattgagg atcgtacgta atcgtacgta atcgtacgta cgattgagg cgattgagg cgattgagg ttaacggtag ttaacggtag ttaacggtag atcgtacgta atcgtacgta atcgtacgta ctataccagtc ctataccagtc ctataccagtc ttaacggtag ttaacggtag ttaacggtag cgattgagg cgattgagg cgattgagg gatccattgga gatccattgga gatccattgga ctataccagtc ctataccagtc ctataccagtc atcgtacgta atcgtacgta atcgtacgta a gtcatcgatgtt gtcatcgatgtt gtcatcgatgtt gatccattgga gatccattgga gatccattgga ttaacggtag ttaacggtag ttaacggtag cgattgagg cgattgagg cgattgagg gtcatcgatgtt gtcatcgatgtt gtcatcgatgtt ctataccagtc ctataccagtc ctataccagtc atcgtacgta atcgtacgta atcgtacgta cgattgagg cgattgagg cgattgagg gatccattgga gatccattgga gatccattgga ttaacggtag ttaacggtag ttaacggtag atcgtacgta atcgtacgta atcgtacgta gtcatcgatgtt gtcatcgatgtt gtcatcgatgtt ctataccagtc ctataccagtc ctataccagtc ttaacggtag ttaacggtag ttaacggtag gatccattgga gatccattgga gatccattgga ctataccagtc ctataccagtc ctataccagtc gtcatcgatgtt gtcatcgatgtt gtcatcgatgtt gatccattgga gatccattgga gatccattgga gtcatcgatgtt gtcatcgatgtt gtcatcgatgtt Genetic Testing • First test in family always done on person who has had the cancer (mutation search test) • If no living affected relatives available – cannot offer genetic test for family • If a mutation is found predictive testing can be offered to at-risk relatives: – If relative doesn’t carry familial mutation they are not at increased risk of cancer (still at population risk) – If a person does carry the familial mutation they are at increased risk of developing cancer Family History of Breast Cancer High Risk Cancer risks associated with BRCA1 and BRCA2 Breast and ovarian cancer Other cancers • Breast cancer risk ~80% • Ovarian cancer risk ~45% • Increased risk of second primary for women who have already had breast cancer • • • • Prostate cancer Male breast cancer Pancreatic cancer Colorectal cancer • Stomach cancer Recent NICE Guidelines on Familial Breast Cancer • Women at or near population risk are cared for in primary care. • Women at moderate risk are cared for in secondary care. • Women at high risk are cared for in tertiary care. Breast cancer case study 1 Ca breast, diag 70y Died 85y 68y Brain tumour, died 67y ? Prev breast cancer in 40s? Breast cancer case study 1 Ca breast, diag 70y Died 85y 68y Brain tumour, died 67y No record of prev ca br Can this patient now be reassured? Population risk Screening and management • National breast screening from 50y • Breast awareness • Reassure patient: – For most women, increasing age is the greatest risk factor. – The great majority of women with a family history of breast cancer do not fall into a high-risk category and do not develop breast cancer. Breast cancer case study 2 Ca breast, diag 54y Patient is requesting screening and is considering prophylactic mastectomies. What is her level of risk? Ca breast, diag 52y 20y What is appropriate management of her risk? Patient is also interested in genetic testing. Can this be offered? Moderate risk Referral to secondary care Female breast cancers • One 1st degree relative diagnosed before age 40 • Two 1st degree relatives (or one 1st degree relative and one 2nd degree relative) diagnosed after average age 50 Moderate risk Screening and management • • • • Annual breast surveillance from age 40 – 50y National Breast Screening from 50y. ?Chemoprevention studies Breast awareness Breast cancer case study 3 Ca breast Died 40y Ca breast Diag 32y What can we offer this family? Considering prophylactic mastecomies Breast cancer case study 3 Ca breast Died 40y Recommend screening Ca breast Diag 32y Blood taken for BRCA1/2 testing Recommend screening Breast cancer case study 3 Ca breast Died 40y Ca breast Diag 35y Ca breast Diag 32y BRCA1/2 testing on-going Breast cancer case study 3 Ca breast Died 40y Ca breast Diag 35y Ca breast Diag 32y BRCA1 mutation found Breast cancer case study 3 Ca breast Died 40y N Ca breast Diag 35y BRCA1 mutation carrier BRCA1 mutation carrier Ca breast Diag 32y BRCA1 mutation found High risk Referral to secondary care, then tertiary care • Two 1st degree relatives (OR one 1st degree relative and one 2nd degree relative) with breast cancer, av age <50 • Three or more 1st or 2nd degree relatives with breast cancer