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WEEK 23:
Cancer Genetics: A clinical perspective:
| Question | Answer |
|---|---|
| all cancer is a genetic disease of what type of cells | somatic cells |
| 5-10% breast cancer cases are due to | germline mutations in cancer predisposition genes where half of these families will have mutations in BRCA1/2 |
| 5% colorectal cancer result from | inherited mutations in one HNPCC related gene |
| variable expression | being predisposed to different tumours in same individual |
| age related penetrance | more likely to have tumour (express mutation) over time |
| proto-oncogenes | genes which promote cell proliferation |
| tumour suppressor genes | genes inhibiting cell proliferation |
| mutator genes | genes whose normal function is to maintain genome integrity eg mismatch repair genes (they correct) |
| multiple endocrine neoplasia (MEN) type 2 | caused by RET gene (proto-oncogene) via germline point mutations leading to medullary thyroid cancer, parathyroid tumour, and phaechromocytoma |
| hereditary papillary renal carcinoma | caused by MET gene (proto-oncogene) via germline missense mutations where MET encodes growth factor receptor |
| Li-Fraumeni syndrome (LFS) | caused by TP53 (mutated tumour suppressor genes) leading to young onset cancer especially sarcoma and breast |
| breast cancer and ovarian cancer caused by | BRAC1+2 (mutated tumour suppressor gene) |
| Cowden syndrome | caused by PTEN (mutated tumour suppressor gene) leading to breast, thyroid and some skin cancers |
| familial adenomatous polyposis | caused by APC (mutated tumour suppressor gene) leading to colorectal and other cancers |
| examples of proto-oncogenes (2) | RET and MET |
| examples of tumour suppressor genes (4) | TP53, BRCA1 +2, PTEN, and APC |
| BRAC1 is linked to breast + ovarian cancer and | prostate cancer |
| BRAC2 is linked to which cancers | prostate, pancreatic and male breast cancer |
| familial adenomatous polyposis (FAP) is caused by | mutation in APC gene (tumour supressor gene) |
| APC mutation is linked to what type of cancer | colorectal cancer |
| features of colorectal cancers | 50% have polyps by 16yrs (7% have CRC at 21yrs if untreated) and average age of CRC is 39yrs if untreated. There are >100 colorectal adenomatous polyps |
| two hit hypothesis | gene mutations may be inherited or acquired during a person life and cells can only form a tumour when it contains two mutant alleles (mutation once gives one and having a mutation again is rate but need both genes to be mutated) |
| mutations in hMLH1 and hMLH2 lead to | problem with DNA repair (mismatch repair) leading to hereditary non polyposis colorectal cancer (HNPCC - Lynch Syndrome) |
| inherited APC (or MLH) mutations increase chance of | CRC |
| how do you respond to high risk | surveillance indicated -> secondary care +/- genetics -> gene testing (clinical genetics) |
| how do you respond to moderate risk | surveillance indicated -> secondary care (screening clinic) |
| how do you respond to low risk | surveillance not indicated (discharge 1st care) |
| what to look for in familial cancer predisposition | early onset tumours, multiple tumours in close relatives, multiple tumours within an individual, and clusters of different tumours in a recognisable pattern |
| risk category is assigned according to what | number of relatives and age of onset |
| low risk in breast cancer | <2x population risk |
| moderate risk in breast cancer | 2-3 population risk |
| high risk breast cancer | >3x population risk |
| low risk in bowel cancer | < 1:10 risk |
| moderate risk in bowel cancer | 1:6 to 1:10 risk |
| high risk in bowel cancer | > 1:6 risk |
| von hippel lindau (VHL) syndrome | caused by the VHL gene and is an uncommon cancer predisposition syndrome. Unusual tumours seen at young ages, is autosomal dominant (need one expressed to occur), incidence is 1:36000, tumours arise in multiple organs eg haemangioblastomas etc |
| pedigree assessments | carried out in family history clinic or clinical genetics service |
| how to do pedigree assessments | take pedigree and confirm family history including diagnoses. If affected individuals are dead take details from cancer registry/ patient notes/ death certificate BUT if they are alive obtain consent to see medial records |
| risk modification options (3) | surveillance, prophylactic surgery and or chemoprevention, and diagnostic and predictive molecular genetic testing |
| what is prophylactic surgery | remove organs/ tissue that do not have cancer but have a high risk of getting it |
| what is chemoprevention | mediation given to delay development/ reverse development of cancer |
