cancer genetics: identification and management of individuals with lynch syndrome
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CANCER GENETICS: IDENTIFICATION AND MANAGEMENT OF INDIVIDUALS WITH LYNCH SYNDROME HENRY T. LYNCH, MD Creighton University School of Medicine Omaha, Nebraska. Hereditary Cancer Syndromes: Nuts and Bolts. Family history; Hereditary cancer syndrome diagnosis; Genetic counseling; - PowerPoint PPT PresentationTRANSCRIPT
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CANCER GENETICS: IDENTIFICATION AND
MANAGEMENT OF INDIVIDUALS WITH LYNCH SYNDROME
HENRY T. LYNCH, MDCreighton UniversitySchool of MedicineOmaha, Nebraska
2Hereditary Cancer Syndromes:Nuts and Bolts
• Family history;• Hereditary cancer syndrome diagnosis;• Genetic counseling;• DNA studies;• Highly targeted surveillance/management;• Extend to all at-risk relatives;• Physician education;• Research problem of discrimination (insurance, employment);• Strategies for wide-spread interest of familial cancer approach to cancer control, malpractice, molecular genetics, other.
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Patient’s Modified Nuclear Pedigree
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Why Pursue Cancer of All Anatomic Sites?
Pertinent for any hereditary cancer syndrome diagnosis;Most identified by pattern of cancer expression, e.g.: • breast and ovary (HBOC syndrome); • CRC, endometrium, ovary, others (Lynch syndrome); • sarcomas, breast, brain, multiple others in SBLA (Li- Fraumeni syndrome); • medullary thyroid carcinoma and pheochromocytoma (MEN-2a and MEN-2b); • melanoma and pancreatic cancer with CDKN2A (p16) mutation (FAMMM syndrome); • diffuse gastric cancer and lobular breast cancer with CDH1 mutation (HDGC syndrome); ...and the list goes on.
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Colorectal Cancer
Worldwide estimates for colorectal cancer during 2008*:Incidence – 1,233,711 Mortality – 608,644
Worldwide estimates for familial/hereditary CRC during 2008*:Lynch syndrome 3-5% of all CRC 37,011-61,686FAP <1% of all CRC <12,337Familial 20% of all CRC 246,742
*GLOBOCAN. The International Agency for Research on Cancer web site. URL: http://www.iarc.fr/
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Familial/Hereditary CRC in US
Annual CRC incidence in US: 142,570
Lynch syndrome 3-5% of all CRC 4,277 - 7,129
FAP <1% of all CRC <1,426
Familial 20% of all CRC 28,514
Jemal et al. CA Cancer J Clin 60:277-300,2010.
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Magnitude of the Problem
Question: Why are these figures of such significant public health impact?
Answer: Each hereditary cancer comes from a family that could benefit immensely from genetic counseling.
DNA testing, surveillance, and highly-targeted management are the key!
Genetic Counseling
• Mandatory
• Centers of Cancer Genetic Expertise
• Physician Role, unfortunately, often insufficient
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Should we test all colorectal cancer for
Lynch Syndrome?
YES! Test everybody.YES! Test everybody.
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Search for LS Among CRC Affecteds*
Evidence:
Among 500 CRC patients, 18 (3.6%) had LS.
Of these 18:
18 (100%) had MSI-H CRCs;
17 (94%) were correctly predicted by IHC;
only 8 (44%) were dx < 50 years;
only 13 (72%) met the revised Bethesda guidelines;
1/35 cases of CRC show LS.
*Hampel et al. J Clin Oncol 26:5783-5788, 2008.
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Molecular Genetic Screening for LS
Recommendation*:
All incident CRC and EC cases should be molecularly screened for LS.
MSI highly sensitive (89.3%).
IHC equally sensitive (91.2%), is inexpensive, is more readily available, and predicts the nonworking gene.
IHC is preferred method to screen for LS*.
*Hampel et al. J Clin Oncol 26:5783-5788, 2008.
