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Hereditary cancer the next generation PowerPoint Presentation

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Description : Check out this medical presentation on Cowden Syndrome, which is titled "Hereditary cancer, the next generation", to know about the genetic terminology and concepts, hereditary cancers, hereditary breast cancer syndromes, hereditary colorectal cancer syndromes, hereditary kidney cancer syndromes, hereditary endocrine cancer syndromes, genetic testing, and genetic counseling.

Tags : Cowden Syndrome, Hereditary cancer, hereditary breast cancer syndromes, hereditary colorectal cancer syndromes, hereditary kidney cancer syndromes, hereditary endocrine cancer syndromes, genetic testing, genetic counseling

Published on : May 13, 2021 | Views : 1310 | Downloads : 4

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Slide 1-

Hereditary cancer, the next generation Raymond Kim MD/PhD, FRCPC, FCCMG, FACMG Medical Geneticist Princess Margaret Cancer Centre
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Outline Genetic terminology and concepts Hereditary cancers When to consider Genetics assessment Surveillance Hereditary breast cancer syndromes Hereditary colorectal cancer syndromes Hereditary kidney cancer syndromes Hereditary endocrine cancer syndromes Genetic testing Genetic counseling 2
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Cancer is a genetic disease 3
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Timing of the genetic change… 4 Sporadic cancer Majority of cancer patients (90%) Genetic change occurs during life Localized mutation detected in tumour “somatic” Both hits in tumour, none in the blood No pattern in family tree Elderly to accumulate second hit Hereditary cancer Minority of cancer patients (10%) Born with genetic mutation All cells in body carry mutation “germline” = first hit Second hit observed in tumour Family tree with a pattern Unusual tumours Multiple cancers in same individual Young cancers
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Key point: rest of body does not have the mutation, sees an oncologist
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Key point: whole body has the mutation, sees a geneticist and oncologist
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Who do medical geneticists see? All diseases have a genetic component Not all diseases require a medical genetics consultation Continuum of genetic contribution Many genes interacting with environment (multifactorial) Coronary artery disease Few genes interacting with environment (poly-genic) Diabetes mellitus, IBD Single gene interacting with environment (incomplete penetrance) Hereditary cancer Single gene (fully penetrant) Huntington disease, Sickle cell anemia 7
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Incomplete Penetrance Penetrance is defined as the proportion of mutation carriers who harbour any manifestations of a disease Hereditary cancer = high penetrance, but not complete penetrance Mutation carriers are at high risk of developing malignancy Some mutation carriers do not develop malignancy 8 BRCA1+ BRCA1+ BRCA1+ BRCA1+ BRCA1+ BRCA1+ BRCA1+ Ovarian Breast Ovarian
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Variable Expressivity Not all individuals with a mutation will develop the same manifestations E.g. BRCA1 patient Mom has ovarian cancer Daughter has breast cancer Von Hippel Lindau Variety of systemic manifestations Not all patients will have same organ involvement 9
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More genetics concepts Hereditary cancer syndrome Familial cancer Mendelian cancer Autosomal dominant (adult) Autosomal recessive (pediatric) Imprinted cancers 10
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Chromosomes vs genes and inheritance 11 Autosomes Chr 1-22 Sex chromosomes
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Hereditary cancer syndromes Over 50 syndromes catalogue in 2008 Over 300 syndromes entered into OMIM (Online Mendelian Inheritance in Man) Under-recognized and under-referred Germline genetic testing results affect Surveillance Surgical management Eligibility for trials Distinct from somatic profiling of the tumour for targeted therapy (non-inherited changes in tumours) 12
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Hereditary Breast and Ovarian Cancer BRCA1 40-70% Breast (vs 12%) 20-40% Ovarian (vs 1.5%) 20-30% Prostate (vs 17%) Surveillance Breast MRI@25years CA-125 and US not offered Management Mastectomy Prophylactic Bilateral Salpingo-oopherectomy Chemoprevention (tamoxifen) PARP trials 13
