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Bill Rooney, MD VP/Medical Director SCOR Global Life
Lynch Syndrome A Presentation for the 2017 NEHOUA Meeting Bill Rooney, MD VP/Medical Director SCOR Global Life
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DNA Agenda Genetic Basics Sequence matters Mismatch Repair Genes
Interesting History Characteristics of Lynch Syndrome When to Suspect the Syndrome Diagnosing the Condition Mortality Data Once Diagnosed, Do Preventative Measures Help?
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Concept The many causes of cancer
Diseases can be a combo of one or more genes, one or more behaviors, and one or more environmental factors, with both good and harmful effects. Gene KEY Harmful Beneficial Gene Gene Behaviors Behaviors CANCER Behaviors Behaviors Gene Gene Behaviors Gene Gene Environmental Factors
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Autosomal Dominant Inheritance
Normal Autosomal Dominant Inheritance Lynch Syndrome Monogenic Diseases ~7,000 known Mendelian diseases Topol, Eric Individualized Medicine from Prewomb to Tomb. Cell 157 March 27,2014 A small modification in a single gene When involving an autosome the inheritance obeys Mendelian laws A a Aa aa Autosomal Dominant Genes Disease in homozygous genotypes Disease in heterozygous genotypes EXAMPLES Huntington’s Disease Lynch Syndrome
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Chromosomes
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Let’s look inside this structure
Sequence Matters Let’s look inside this structure
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Polymer of sugar and phosphate groups
Sequence matters Sequence Matters Polymer of sugar and phosphate groups Nucleobases Deletions Adenine Thymine Cytosine Guanine Insertions Switches Repeats
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Polymer of sugar and phosphate groups Large genomic rearrangements
Sequence matters Sequence Matters Polymer of sugar and phosphate groups Nucleobases Deletions Adenine Thymine Cytosine Guanine Insertions Large genomic rearrangements Switches Repeats
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Examples of Protein function:
Cell Structure Cell Function Cell Regulation Abnormal mRNA mRNA Abnormal Protein Protein Examples of Protein function: Antibodies Enzymes Structural component Transport Sequence Does Matter! Image downloaded 8/5/16 from Bing “free to modify, share, and use commercially
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BRCA Genes Mismatch Repair Genes
Genes Involved in Cancer Oncogenes Tumor Suppressor Genes A gene that has the potential to cause cancer A gene that protects from getting cancer ~84 known ~54 known BRCA Genes Repair damaged DNA (radiation or other environmental/chemical injuries) Mismatch Repair Genes Repair DNA as its being reproduced
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Occasional mistakes in typing The all important “Backspace”
Mismatch Repair Genes Occasional mistakes in typing Think of an author The all important “Backspace” “Insert” “Delete” Buttons
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DNA Polymerase: Extremely accurate!
~1:10 million nucleotides a mistake does occur
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Mismatch Repair Proteins
MutL MutH MutS All images obtained using Google’s filter “labeled for reuse with modification” 3/20/17
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Aldred Scott Warthin MD
Time For a Story Aldred Scott Warthin MD Seamstress Labeled for reuse with modification. Retrieved 4/17/17
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By 3rd generation Died 1856, age 60, of cancer
70 descendants 33 had uterine, gastric or colon cancer Died 1856, age 60, of cancer Downloaded 3/22/17
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Timeline of Discoveries
Human Genome Project Started Completed Darwin 1859 Mendel 1865 Aldred Warthin and the Seamstress 1895 Warthin published an articles on Family G in 1913 and 1925 Watson and Crick 1953 1850 German immigrant (Family G) died 1856 Henry Lynch published first article 1966 Today May 10th, 2017 Douglas et al reported on Family G 2005 2 families Family N from Nebraska Family M from Michigan Studied Family G 929 descendants Genetic studies showed a MSH2 gene mutation Also studied Family G >650 family members 95 had developed cancer
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Naming the Condition Hereditary Lynch Nonpolyposis Syndrome
Colorectal Cancer Lynch Syndrome Type 1 Type 2 Henry T Lynch, MD in Oct 2016 filterui%3alicense-L2_L3&ajaxhist=0 Bing images search used “free to modify, share and use commercially” Bing images search used “free to modify, share and use commercially” Retrieved 3/13/17 Retrieved 3/13/17 from Google using “Labeled for reuse with modification” usage rights search.