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Cost-effectiveness of DNA Testing
Estimate the cost-effectiveness of genetic testing strategies to identify LS among newly dx CRC patients using MSI and IHC.*
Conclusion:
Preliminary tests seem cost-effective from the U.S. health care system perspective.
Detects nearly twice as many cases of LS as targeting younger patients.
MMR testing is not cost effective.
*Mvundura et al. Genet Med 12:93-104, 2010.
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Familial CRC Type “X”
Amsterdam Criteria positive but lacking MSI and MMR mutations will constitute ~ 40% of those AC-I without MMR mutations and therein referred to as familial CRC type X.*
1) CRC > left side
2) CRC and extra colonic CRC
3) Later age CRC onset
4) Molecular genetics (MSI and IHC or MMR
mutation) ABSENT!
*Lindor et al. JAMA 293:1979-1985, 2005.
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Screening for Amsterdam Criteria LS*
a) Screening of all CRC patients meeting Amsterdam Criteria (AC) would fail to detect half of all cases;
b) Screening those aged 50 would detect only half of all cases;
c) Screening of all patients using Bethesda Guidelines for MSI would fail to detect at least 1/3 of all cases.
*Boland & Shike. Gastroenterology 138:2197.e1- 2197.e7, 2010.
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Familial CRC
Familial clustering of CRC, like that for carcinoma of the breast and stomach, has been discussed for more than 100 years.
What does it mean from the standpoint of risk?
Best answer – First- degree relative of CRC affected has 2-3 fold excess risk for CRC compared to population expectations.
But is type X different?
Answer – Risk remains elusive!
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Genetic Heterogeneity in HNPCC
HNPCC is associated with germline HNPCC is associated with germline mutations in any one of at least five genesmutations in any one of at least five genes
Chr 2Chr 2Chr 3Chr 3
Chr 7Chr 7
MSH2MSH2
PMS1PMS1
MLH1MLH1PMS2PMS2
MSH6MSH6
Mismatch Repair (MMR) Mutations
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Cardinal Features of Lynch Syndrome
• Family pedigree shows autosomal dominant inheritance pattern for syndrome cancers.
• Proximal (right-sided) CRC predilection: 70-85% of Lynch syndrome CRCs are proximal to the splenic flexure.
• Earlier average age of CRC onset than in the general population: - Lynch syndrome: 45 years;- general population: 63 years.
• Accelerated carcinogenesis, i.e., shorter time for a tiny adenoma to develop into a carcinoma:
- Lynch syndrome: 2-3 years;- general population: 8-10 years.
• High risk of additional CRCs:25-30% of patients who have surgery for a LS-associated CRC willhave a second primary CRC within 10 years, if surgery was < asubtotal colectomy.
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Increased risk for certain extracolonic malignancies
Endometrial Ovary Stomach Small bowel Pancreas Liver and biliary tree Muir-Torre cutaneous features Brain, (glioblastoma) – Torre syndrome features Prostate cancer Breast Possible Adrenal cortical carcinoma and others.
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Cardinal Features of Lynch Syndrome
• Differentiating pathology features of LS CRCs:
- more often poorly differentiated;
- excess of mucoid and signet-cell features;
- Crohn’s-like reaction;
- significant excess of infiltrating lymphocytes
within the tumor.
• Increased survival from CRC.
• Sine qua non for diagnosis is identification of germline mutation in MMR gene (most commonly MLH1, MSH2, MSH6) segregating in the family.
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COLONOSCOPY
Initiate age 20 – 25
every other year to age 40; annually thereafter
must get good cleanout and visualize cecum
CRC – need subtotal colectomy
EC Screening
Effectiveness of screening for EC is unproven;
Consequently, prophylactic surgery is the best option for ♀ who have completed their families.*
*Manchanda et al. Curr Opin Obstet Gynecol 21:31-38, 2009.
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Screening for EC in LS*
No screening tool has been validated.
Ultrasonography (US) used to screen for atypical hyperplasia and cancer.
