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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;

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slide1

CANCER GENETICS: IDENTIFICATION AND MANAGEMENT OF INDIVIDUALS WITH LYNCH SYNDROME

HENRY T. LYNCH, MD

Creighton University

School of Medicine

Omaha, Nebraska

slide2

Hereditary 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.
why pursue cancer of all anatomic sites
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.

colorectal cancer
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 37,011-61,686
  • FAP <1% of all CRC <12,337
  • Familial 20% of all CRC 246,742
  • *GLOBOCAN. The International Agency for Research
  • on Cancer web site. URL: http://www.iarc.fr/
slide8

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.

8

magnitude of the problem
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
Genetic Counseling
  • Mandatory
  • Centers of Cancer Genetic Expertise
  • Physician Role, unfortunately, often insufficient
slide12

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.

molecular genetic screening for ls
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.
cost effectiveness of dna testing
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.
familial crc type x
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.
screening for amsterdam criteria ls
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.
familial crc
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!
genetic heterogeneity in hnpcc

Mismatch Repair (MMR) Mutations

Genetic Heterogeneity in HNPCC

MSH6

MLH1

MSH2

PMS2

PMS1

Chr 7

Chr 3

Chr 2

HNPCC is associated with germline mutations in any one of at least five genes

cardinal features of lynch syndrome
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 will

have a second primary CRC within 10 years, if surgery was < a

subtotal colectomy.

increased risk for certain extracolonic malignancies
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.
cardinal features of lynch syndrome1
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.
colonoscopy
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
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.
screening for ec in ls
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.
slide28

Could this be

hereditary

Colon Cancer

targeted crc screening
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
extended colectomy
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.
slide37

Familial

Hereditary

AC-1 without MMR

(Familial CRC of syndrome “X”)

Lynch Syndrome

TACSTD1 (EPCAM)

Sporadic

FAP; AFAP

Mixed Polyposis Syndrome

Ashkenazi I1307K

CHEK2 (HBCC)

MUTYH (MAP)

TGFBR1

PJSFJP

CD

BRRS

= as yet undiscovered

hereditary cancer variants

Hamartomatous

Polyposis

Syndromes

attenuated fap
Attenuated FAP
  • Later onset (CRC ~age 50)
  • Few colonic adenomas
  • Not associated with CHRPE
  • UGI lesions
  • Associated with mutations at extreme 5’, 3\' ends of APC gene, & exon 9A
molecular diagnosis of ls toward a consensus
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.
braf v600e mutation and ls
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.
slide44

MORPHOLOGY

SUSPICIOUS

FOR MSI-H

Run PCR test

for MSI status

Is there

MSI-H?

FAMILIAL CRC

TYPE “X”

NO EVIDENCE OF

LYNCH

SYNDROME

NO

NO

YES

Is there loss

of staining

with any of

the Abs?

PUTATIVE

LYNCH

SYNDROME

Run mutation analysis

for BRAF V600E

YES

Is there

BRAF V600E

mutation?

NO

MMR GENES MUTATION

ANALYSIS

IHC for MLH1,

MSH2, MSH6, PMS2

YES

Is there

a mutation in MMR

gene?

SPORADIC CRC

WITH MSI-H

NO

YES

LYNCH

SYNDROME

Gatalica Z, Torlakovic E. Fam Cancer 2008;7:15-26

frequency of mmr mutations
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.
frequency of mmr mutations1
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.
epithelial cell adhesion molecule epcam gene and its lynch syndrome connection

Diagnosis

Genetic Counseling

Phenotype site specific CRC

Pathogenesis

Pharmacogenetics

Impacts

Epithelial Cell Adhesion Molecule (EPCAM) Gene and Its Lynch Syndrome Connection
slide48

5’ EPCAM deletion

Exons 8 and 9 and polyadenylationsequence

Polyadenylation Sequence

Transcriptional read through

Hypermethylation of the MSH2 promoter

Ligtenberg MJ, Nature Genetics 2009.

why ls with site specific crc
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.
slide50

American and Dutch families have the same deletion in the EPCAM gene

MSH2

EPCAM

Deletion

c.859-1462_*1999del

(4.9 kb, starting in intron 7 and including exons 8 & 9)

Lightenberg, Nature Genetics 2009.

history of family r
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.
slide53

American and Dutch EPCAM mutations originate from a common ancestor

Chromosome2

Chromosome 2

Dutch Families

Family R

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.

Deletion and Region inherited from common ancestor

who should be tested
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.

slide56

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.

conclusions for epcam
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.
slide60

Personalized Medicine

Patients

Need Individual management

based upon Genetic diagnosis

(deleterious mutation helpful)

Need more clinical genetic education. Example: multiple

polyps = FAP; multiple primary cancer pattern = syndrome identification

Physicians

What is advantage of extensive family history; genetic counseling; genetic testing (MMR, MSI, IHC, BRCA1/2); screening?

Payers

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