Clinical Cancer Genetics
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- Loreen Lawson
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1 Clinical Cancer Genetics Lisen Axell, MS, CGC University of Colorado Cancer Center Individuals with cancer Making surgical decisions (lump vs. mast) Making treatment decisions (XRT) Concerns for additional cancers Individuals with no cancer Assessing risk for cancer(s) Making screening/surgical decisions Making lifestyle decisions Likelihood: Developing cancer based on family history Inherited cancer syndrome Detectable mutation Medical management recommendations Recommendations for at risk family members Discussion of genetic testing and if patient wants to pursue testing
2 BOTH SIDES OF THE FAMILY At least 3 generations Family History Establish age at diagnosis Clarify the exact diagnosis (pathology reports can be invaluable) Determine the number of family members without cancer Hereditary Cancer Patterns Breast, ovary, prostate cancer, pancreas Colon/GI, uterine and ovarian cancer Melanoma and pancreatic cancer Gastrointestinal polyposis Brain tumors and kidney cancer Breast, thyroid and uterine cancer Different endocrine gland tumors Breast and childhood cancers Cancer Risk Based on Family History Sporadic 70% Hereditary 5% Familial 25%
3 Sporadic Cancer Sporadic 70% Familial 25% Hereditary 5% Sporadic Cancer Dx 73 Dx Onset later in life No clear pattern on one side of family No inherited gene Family members have a small if any increase in cancer risk Familial Cancer Sporadic 70% Hereditary 5% Familial 25%
4 Familial Cancer Dx 78 Dx Dx 60 Clustering of cancer but no clear pattern Typically later in life May be due to: inherited unknown genes (less penetrant) environment combination of the two All cancer is genetic but only a small portion is inherited Inherited Cancer Sporadic 70% Hereditary 5% Familial 25%
5 Inherited Cancer Dx 55 Dx 35 Dx Dx 45 Cancer in young individuals (less than age 50) Many generations affected with the same type or related cancer on the same side of the family Two primary cancers or two related cancers in same individual Myths about Inherited Cancer Cancer on the father s side of the family doesn t count. Even if I have the genetic mutation, I can t do anything about it Cancer runs in my family, so I already know that I have the genetic mutation I ve already had cancer, so knowing whether or not I have the genetic mutation isn t important for me Half of all women with hereditary risk inherited it from their father. Early detection and risk reduction Only a 50% risk to inherit a family mutation There may be risk for other cancers. There may be targeted treatment options. is the best family member to test. Classification: Who Needs What? Sporadic Risk: Average General population screening recommendations Family History Familial Risk: Moderate Personalized screening recommendations Inherited Risk: High genetic evaluation/testing personalized screening and risk reduction recommendations
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8 In Cancer Risk Assessment & Buy One, Get a Dozen Hereditary Cancer Risk and NextGen Sequencing
9 Next Generation Sequencing Traditional Sanger sequencing can be cumbersome and expensive. NGS allows for rapid analysis of multiple genes at a lower cost compared to traditional sequencing techniques Panels: CancerNext (44 genes) ColoNext (colon 14 genes) BreastNext (breast 18 genes) OvaNext (ovarian 23 genes) PancNext (pancreas 13 genes) PGLNext (paraganglioma 10 genes) RenalNext (kidney 18 genes) GynPlus (gynecologic 9 genes) MyRisk (25 genes) BRCAplus (6 clinically actionable genes only)
10 49% 25% 15% BRC A1 BRC A2 PTEN p53 2% 4% 4% 1% Distribution of pathogenetic mutation in BRCAplus BRCA2 37% PTEN 2% CDH1 1% STK11 1% TP53 11% BRCA1 48% PLOS ONE, May 2014
11 Gene Syndrome Characteristics BRCA1/2 Hereditary Breast and Ovarian Cancer Syndrome (HBOC) Breast Cancer Ovarian Cancer PTEN Cowden Syndrome Skin findings Breast Cancer Thyroid Cancer Endometrial Cancer Kidney cancer Large Head Colon polyps (hamartomas) TP53 LiFraumeni Syndrome Childhood cancers (sarcomas) Brain tumors Breast Cancer Adrenal Cortical Cancers STK11 CDH1 BRCAPlus Ambry Gene2cs NextGen Sequencing Peutz Jeghers Syndrome Diffuse Hereditary Gastric Syndrome Lip, hand and foot freckling Colon Polyps (Peutz Jeghers Polyps) Colon Cancer Breast Cancer Pancreatic Cancer Diffuse Gastric Cancer Lobular Breast Cancer Result Interpretation No Mutation (Negative) VUS- Likely Benign Uncertain Significance (VUS) VUS- Likely Pathogenic Pathogenic Mutation (Positive) Medical management based on personal and family history. Uncertain results do not influence recommendations for care. Medical management based on cancer risks linked with gene where mutation found. Breast Next Results 10% 56% 34% Mutation Variant of uncertain significance Negative
12 Rates of Uncertain Variants 40.0% Decline in Rate of BRCA1/2 Variants of Uncertain Significance 35.0% 30.0% 25.0% 20.0% 15.0% 10.0% All Patients Middle Eastern Asian African Native American Latin American Central European Western European 5.0% 0.0% Eggington et. al. Current Variant of Uncertain Significance Rates in BRCA1/2 and Lynch Syndrome Testing (MLH1, MSH2, MSH6, PMS2, EPCAM), March 2012, ACMG Poster Presentation.