Considered normal if no polyps or intrauterine abnormalities seen and if maximum endometrial thickness < 4mm in postmenopausal ♀ on hormonal replacement therapy or < 6mm in other ♀.
*Lécuru et al. Int J Gynecol Cancer 20:583-587, 2010.
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N Engl J Med 354: 261-269, 2006.
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Could this behereditary
Colon Cancer
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Targeted CRC Screening
Screening is melded to LS’s natural history:
Proximal location colonoscopy
Early age of onset beginning at age 25
Accelerated carcinogenesis every 1-2 yrs < age 40, then annually
Pattern of extracolonic cancers targeted screening
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Dis Colon Rectum 53:77-82, 2010.
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Extended Colectomy*Continued:
Times to subsequent CRC and subsequent abdominal surgery were significantly shorter in the control group (P < .006 and P < .04, respectively).
No significant difference in survival time between the cases and controls.
Conclusion: Even though no survival benefit the increased incidence of metachronous CRC and increased abdominal surgeries among controls warrant subtotal colectomy in patients with LS.
*Dis Colon Rectum 53:77-82, 2010.
Cancer Control 16:14-22,2009.
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Meyer et al. Cancer Control 16:14-22,2009.
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J Clin Pathol 62:679-684, 2009.
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J Clin Pathol 62:679-684, 2009.
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J Clin Pathol 62:679-684, 2009.
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Sporadic
Lynch Syndrome
Familial Hereditary
FAP; AFAPMixed Polyposis SyndromeAshkenazi I1307KCHEK2 (HBCC)MUTYH (MAP)TGFBR1
PJSFJPCDBRRS
= as yet undiscovered hereditary cancer variants
HamartomatousPolyposisSyndromes
AC-1 without MMR(Familial CRC of syndrome “X”)
TACSTD1 (EPCAM)
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Hereditary Polyposis Syndromes
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Attenuated FAP
Later onset (CRC ~age 50)Later onset (CRC ~age 50) Few colonic adenomasFew colonic adenomas Not associated with Not associated with
CHRPECHRPE UGI lesions UGI lesions Associated with Associated with
mutations at extreme 5mutations at extreme 5’’, 3, 3'' ends of ends of APCAPC gene, & exon gene, & exon 9A9A
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Molecular Diagnosis of LS: Toward a Consensus
If tumor is MSI-positive, IHC is then done to direct mutational testing to a specific MMR gene, which MSI alone cannot do.*
If tumor is MSS, must weigh low probability of an informative IHC test and cost of performing it.**
*Engel et al. Int J Cancer 118:115-122, 2006.
**Lynch et al. J Natl Cancer Inst 99:261-263, 2007.
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BRAF V600E mutation and LS
BRAF V600E mutation can sort this out since when detected it excludes LS and contributes to improved cost-effectiveness of genetic testing for LS.
*Clin Gastroenterol Hepatol 6:206-214, 2008.
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MORPHOLOGYSUSPICIOUS
FOR MSI-H
Run PCR testfor MSI status
Is thereMSI-H?
Run mutation analysisfor BRAF V600E
Is thereBRAF V600E
mutation?
SPORADIC CRCWITH MSI-H
NO EVIDENCE OFLYNCH
SYNDROME
Is there lossof stainingwith any ofthe Abs?
IHC for MLH1,MSH2, MSH6, PMS2
PUTATIVELYNCH
SYNDROME
MMR GENES MUTATIONANALYSIS
Is therea mutation in MMR
gene?
LYNCHSYNDROME
YES
YES
NO
NO
NO
YES
YES
NO
Gatalica Z, Torlakovic E. Fam Cancer 2008;7:15-26
FAMILIAL CRCTYPE “X”
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Frequency of MMR Mutations*
~60% of Amsterdam+ families with clinically defined LS phenotype carry point mutations or large genomic deletions in the transcription of either MLH1 or MSH2 genes.