| when is surveillance offered | when there is a greater than 10% risk of developing cancer |
| surveillance has to be (3) | balanced against side effects of screening, cost effective, and regularly reviewed |
| mammography for breast/ ovarian cancer | given from 40-50 via national breast screening programme |
| MRI for breast/ ovarian cancer | scanning from 35-50 yrs |
| ovarian cancer surveillance includes | transvaginal ultrasound scan and CA125 levels tested anually |
| surveillance for breast cancer includes | mammography and MRI |
| surveillance given in FAP includes | annual flexible sigmoidoscopy (11-15yrs) and once polyps identified discuss prophylactic colectomy. Annual rectal stump surveillance is used and upper GI endoscopy from 25 yrs (initially 3 yearly but depends on number of polyps) |
| surveillance in HNPCC includes | 1-2 yearly colonoscopy from 25-65years, endometrial and ovarian surveillance from 30yrs, 2 yearly upper GI endoscopy from 50-75yrs, and annual urine cytology from 30-60 years (if family history has transitional cell carcinoma) |
| options for prophylactic surgery for BRCA1/2 genes (2) | prophylactic masectomy (remove breast tissue) and prophylactic salpingo-oopherectomy (remove ovaries and fallopian tube) |
| chemoprevention for BRCA 1/2 (2) | oral contraceptive pill and tamoxifen |
| effect of oral contraceptive pill | may increase risk of breast cancer in women over age of 35 but appears to reduce risk of ovarian cancer |
| what is tamoxifen | chemoprevention drug which appears to reduce risk of contralateral breast cancer in carriers of BRCA1/2 mutations |
| role of NSAIDs in treating HNPCC | role of NSAIDs on colonic adenomas being investigated but aspirin recommended for Lynch syndrome |
| role of progesterone IUD in treating HNPCC | acts on endometrial cancer being investigated |
| role of OCP (oral contraceptive pill) in treating HNPCC | acts on endometrial and ovarian cancer (UNPROVEN) |
| prophylactic surgery in treating HNPCC (2) | colectomy and TAH (total abdominal hysterectomy)& BSO (bilateral salpingo oopherectomy) |
| who is eligible for molecular genetic testing | MOST high risk category patients. Determined which high risk patients can using Manchester score, Boadicea for breast and Amsterdam in bowel |
| where is genetic testing carried out | clinical genetics service/ cancer services |
| Manchester score | used for testing BRCA1/2 where test at score >15 means affected individual and equates to 10% BRCA1/2 positive rate |
| Boadicea | (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) computer algorithm which estimates risk of individual developing breast cancer/ carrying BRCA1/2 mutation. Test with >10% is at risk of being carrier |
| Amsterdam criteria for Lynch syndrome (3-2-1) | 3+ relatives with verified Lynch syndrome associated cancers (where one relative must be first degree relative of the other two), cancers occur across at least 2 generations, and at least 1 cancer diagnosed before 50yrs. Fap must be excluded |
| what is Lynch syndrome | inherited condition that greatly increases risk of certain cancers eg CRC (colorectal cancers) and endometrial (uterine) cancer etc |
| Lynch syndrome causes MSI which is | microsatellite instability indicates MMR gene dysfunction observed in both somatic and germline cancers (It indicates that the cell's DNA repair mechanism isn't working correctly) |
| IHC | immunohistochemistry - stains proteins within histology sections and a lack of stain indicates absence of protein MMR. This is present in both somatic and germline cancers. |
| sometimes MLH1 is not mutated by methylated (so gene switched off) - what is used to test this | this is a sporadic (somatic) not inherited thing - use MLH1 promoted methylation tests |
| Bethesda criteria | test used to see who should be test for Lynch syndrome eg young age, family history etc |
| patient counselling includes | issues to discuss before diagnostic testing (timescale of results, reaction to result, what results may mean) |
| predictive genetic testing includes | patient at 50% risk (dominant condition) with known mutation -> referral to clinical genetics service -> confirmation of mutation result in affected relative -> issues to discuss with predictive -> written consent -> result appointment arranged |
| test if no living relative available | tumour testing (obtain tumour sample from deceased relative to test DNA to see it mutation germline or somatic) |
| test if no sample available | indirect testing (test unaffected 1st degree relative using risk-based criteria eg Manchester) and if no mutation continue to surveillance based on risk |
Created by:
kablooey
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