Genetic of CRC_Prof Soetamto (distributed).pdf

Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)
Genetic of CRC_Prof Soetamto (distributed)

1. GENETIC OF COLON CANCER
FOCUSED ON HEREDITARY CANCER SYNDROME
Prof. P. Soetamto Wibowo, dr. Sp.B-KBD
FK. Unair –RSUD Dr. Soetomo Surabaya
Webinar Colorectal Cancer Management –9 August 2020 COPYRIGHT COPYRIGHT

2. Epidemiology
Colorectal cancer (CRC) is the 4
th
most frequently diagnosed cancer in US and the
2
nd
leading caused of cancer death in the US; on 2019 [1]
35% of CRC due to the Hereditary Factor [2,3]
at least one first-degree relative with CRC
Highly penetrant syndrome such as Lynch Syndrome (LS) and Familial Adenomatous
Polyposis (FAP) account for 5% -10% of CRC [2]
Nearly 1 million carriers in the US remain unidentified [4]
1Siegel RL et al. Cancer Statistic. CA Cancer J.Clin 2019; 69 : 7 –34
2Valle R et al. Update in genetic predisposition to colon rectal cancer and polyposis. Molecular Aspect of Medicine 2019; 69 : 10 –26
3Gupta S et al. Genetic / Familial High Risk Assessment : Colorectal. Version 2. 2019. JNCCN Org 2019; 17(9):1033-4
4Kastrinos F et al. Development and Validation of the PREMM model for Comprehensive Risk Assessment of Lynch Syndrome. J. ClinOncol. 2017;
35(19):2165-72COPYRIGHT COPYRIGHT

3. Assessment the Risk for Hereditary Colorectal Cancer Syndrome [1, 2]
Improved Cancer Surveillance
Reduced morbidity of surveillance and treatment
Faster and early diagnosis –better prognosis
Risk reduction
Improved identification of hereditary CRC
Risk of extra-colonic cancers
Optimized management
Improved pathways from diagnosis to treatment
Prevention of CRC / associate cancer
Surgery –Colonoscopy –Aspirin
[1] Gupta S, ProfenzaleD, LlorX et al. Genetic / Familial High Risk Assessment : Colorectal. Version 2. 2019. JNCCN Org 2019; 17(9):1033-4
[2] Monahan K. Bradshaw N. Dolwaniet al. Guideline for The management of hereditary colorectal cancer from The British Society of Gastroenterology (BSG) Association
of Coloproctology Great Britain and Ireland (ACGBI) United Kingdom Cancer Genetics Group (UKCG. GUT 2020; 69 : 411 –444. doi10.36/gutjnl-2019-3/4915
1990 –begin understanding The Mechanism
of Familial Clustering of CRC
Risk Management Surveillance COPYRIGHT COPYRIGHT

4. Risk of Hereditary Cancer
Identification of Risk [1, 2]
Phenotype Criteria
Family History of cancer –Pedigree
Patient Specific Factors :
Age at diagnosis
Tumor phenotype
1.Gupta S et al. Genetic / Familial High Risk Assessment : Colorectal. Version 2. 2019. JNCCN Org 2019; 17(9):1033-4
2.Giardiello FM, Allen JI, AxilbundJE et al. Guideline on genetic evaluation and management of Lynch Syndrome : Aconcensusstatement by the US. Multi-
society task force on colorectal cancer. The Am.J. Gastroenterology 2014; 147 : 502 –26.COPYRIGHT COPYRIGHT

5. Case
2017
X
→X –PREMM5 Score 41.0% COPYRIGHT COPYRIGHT

6. Empathy –Medicolegal
Psychosocial assessment
Informed Consent
Advocacy
[1] Gupta S, Provenzale D, Llor X. et al. Genetic / Familial High Risk Assessment : Colorectal. Version 2. 2019. JNCCN Org 2019;17(9):1033-4COPYRIGHT COPYRIGHT