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BRCA2 40-70% Breast cancer 10-20% Ovarian cancer 30-40% Prostate cancer 6% Male breast cancer (vs 0.1%) 3% Melanoma (vs 1%) 5% Pancreatic (vs 1%) One mutation leads to hereditary breast and ovarian cancer Two mutations lead to Fanconi Anemia, childhood recessive disorder 14
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When to suspect BRCA1/2 in the medical oncology clinic? Patient is from a BRCA1/2 family (need to ASK!) Ethnicity: Ashkenazi Jewish Bilateral breast cancer Age: under 35 Male Breast cancer Invasive Serous Ovarian cancer Medullary breast cancer ~11% BRCA1 Triple negative breast cancer <60 (NCCN) Strong family history of breast and ovarian cancer Variety of criteria, depends on age and number of family members affected Ontario Ministry of Health Guidelines National Comprehensive Cancer Network Guidelines Guidelines exist to have a diagnostic yield ~10% 15
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Who to test? Medical Oncologists usually see patients with cancer Patients affected with cancer are the most appropriate individuals to test to interpret the genetic results If no family members, available, some high risk families can have testing on unaffected individuals if probability of mutation based on computer models >10%, but many limitations of this Need to consider DNA banking on all individuals with cancer as new genes are discovered (panel testing)
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LiFraumeni Syndrome 19 When to suspect: Young breast cancer <35 Strong family history of core cancers All adrenocortical carcinomas All sarcomas <45 years TP53 germline mutations, tumour suppressor Core cancers: Brain Choroid plexus carcinoma Breast cancer Sarcoma Adrenocortical carcinoma Bronchoalveolar cancer GI malignancy
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LiFraumeni surveillance Risk of cancer in women 100%, men 75% Risk reduction options include Bilateral mastectomy Screening using the Toronto Protocol (Villani et al 2011) Annual Breast MRI, beginning @ 20-25y Annual Rapid whole body MRI (not CT) Annual Brain MRI q6m Abdominal US, CBC, LDH, ESR Annual dermatology exam q2y C-Scope, beginning @ 25y Consideration of metformin for chemoprophylaxis Done through Princess Margaret Familial Breast and Ovarian Cancer Clinic 20
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Cowden syndrome Germline mutation in PTEN, PIK3CA, AKT1 Cancer risks Breast cancer 85% lifetime risk Thyroid disease in 75% of Cowden patients Multinodular goitre Epithelial thyroid cancer follicular>papillary Endometrial Cancer Colorectal Cancer 21 Physical features Developmental Delay Head circumference >59cm Papillomas on skin and mucosa Dysplastic gangliocytoma of cerebellum Skin lesions such as acral keratoses
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Surveillance in Cowden syndrome Annual thyroid ultrasound from childhood High risk Breast screening MRI/mammography @30 Colonoscopy @35, q5years Renal ultrasound @40 Endometrial biopsy@30 Annual dermatologic exam Conducted through Princess Margaret Familial Breast and Ovarian Cancer Clinic 22
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Lynch syndrome Mismatch repair pathway deficiency Colorectal cancer (50-80%) Endometrial (25-60%) Ovarian (5-10%) Hepatobiliary (1-5%) Adrenocortical carcinoma (3%) MLH1, MSH2, MSH6, PMS2 Consider if: Amsterdam criteria 3 individuals 2 first-degree relatives 1 under 50 CRC<35 years of age CRC+another Lynch cancer Other ongoing screening protocols NCCN all CRC<70, UHN endometrial <70 Annual Colonoscopy ~25y, consider endometrial surveillance 23
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Immunohistochemistry in Lynch syndrome 24 normal abnormal
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MSH2 loss of expression caused by upstream gene, EPCAM 25 Deletion of EPCAM gene causes methylation of MSH2 region preventing MSH2 expression, an epigenetic mechanism
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Microsatellite Instability in Tumours with Lynch syndrome 26
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Mismatch repair deficient (Lynch and others) respond to PD-1 blockade 28 1782 somatic mutations 73 somatic mutations
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Hereditary kidney cancer, rare histologies could be hereditary Birt-Hogg-Dube Syndrome (FLCN) Fibrofolliculomas and lung pneumothorax 29 Hereditary leimyomatosis and RCC (FH) Fibroids Children with fumarate hydratase deficiency (severe metabolic disorder) Hereditary papillary RCC MET Eligible for MET inhibitors