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The Genetic Basis of Lynch Syndrome
Lynch Syndrome is an autosomal dominant genetic disorder It typically involves mutation in one of 4 genes: MLH MSH MSH PMS2 However, more recently discovered, the MSH2 gene can also be silenced when a neighboring gene (EPCAM) is mutated.
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% of the time this gene involved in Lynch Syndrome
Mismatch Repair Genes--Location % of the time this gene involved in Lynch Syndrome MSH 6 MSH 2 MLH 1 PMS 2 15% 39% 32% 14%
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Concept Lynch Syndrome ~1:370 people have this disorder.
Is one of the most common cancer susceptibility syndromes. Is a result of a germline mutation in one of the DNA mismatch repair genes Predisposes an impacted individual to a high incidence of cancer. Can be the cause of many common cancers: Is commonly involved with synchronous and metochronous cancers ~1:370 people have this disorder. ~1.2 % people with it know they have it Colon Uterus Ovary Gastric Small intestine Urinary tract Pancreas Brain
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2013 data (US general population) Lifetime Risk (general population)
Cancer Statistics 2013 data (US general population) Colon cancer Endometrial cancer Ovarian cancer Cancer Frequency 3rd 4th 9th 136,000 dx 52,000 died 50,500 dx 9,300 died 21,000 dx 14,000 died Cancer-Related Mortality 2nd 9th 5th Lynch Syndrome Cause ~3% ~5% ~1% Lifetime Risk (general population) ~5.5% ~2.7% ~1.6% Lifetime Risk (Lynch) ~80% ~60% ~12-24% Sources: CDC.gov Strafford, C. Genetic Testing for Lynch Syndrome, an Inherited Cancer of the Bowel, Endometrium, and Ovary, Rev Obstet Gynecol 2012; 5(1): 42-49 NCCN Guidelines Version
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Cancer Risk Increases with Lynch Syndrome
Risk varies by gene involved and screening as well as preventative surgery activity (It also varies by reference used) Cancer Risk up to age 70 years old for Lynch syndrome patients Colorectal Up to ~80% Endometrium ~60% Stomach ~13% Ovary ~24% Hepatobiliary ~4% Urinary tract ~7% Small bowel ~6% Brain ~3% Pancreas ~6% Source: NCCN Guidelines Version
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Lynch Syndrome and Colon Cancer
Typical Colon Cancer Younger Age of patient Older Right side commonly Location Left side commonly Sessile/serrated if any at all Polyps Pedunculated Frequent 1:1 Rate of polyps turning malignant Less common 30:1 Fast 1-3 years Time from polyp to development of cancer Slow 8-17 years Common Synchronous or metachronous cancer Not as common
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Sessile serrated polyp
Polyps Can Look Different Sessile serrated polyp Adenomatous polyp Retrieved 3/13/17 from Google using “Labeled for reuse with modification” usage rights search. Retrieved 3/20/17 with use of Bing’s “free to modify, share and use commercially” search function.