13 Prior to July 2013 all BRCA testing was done at Myriad Genetics Testing was done in two parts: Sequencing Deletion/duplication (BART) (6-10% of BRCA mutations) (started in 2006, included in Integrated BRACAnalysis in Jan 2013) Now all labs include both parts ** IMPORTANT: if testing was done in a family, must look at test results to be sure what testing was completed** Multigene Panels Benefits Ability to look at several genes at one time Clarify risk (but how much do we know?) Offer medical management guidance (but how much do we know?) Challenges How much do we know? Risks? Management? How to interpret results for family members? Variant results How to consent? Follow up for reclassifications
14 Indications for Genetic Testing Test to confirm the diagnosis of hereditary cancer in an affected individual Test to establish risk in relatives of affected Test if knowing would alter management Whom Do We Test? Informed patients Reasonable likelihood of positive test Youngest affected individual?minors?prenatal Fear of Genetic Discrimination Creates barriers to Health care providers referring their patients for hereditary cancer risk assessment Patients seeking hereditary cancer risk assessment Patients willingness to have genetic testing or participate in research
15 GINA Prohibits: Genetic Information Non-Discrimination Act (2008) Use of genetic information in setting eligibility or premiums Health insurers from requesting a genetic test Use of genetic information in employment decisions Employers from requesting genetic information Hereditary Breast Cancer Syndrome HBOC Li Fraumeni Cowden Hereditary Diffuse Gastric Cancer (lobular pathology) Peutz-Jeghers CHEK2 HNPCC (Lynch) Ataxia Telangiectasia Bloom s syndrome Gene BRCA1 and BRCA2 TP53 PTEN CDH1 STK11 CHEK2 MMR genes ATM BLM Male Breast Cancer Syndrome Gene Risk HBOC BRCA1 and BRCA2 Klinefelter 46, XXY 3% 6-10% (less with BRCA1) Cowden PTEN Case reports
16 Hereditary Ovarian Cancer Syndrome Gene Pathology HBOC BRCA1 and BRCA2 Adenocarcinoma (non-mucinous) HNPCC (Lynch) MMR genes Adenocarcinoma Peutz-Jeghers STK11 Sex cord tumors Hereditary Uterine Cancer Syndrome Cowden Lynch Peutz-Jeghers Gene PTEN MMR genes STK11 Hereditary Colon Cancers Syndrome HNPCC (Lynch) FAP MYH polyposis (MAP) Li-Fraumeni Peutz-Jeghers Juvenile Polyposis Birt-Hogg-Dube Gene MMR genes APC MYH TP53 STK11/LKB1 BMPR1A and SMAD4 FLCN
17 Hereditary Gastric Cancers Syndrome HNPCC (Lynch) Familial Adenomatous Polyposis (FAP) Li-Fraumeni Peutz-Jeghers HDGC Juvenile Polyposis Gene MMR genes APC TP53 STK11/LKB1 CDH1 BMPR1A and SMAD4 Hereditary Pancreatic Cancer Syndrome (adenocarcinomas) Gene Familial Pancreatic Ca? FAMMM CDKN2A (p16) HBOC BRCA1 / BRCA2 Lynch MMR genes PALB2 PALB2 Peutz-Jeghers STK11 Syndrome (neuroendocrine) Gene VHL VHL MEN1 MEN1 Hereditary Renal Cell Cancer Syndrome Gene Pathology Von Hippel Lindau (VHL) Birt-Hogg-Dube Hereditary papillary RCC (HPRCC) Hereditary leiomyomatosis and RCC (HLRCC) VHL FLCN (aka BHD) Clear Cell Oncocytic chromophobe C-MET Papillary RCC type 1 FH Papillary RCC Type 2 Cowden PTEN Papillary RCC Tuberous Sclerosis TSC1 and TSC2 Angiomyolipoma, oncoytoma, and RCC
18 Hereditary Pheochromocytoma Syndrome Hereditary paraganglioma/ pheochromocytoma Von Hippel-Lindau MEN2A and 2B Neurofibromatosis Type 1 Gene SDH gene family VHL RET NF1 Questions? Lisen Axell, MS, CGC Lisen.Axell@ucdenver.edu
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