Conversely, the pathogenic change inactivating the MMR system is not known or not fully understood in the remaining ~40%.
*Lagerstedt-Robinson et al. J Natl Cancer Inst 99:291-299, 2007.
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Frequency of MMR Mutations*
A portion of this ~40% lacking MMR mutations is caused by a mutation mechanism in the gene known as EPCAM.
Others have been classified as familial colorectal cancer Type “X”.**
*Kovacs et al. Hum Mutat 30:197-203, 2009.**Lindor et al. JAMA 293:1979-1985, 2005.
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Epithelial Cell Adhesion Molecule (EPCAM) Gene and Its Lynch Syndrome Connection
Impacts
Diagnosis
Genetic Counseling
Phenotype site specific CRC
Pathogenesis
Pharmacogenetics
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Polyadenylation Sequence
5’ EPCAM deletion Exons 8 and 9 and polyadenylation sequence
Ligtenberg MJ, Nature Genetics 2009.
Transcriptional read throughHypermethylation of the MSH2 promoter
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Why LS with Site-Specific CRC?
Deletion in EPCAM results in hypermethylation and incomplete silencing of MSH2.
EPCAM mutation carriers may have phenotypic features that differ from carriers of MSH2 mutations – namely, an almost exclusive expression of site-specific CRC, thereby lacking extracolonic cancers.
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c.859-1462_*1999del (4.9 kb, starting in intron 7 and including exons 8 & 9)
EPCAM MSH2
American and Dutch families have the same deletion in the EPCAM gene
Deletion
Lightenberg, Nature Genetics 2009.
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History of Family R*
Ascertained by us in 1970 and followed continuously.
700 blood line relatives
327 individuals age ≥ 18, ≥ 25% pedigree risk
Phenotype strikingly similar to LS but integral extracolonic cancers absent (site-specific CRCs)
*Lynch et al. Cancer 56:934-938, 1985.
Lynch et al. Cancer 56:939-951, 1985.
52First patient identified with EPCAM mutation
CRC affecteds EPCAM results
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American and Dutch EPCAM mutations originate from a common ancestor
Deletion and Region inherited from
common ancestor
Family R and the Dutch families share a 6.1 MB region surrounding the same EPCAM deletion indicating a common ancestor. Based on the size of the
shared region it is estimated the deletion occurred 10 generations ago.
Dutch Families
Chromosome 2
Family R
Chromosome 2
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J Clin Oncol25:3534-3542, 2007.
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Who Should Be Tested?1. Pedigree consistent with hereditary colorectal cancer (CRC) syndrome;
2. Known germline mutation predisposing to
cancer;
3. Patients at acceptable high cancer risk status;
4. Presence of cancer syndrome stigmata (phenotype): e.g., polyposis in FAP;
5. Genetic counseling, risks/benefits understood;
6. Consent given;
7. Results: full explanation of surveillance/management advice.
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Family Information Service (FIS)
Cost-effective and highly efficient way of educating and counseling all available family members from a geographic catchment area during a single setting.
Makes best use of physician’s time and effort, has group therapy potential and patients welcome it.
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Conclusions for EPCAM
Conclusions:
1) Cancer control compliance in Family R profound;
2) 40% of AC-I cases lack MMR mutations – how many may qualify as EPCAM?
3) Likely EPCAM phenotype site-specific CRC;
4) What can we learn from molecular features of EPCAM for pharmacologic benefit?
5) 1/35 CRC affecteds likely LS (Hampel et al.*).
*J Clin Oncol 26:5783-5788, 2008.
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Physicians
Payers
Patients
Personalized Medicine
Need Individual managementbased upon Genetic diagnosis(deleterious mutation helpful)
Need more clinical genetic education. Example: multiplepolyps = FAP; multiple primary cancer pattern = syndrome identification
What is advantage of extensive family history; genetic counseling; genetic testing (MMR, MSI, IHC, BRCA1/2); screening?
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J Clin Pathol 62:679-684, 2009.