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Lynch Syndrome and Endometrial Cancer
Typical Endometrial Cancer Younger Mean y/o Older Mean 60 y/o Early Discovery Early Discovery Synchronous or Metachronous Tumors Common Synchronous or Metachronous Tumors Uncommon Image obtained using Google’s search “labeled for reuse with modification”
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When is Lynch Syndrome Suspected
The Amsterdam criteria The Bethesda criteria Tumor analysis
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The Amsterdam II Criteria
3 3 (or more) relatives with verified Lynch syndrome-associated cancers One of whom is a first degree relative of the other two Familial adenomatous polyposis (FAP) has been ruled out 2 2 generations of Lynch syndrome associated cancers involved 1 1 (or more) cancers diagnosed in those <50 y/o Gene mutation Sensitivity Specificity Any of the four 22 % 80-98 %
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The Revised Bethesda Criteria
The Bethesda criteria The Revised Bethesda Criteria Any of the following: Colorectal cancer dx <50 yrs of age Synchronous Lynch syndrome-related cancers (regardless of age) Colorectal cancer with MSI-H like histology dx <60 years of age Colorectal cancer dx with a first-degree relative with a Lynch syndrome-related cancer and that cancer dx <50 years of age Colorectal cancer dx with two first-degree or second-degree relatives with a Lynch syndrome-related cancer, regardless of age Gene mutation Sensitivity Specificity Any of the four 82 % 77 %
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Microsatellite Instability Immunohistochemistry Testing (IHC)
Tumor Analysis Cancer tumor analysis consists of checking the tumor and the surrounding tissue for evidence of microsatellite instability as well as for the presence of the mismatch repair proteins Microsatellite Instability Immunohistochemistry Testing (IHC)
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Microsatellite Instability
Tumor Analysis Microsatellite Instability Microsatellites are sections of DNA which have repeats of nucleotide base sequences Involves 1-7 base pairs These areas are prone to replication errors which are repaired by MMR enzymes MMR enzyme loss causes these areas to become unstable and will have unusual repeat activity
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Microsatellite Instability
Tumor Analysis Microsatellite Instability Microsatellite instability is found in most Lynch syndrome tumors but is also found in 15% of sporadic colorectal cancers. ………Therefore… Beware: Not all abnormal microsatellite instability is secondary to Lynch syndrome Question: What is the sensitivity and specificity of this test? Answer: It depends on the genetic mutation? Gene mutation Sensitivity Specificity MLH1 or MSH2 80-91 % 90 % MSH6 or PMS2 55-77 % AMA’s MCHPEG quick facts. accessed 3/31/2017
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Immunohistochemistry Testing (IHC)
Tumor Analysis Immunohistochemistry Testing (IHC)
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Immunohistochemistry Testing (IHC)
Tumor Analysis Immunohistochemistry Testing (IHC) IHC testing detects the presence of the proteins produced by the MMR genes A missing protein suggests the presence of a genetic mutation Same question: What is the sensitivity and specificity of this test for Lynch syndrome? Gene mutation Sensitivity Specificity Any of the four 83 % 89 % Beware: When either MSI-high or abnormal IHC is found the odds of having Lynch syndrome is 1 in 5. Genetic testing is then recommended. AMA’s MCHPEG quick facts. accessed 3/31/2017
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So, is testing being done ideally?
Lynch Syndrome Testing So, is testing being done ideally? Ethical, legal and psychosocial concerns Fears of genetic discrimination Clinical utility and validity concerns Family dynamics Small families/Adopted individuals Lack of patient and physician knowledge Study1: 387 patients seen in a GI clinic with FH compatible with Lynch Syndrome 17% were referred for genetic counseling/testing 1 Grover S, et al. Clin Gastroenterol Hepatol ; 2: 813
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Genetic Testing in Lynch Syndrome
Gene Testing For Lynch Syndrome Expensive Can be challenging Can require several blood samples Can require several different labs 2013 data $3, genes $ gene Therefore Many patients have incomplete testing Not all 4 genes are tested Testing only for sequence abnormalities may occur (not large rearrangement mutation testing) ~7% of the time a result of variant of uncertain significance occurs Hampel, H et al, The Search for Unaffected Individuals with Lynch Syndrome: Do the Ends Justify the Means? Cancer Prev Res 2011 January:
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Category Characteristics
12,006 Genetic Testing Results MMR Gene variants Category Characteristics Pathogenic Variant previously associated as cause of the disorder Likely Pathogenic Variant expected to cause the disorder Variants of uncertain significance Variant that might be causative Likely benign Variant probably not causative Benign Variant recognized as neutral 2,641 239 6,982 53 2,091 Numbers based upon the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database as described in Sehgal, R et al’s “Lynch Syndrome: An Updated Review”Genes 2014
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Lynch Syndrome Testing Guidelines
Guidelines for testing an individual for Lynch syndrome NCCN Guidelines Meets revised Bethesda Guidelines Meets Amsterdam II criteria Endometrial cancer at age <50 Known LS in family Consider testing those with 5% or greater risk by prediction models (MMRpro, PREMM, or MMRpredict) EGAPP Guidelines MSI/IHC testing of all newly diagnosed colorectal tumors F/u genetic testing as warranted The trend is for increased evaluation of all newly diagnosed colon and endometrial cancers AMA’s MCHPEG quick facts. accessed 3/31/2017 EGAPP: The evaluation of genomic applications in practice and prevention
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Variable expressivity
Lynch Syndrome Expression Variable expressivity Which gene is impacted Age Mutation type Epigenic influences = Cancer Abnormal gene Penetrance Full Incomplete Variable Manifestation Cancer involved varies even within the same family
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Clinical Validity and Clinical Utility
The ability of a genetic test to predict a phenotype APC gene: Familial adenomatous polyposis MMR gene: Lynch syndrome APOE e4/e4: Alzheimer disease ~ 100% ~ 80% ~ 30% Clinical Utility The impact of the genetic test on clinical care Huntington Lynch syndrome: BRCA Minimal Significant
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Genetic Testing—Who got tested???