at any age • One 1st degree male relative with breast cancer at any age • One 1st degree relative with bilateral breast cancer where 1st primary diagnosed <50 • One 1st or 2nd degree relative with ovarian cancer at any age and one 1st or 2nd degree relative with breast cancer at any age High risk Screening and management • 30-39y: may be eligible for annual mammograms • 40-49y: annual mammograms • >50y: NBSP, plus may be eligible for additional screening • Refer to genetics to discuss genetic testing • ?MRI screening in the future • ?Prophylactic surgery • ?Ovarian screening Breast cancer case study 4 What should we do for this family? Ca ?type Ca breast, diag 51y Died 53y Ca breast, diag 41y Breast cancer case study 4 Ca ovary, died 48y Ca breast, diag 51y Died 53y Breast & ovarian screening Ca breast, diag 41y Breast cancer case study 4 Ca ovary, died 48y Ca breast, diag 51y Died 53y Breast & ovarian screening Ca breast, diag 41y Blood taken for BRCA1/2 testing Breast cancer case study 4 Ca ovary, died 48y Ca breast, diag 51y Died 53y Considering surgery Ca breast, diag 41y BRCA1/2 tested No mutations found Other factors to consider: • Paternal history: two or more breast cancers on father’s side of family • Unusual cancers: Bilateral breast cancer Male breast cancer Ovarian cancer Sarcoma <45y Glioma or childhood adrenal cortical carcinoma Complicated patterns of multiple cancers at young age • Jewish ancestry Women with Jewish ancestry are around 5–10 times more likely to carry BRCA1 or BRCA2 mutations than women in non-Jewish populations. Family History of Colorectal Cancer FAP HNPCC Familial Adenomatous Polyposis Hereditary Non-Polyposis Colon Cancer • 100% affected by 35y • Hundreds/thousands of polyps in colon • Mutation on APC gene • Accounts for <1% colon cancers • Other cancer risks: duodenal, gastric • Up to 80% lifetime risk • Less than 10 polyps found • At least 5 genes found • Accounts for up to 5% of colon cancers • Other cancer risks: endometrial, ovarian, gastric Familial Adenomatous Polyposis (FAP) CRC FH Risk categorisation Low risk One FDR with CRC at > 45 (No screening required, bowel awareness) Low-Moderate risk Two FDRs with CRC at average age > 60. Screening: One colonoscopy at 35y-40y and one at 55y High-Moderate risk One FDR with CRC <45, or three older FDRs i.e. >50. Screening: Begins at 45 or 5yrs prior to youngest diagnosis (not prior to 35). Repeat 5yrly to 75y. What is High Risk? • A known polyposis syndrome e.g. FAP Be sure to ask if there is any history of polyposis in the family. • HNPCC (Amsterdam positive families). – At least 3 of HNPCC related cancers (CRC, endometrium, ovarian, small bowel, ureter or renal pelvis) – One should be a FDR of the other two – At least two successive generations affected – At least one cancer diagnosed < 50 years High risk screening/management HNPCC • Colonoscopies from 25y, continuing 2 yearly to 75y • ?Endometrial/ovarian screening annually from 35y (research) FAP • Colonoscopies annually from teens (or younger depending on family history) • Prophylactic colectomy offered • ?Upper GI screening annually (research) Summary • Most cancer is not due to dominant, high-risk genes. • Most patients with a family history of cancer can be reassured and possibly referred for screening. • For most patients with a family history of cancer, current genetic testing is not helpful and is not available. • Patients with a high risk of cancer due to family history can have screening, and genetic testing may be available. • Patients who inherit a mutation in a high risk gene have a high risk of developing cancer themselves. Take-home messages • Young diagnoses of cancer (<45y) may be significant • Three or more cases of the same / related types of cancer, in one family (even if older ages) may be significant • Genetic testing may or may not be available / informative for a given family • Genetic testing must start with a living affected relative • Screening may be available If you have enquiries about a family history : Contact your local Clinical Genetics dept: Clinical Genetics Great Ormond Street Hospital London WC1N 3JH Tel: 0207 905 2138 Clinics held at Barts and The London.