7. Carcinogenesis of Colorectal Cancer [1]
COLORECTAL
CARCINOMA
Microsatellite Instability
MSI-H (15%)
Chromosomal Instability
CIN (85%)
Lynch Syndrome
(3%)
Sporadic CRC
(12%)
Sporadic
CRC
Familial Adenomatous
Polyposis (FAP) 1%
Germline mutation
MMR genes MLH1
MSH2 MSH6 PMS2
Epigenetic Silencing
of MSH1 by
hypermethylation
Germline mutation
of APC gene
Somatic mutation
Polymorphism
[1] de la Chapalle A. Hampel H. Clinical relevance of Microsatellite Instability in Colorectal Cancer. J.Clin 0100 2010; 28(20)3380COPYRIGHT COPYRIGHT

8. Polyposis Syndrome
Previously Identified POLYPOSIS SYNDROME [1]
Familial Adenomatous Polyposis (FAP)
Attenuated FAP (AFAP)
MUTYH Associated Polyposis (MAP)
HamartomatousPolyps : PeutzJeger, Juvenile polyposis
Serrated Polyps
Much of the genetic predisposition to CRC and polyposis is still unexplained [2]
[1] Gupta S, Provenzale D, Llor X, et al. Genetic / Familial High Risk Assessment : Colorectal. Version 2. 2019. JNCCN Org 2019;17(9):1033-4
[2] Valle L. de Voer RM. Goldberg T et al. Update in genetic predisposition to colorectal cancer and polyposis. Molecular Aspectof Medicine 2019;69:10-26COPYRIGHT COPYRIGHT

9. Familial Adenomatous Polypsis (FAP) [1]
Germline Mutation in the APC gene 5q 22-23
High risk of malignancy
High penetrance –phenotype
Autosome dominant
Early onset 20 –30 yrs
> 100 polyps –left colon
Extra colonic malignancy
Genetic counselling
Informed consent
Advocacy
[1] Gupta S, Provenzale D, Llor X, etal. Genetic / Familial High Risk Assessment : Colorectal. Version 2. 2019. JNCCN Org 2019; 17(9):1033-4
[2] Boland PM, Matthew B, Yurgelun MB et al. Recent progress in Lynch Syndrome and other Familial Colorectal Cancer Syndrome.CACancer J.Clin 2018; 68 :
217-231COPYRIGHT COPYRIGHT

10. Lynch Syndrome –1966 [1,2,3]
The most common form of hereditary colorectal cancer (3-5%) –
2% endometrial cancer
Autosome dominant
Defect in DNA mismatch repair (MMR) gene:
MLH1, MSH2, MSH6, PMS2.
→ Microsatellite Instability (MSI –H)
1.Lynch HT, Lynch PM, LonspaSJ et al. review of the Lynch syndrome : History molecular genetics, screening, differential diagnosis and medicolegal ramification. Clin Genet 2019; 76 : 1 –18.
2.Gupta S, ProvenzaleD, LlorX et al. Genetic / Familial High Risk Assessment : Colorectal. Version 2. 2019. JNCCN Org 2019; 17(9):1033-4
3.Monahan K. Bradshaw N. Dolwaniet al. Guideline for The management of hereditary colorectal cancer from The British Society of Gastroenterology (BSG) Association of Coloproctology
Great Britain and Ireland (ACGBI) United Kingdom Cancer Genetics Group (UKCG. GUT 2020; 69 : 411 –444. doi: 10.36/gutjnl-2019-3/4915COPYRIGHT COPYRIGHT

11. Lynch Syndrome
Clinical Manifestation –Phenotype [1,2]
Reduces penetrance –50%
Mean age of CRC 44 –61 yrs
Primary on the right colon 60 –80%
Synchronous CRC or associated cancer (endometrial-ovary, small bowel, stomach,
pancreas, hepatobiliary, ureter, renal pelvis, bladder and skin) –7%
Metachronous CRC or associated cancer
16% at 10 years
41% at 20 years
62% at 30 years
Diploid DNA content →better prognosis (2)
1.Kawakami H, ZannanA, SincropeFA. Microsatellite Instability testing its role in the management of colorectal cancer. CurrTreatment options in Oncol 2015;16:30-45
2.Boland PM, Matthew B, YurgelunMB et al. Recent progress in Lynch Syndrome and other Familial Colorectal Cancer Syndrome. CA Cancer J.Clin2018; 68 : 217-231 COPYRIGHT COPYRIGHT