3 scenarios 1 2 3 Family member with known disease FH of Lynch-like tumors No personal hx. of cancer No specific mutation known in the family FH of Lynch-like tumors Lynch-type cancer found No specific mutation known in the family
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If test is negative, is it:
Genetic Testing—Scenarios 1 and 2 1 If negative this is a true negative genetic test Mutation found This individual would typically be managed like those with Lynch syndrome Test for that specific mutation in all family members If positive, the individual has Lynch syndrome Family member with known disease 2 Increased chance for inconclusive results If test is negative, is it: Because that gene is not mutated in the family?? or The mutation does exist in the family but the tested person doesn’t have it?? FH of Lynch-like tumors No personal hx. of cancer No specific mutation known in the family
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Genetic Testing—Scenario 3
FH of Lynch-like tumors Lynch-type cancer found No specific mutation known in the family Gene mutation not currently known or is from MLH1 promoter hypermethylation Negative results No Lynch syndrome Tumor testing for MSI and ICH Positive results Gene sequencing testing needed Mutation found Lynch Syndrome Gene sequencing testing No mutation found Diagnosis of Lynch Syndrome not established at this time
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Methyl group added to the DNA base cytosine at CpG sites
Epigenetics: Methylation Example Epigenetics: The study of how environmental factors impact gene expression. A G C Instead of gene sequence disturbances the impact of epigenetics is with turning off or on how cells read the genes Methyl group added to the DNA base cytosine at CpG sites Image from: Accessed 9/29/15 (Bing listed as “Free to modify, share, and use commercially”
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Environmental Factors
Concept Lynch Syndrome Cancer Genetics: It can be complicated Diseases can be a combo of one or more genes, one or more behaviors, and one or more environmental factors, with both good and harmful effects. Methylation Behaviors BRAF Gene mutation MLH 1 Gene Behaviors Colon cancer Environmental Factors MSH 2 Gene PMS 2 Gene Environmental Factors EPCAM Gene mutation MSH 6 Gene KEY Harmful Beneficial To test for MLH1 proximal promoter region problems testing for methylation-specific PCR for MLH1 promoter region -248 to -178 relative to the gene transcription start region. If methylation is present, the pat most likely has a sporadic carcinoma rather than Lynch.
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Cancer Prevention Recommendations
When diagnosed with Lynch syndrome What are the recommendations for cancer prevention?
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Cancer Prevention Recommendations
Lynch Syndrome: Cancer Prevention Recommendations Colon cancer Colonoscopy q 1-2 years after age 20-25 (or starting 2-5 years prior to earliest colon cancer) Endometrial and ovarian cancer Prophylactic Surgery Prophylactic hysterectomy with BSO should be considered after completing childbearing Education All dysfunctional bleeding requires evaluation To be considered: Endometrial biopsy Transvaginal US (neither has been shown to be effective thus far) To be considered: EGD with extended duodenoscopy Test for H. pylori (neither has been shown to be effective thus far) Gastric and Small Bowel cancer Urothelial cancer Testing Consider U/A yearly starting at y/o Adapted from the NCCN Guidelines Version Lynch Syndrome. See this document for exact wording
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However, cancer can still occur
Prevention/Screening Mortality Results Some prevention activities have been shown to decrease the incidence of cancer or detect it at an early age However, cancer can still occur Awareness One study found only 65% of women with families of Lynch syndrome were aware of the increased chance for endometrial cancer
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A 2013 article by H. Jarvinen et al proclaims that CRC screening
Prevention/Screening Mortality Results Adherence Colonoscopy: 80% Endometrial cancer surveillance: 63% Hysterectomy and BSO choice: 19% Impact A 2013 article by H. Jarvinen et al proclaims that CRC screening Decreases incidence of invasive colon cancer by 62%. Decrease mortality by 65%. Palomaki, Glenn et al EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genetics in Medicine. Volume 11, Jan, 2009
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Prevention/Screening Mortality Results