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ccRCC, Von Hippel Lindau Multi-system disorder Mutations in VHL gene responsible for degradation of hypoxia inducible factor 1-alpha (HIF1α) Results in hemangioblastomas Eye Brain Spine Deafness (endolymphatic sac tumours) Pancreatic cysts variable expressivity = not all mutation carriers develop all manifestations Frameshift mutations result in risk of renal cell carcinoma “type 1” Missense mutation result in pheochromocytoma “type 2” 30
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Von Hippel Lindau Surveillance Not uniform National Cancer Institute US Von Hippel Lindau Alliance Danish Von Hippel Lindau Alliance Abdominal Imaging annual 8-18: ultrasound >18: CT/MRI Annual CNS brain and spine MRI Start at 8 years Annual neuroendocrine biochemical surveillance Start at 2 years Dilated fundoscopy From birth Annual audiology 31 UHN Von Hippel Lindau Alliance Clinical Centre of Excellence Endocrinology Neurosurgery Ophthalmology Neurology Urology Medical Oncology Genetics Gynecology Otolaryngology Direct link to SickKids program Coordinator: Laura Legere laura.legere@uhn.ca
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Multiple Endocrine Neoplasia type 2 (RET) All Medullary thyroid cancer should have RET analysis 25% of all MTC are hereditary vs 75% sporadic, more often bilateral and multifocal 32 Cote, Gilbert
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33 Genotype phenotype correlation -rearranged during transfection (RET) receptor tyrosine kinase -ATA risk stratification All missense mutations, sequencing should detect Waguespack, S. G. et al. (2011)
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Isolated hereditary paraganglioma-pheochromocytoma 34 Dahia P et al. (2014)
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Succinate dehydrogenase Subunits SDHA SDHB SDHC SDHAF2 (assembly factor) Some genotype, phenotype correlation Norepinephrine, dopamine SDHB high malignancy and recurrence risk All pheochromocytoma and paraganglioma cases should have a genetics assessment 35
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Succinate dehydrogenase D (maternally imprinted, paternally inherited) 36 Only individuals who inherit the mutation from their father are affected If the mutation was inherited from the mother, they are not affected
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Succinate dehydrogenase immunohistochemistry 37 Tischler AS et al. (2015) Staining normal Loss of staining/abnormal Syndromic (MEN2, NF, VHL) Non-syndromic (MAX, TMEM127) Isolated (SDHA, SDHB, SDHC, SDHD, SDHAF2)
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Genetic Testing
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What to analyze: Chromosomes vs Genes -chromosome analysis does not analyze genes -most hereditary cancer syndromes are caused by gene mutations
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Molecular genetic testing, know your alphabet! 40
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Select the individual to test -select the youngest living individual affected with cancer 41 MTC 65 PHEO 38 Breast 70 CRC 75
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Select the gene to test Straightforward disorders: one disorder, one gene Von Hippel Lindau = VHL Multiple endocrine neoplasia type 2: RET Li Fraumeni Syndrome = TP53 Slightly more complicated: one disorder, more genes: Lynch syndrome (5 genes): rely on immunohistochemistry of deficient protein Cowden syndrome: test for more prevalent gene (e.g. PTEN, then PIK3CA, then AKT1) Much more complicated: one tumour, many genes Pheochromocytoma, paraganglioma 42
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Structure of a gene 43 Mutations can occur anywhere and affect gene function Some diseases have certain mutations which are more prevalent The right technique needs to be chosen
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What type of test do you need? Full Gene sequencing ($1500) When a single gene is suspected, but exact mutation is not known (first testing in a family) Techniques: Sanger Sequencing Single mutation analysis ($100) A known mutation in a family or founder mutation in an ethnicity Techniques: PCR amplification, allele specific oligonucleotides Copy number variation ($1500) When a whole exon of a gene is deleted and sequencing will read the other normal copy Techniques: Multiplex-ligation probe ligation assay, array CGH Triplet repeat expansion ($500) Mutation is a repeat-type expansion not easily amplified by DNA polymerase Techniques: Southern blot, quantitative PCR Imprinted genes ($1500) Gene is affected by methylation of the bases, not the sequence change Techniques: Methylation-specific enzyme digestion 44