Finland Mortality Study Details Results 2009 publication 242 mutation carriers 367 mutation negative family members 242 mutation carriers 367 mutation negative family members Cancer incidence: Colon: /242 Endometrial: 19/103 Ovarian: /112 Cancer incidence: Colon: /242 Endometrial: 19/103 Ovarian: /112 No previous cancer Age: y/o Age: y/o Median age 36 y/o with Lynch 42 y/o without Mortality 3 died of colon cancer 1 died postop PE 2 died upper GI cancer 2 died of GU cancer Mortality 3 died of colon cancer 1 died postop PE 2 died upper GI cancer 2 died of GU cancer Compliance: Colonoscopy: 95.9% GYN surveillance: 97.1% Observation period: 10 years Observation period: 10 years Heikki, J. et al. Ten years after mutation testing for Lynch syndrome: Cancer Incidence and outcome in mutation-positive and mutation-negative family members. Journal of Clinical Oncology ; Volume 27 #28
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Prevention/Screening Mortality Results
Norwegian Mortality Study Details Results 2017 publication Colon: Endometrial: 72 Upper GI: Ovarian: Urinary tract: 17 Colon: Endometrial: 72 Upper GI: Ovarian: Urinary tract: 17 1,942 mutation carriers 1,942 mutation carriers 314 developed cancer 314 developed cancer No previous cancer 10 year survival Any cancer: 87% 10 year survival Any cancer: 87% Age: y/o All were offered surveillance 21 had synchronous cancers 21 had synchronous cancers Surveillance changed over time based upon changing guidelines 186 females had a prophylactic hysterectomy 153 had an oopherectomy Cancers occurring after the first cancer were not included in this study Calculated cumulative incidence of cancer at age 70 Men: 58% Women: 75% 13, 782 observation years Mean observation time 7.1 years 13, 782 observation years Mean observation time 7.1 years No control group so value of surveillance in preventing cancers could not be calculated No control group so value of surveillance in preventing cancers could not be calculated Pål Møller et al. Gut 2017;66:
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Interesting Findings Norwegian Study Mutated Gene Matters MLH 1
Calculated cumulative incidences by age and mutated gene for any cancer. MLH 1 % with cancer MSH2 MSH6 PMS 2 Calculated cumulative incidences by age and mutated gene for any cancer. Age Pål Møller et al. Gut 2017;66: Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.
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Treatment of Colon Cancer in Lynch Syndrome
Surgery--Typically a total colectomy Followed by annual endoscopic screening of the rectum One retrospective study of segmental colectomy was interesting Median f/u of 8.6 years Interesting Finding In this study a few patients did get a total colectomy 11 % developed adenomas 8 % developed cancer 33% of patients developed an adenoma 25% of patients developed colon cancer 25% of patients developed colon cancer
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In Summary Remember this slide? The sequence of the DNA nucleotides is very important The Mismatch Repair Proteins are instrumental in keeping this sequence intact Mutations in a Mismatch Repair Gene cause Lynch Syndrome Lynch syndrome is associated with a variety of cancers
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In Summary It is very important to know who is being tested
Testing the tumor itself for MSI or IHC commonly occurs Sequence testing for the genetic mutation also occurs There are specific recommendations for cancer prevention Unfortunately, even with screening exams cancer can still occur and mortality is still impacted
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Bill Rooney, MD VP/Medical Director
Lynch Syndrome Questions???? Bill Rooney, MD VP/Medical Director
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The following slides are
Lynch Syndrome The following slides are Bonus Slides NCCN Guidelines Additional information regarding the Norwegian study
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Adapted from the NCCN Guidelines Version 2. 2016 Lynch Syndrome
Adapted from the NCCN Guidelines Version Lynch Syndrome. See this document for exact wording
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Cancer Survival by Cancer Type
Interesting Findings Norwegian Study Cancer Survival by Cancer Type 87% 91% 98% 89% 53% 73%
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Months since colonoscopy
Interesting Findings Norwegian Study Colon cancer discovered When was the last colonoscopy? Months since colonoscopy Cumulative % 12-17 22 24-29 58
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