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Which lab to choose? 45
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47 Next generation sequencing, multiple genes concurrently read depth exon 1 exon 2
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48 Interpretation of Genetic testing results Positive Mutation is found “have the gene” Seen in other individuals with disorder Surveillance decisions can be made Maybe Genetic change is found Not seen in other individuals with disorder Significance uncertain “Variant of uncertain significance” Seen 30% during panel testing Management decisions NOT made Revisit the clinic Negative No genetic change is found Limitation of the technology May have another gene involved Revisit the clinic, other gene testing
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Genetic counselling Informed consent for genetic testing Genetic testing is different than other types of medical investigations Implications on family members Implications on insurance policies Appropriate interpretation of results Positive vs negative vs Variant of uncertain significance Subsequent follow-up actions based on these results, eg surveillance Family member cascade testing (asymptomatic positive  surveillance) Prenatal genetics family planning Some case examples… 49
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Referral for ccRCC, “Robert” 43M diagnosed with a bilateral clear cell RCC five years ago Has a negative family history VHL genetic testing was conducted A novel variant in the Von Hippel Lindau gene is found and called “Variant of uncertain significance” Database search shows similar types of mutations in the same region in VHL pts Further investigations show a cerebellar hemangioblastoma and pancreatic cysts Patient is diagnosed with Von Hippel Lindau and the variant is deemed to be pathogenic after discussion with the laboratory 50
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A call to the genetic counselor Robert’s 18 year old daughter Mary is now pregnant and she has not shared this information with her yet Expedited genetic testing on the familial mutation is conducted on Mary and she is referred to high risk obstetrics at Mount Sinai Hospital Biochemical screening and imaging is requested on Mary Mutational analysis confirms Mary is a carrier and asymptomatic What about her baby? 51
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A call to the genetic counselor Prenatal chorionic villus sampling at 10 weeks is conducted and the baby is a carrier of the VHL variant After a long discussion Mary decides to terminate the pregnancy Mary is enrolled in surveillance 53
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Two years later, when Mary is ready preimplantation genetic diagnosis… 54
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A young breast cancer patient Charlotte 29 year old lady with ER/PR neg, Her2 positive breast cancer Due to young age, gene panel is sent for genetic testing including: BRCA1, BRCA2, TP53, CDH1, PTEN, STK11 Has a mutation in TP53, c.1010G>A; p.R337H Diagnosed with Li-Fraumeni syndrome Undergoes high risk surveillance She comes in and asks for her 2 year old daughter Mary to get tested Do you test the daughter? 55
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Family testing in hereditary cancer The identification of a mutation in the family allows that mutation to be tracked in asymptomatic individuals “Predictive Genetic testing” This facilitates early initiation of surveillance on family members to detect and prevent cancer So, do you test Charlotte’s daughter Mary? 56 Yes, Mary is at 50% risk (1st degree relative) of sharing the same mutation as Charlotte, and should have whole body MRI and surveillance for Li-Fraumeni syndrome
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Family testing in hereditary cancer Would your answer be different if Charlotte was diagnosed with a BRCA1 mutation? 57
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Family testing in hereditary cancer 58 Would your answer be different if Charlotte was diagnosed with a BRCA1 mutation? Predictive genetic testing for BRCA1/BRCA2 is deferred until adulthood as there are no childhood manifestations Unlike Li-Fraumeni (childhood manifestations)
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Outline Genetic terminology and concepts Hereditary cancers When to consider Genetics assessment Surveillance Hereditary breast cancer syndromes Hereditary colorectal cancer syndromes Hereditary kidney cancer syndromes Hereditary endocrine cancer syndromes Genetic testing Genetic counseling 59
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61 raymond.kim@uhn.ca