12. Lynch Syndrome –Diagnosis (I)
Family history –pedigree [1]
1990 Amsterdam I criteria –colorectal cancer
1999 Amsterdam II criteria –CRC and associate cancer
3 –2 –1
3Affected members with one should be a first degree relative of the other two
2or more successive generation affected
1or more diagnosed before the age of 50 yrs
Familial adenomatous polyposis should be excluded sensitivity 22%, specificity 98%
1.Giardiello FM, Allen JI, AxilbundJE et al. Guideline on genetic evaluation and management of Lynch Syndrome : A Concensusstatement by the US. Multi-
society task force on colorectal cancer. The Am.J. Gastroenterology 2014; 147 : 502 –26.
2.Monahan K. Bradshaw N. Dolwaniet al. Guideline for The management of hereditary colorectal cancer from The British Society of Gastroenterology
(BSG) Association of Coloproctology Great Britain and Ireland (ACGBI) United Kingdom Cancer Genetics Group (UKCG. GUT 2020; 69 :411 –444. doi:
10.36/gutjnl-2019-3/4915COPYRIGHT COPYRIGHT

13. Case
60 –endometrial
30 –ovarian
55 –caecum 1990
63 –rectal 1998
49 -caecum
A -45
B -23
2001
2013
→A –PREMM5 Score 24.8 % COPYRIGHT COPYRIGHT

14. Lynch Syndrome –Diagnosis (II)
2004 Revised Bethesda Guidelines [1]
1.CRC diagnosed at younger than 50 years
2.Presence of synchronous or metachronous or other LS associated tumor
3.CRC with MSI high pathologic associated features (Crohn like lymphocytic reaction
mucinous/signet cell differentiation, or medullary growth pattern) diagnosed in an
individual younger than 60 years old
4.CRC diagnosed in a patient with a family history of LS associated cancer diagnosed before
the age of 50 years
5.CRC diagnosed in more than 1 relative with LS associated cancer regardless of age
Fulfillment of any criteria meets guidelines to identify individuals with CRC who should undergo
tumor testing for microsatellite instability (MSI)
Sensitivity 82% -specificity 77%
[1] Giardiello FM, Allen JI, AxilbundJE et al. Guideline on genetic evaluation and management of Lynch Syndrome : A concensusstatement by the US. Multi-
society task force on colorectal cancer. The Am.J. Gastroenterology 2014; 147 : 502 –26. COPYRIGHT COPYRIGHT

15. Case
2015
2020
Bethesda pos →MSI / IHC
Diagnosis –Universal Screening (1.2)
Universal Screening Cost Effective
1.GiardielloF.M
2.Gupta SCOPYRIGHT COPYRIGHT

16. Immunohistochemistry (IHC) test –d MMR gene
UNIVERSAL SCREENING
Personal and Family History of CRC,
Endometrial, or Other Lynch Syndrome-
Associated Cancer
Loss of MLH1 gen
Diagnosis Lynch SyndromeCOPYRIGHT COPYRIGHT

17. Lynch Syndrome –Diagnosis (III)
Prediction Models –Statistical
PREMM 5 [1,2]
•Predict risk for carrying mutation in MMR gene
•It is a simple and efficient online tool form or diverse array of health care provider
•For individual who have not been affected by cancer, where tumor tissue is unavailable for
MMR-IHC / MSI testing
Can be applied online
Personal / family history
Type of cancer and ages of 1
st
degree family
Type of cancer and ages of 2
nd
degree family
Threshold of ≥ 2.5% PREMMS score ---Negative Predictive Value 99% [3]
NCCN (2019) –Threshold ≥ 5% [1]
1.Gupta S, ProvenzaleD, LlorX et al. Genetic / Familial High Risk Assessment : Colorectal. Version 2. 2019. JNCCN Org 2019; 17(9):1033-4
2.Boland PM, Matthew B, YurgelunMB et al. Recent progress in Lynch Syndrome and other Familial Colorectal Cancer Syndrome. CA Cancer J.Clin2018; 68 : 217-231
3.KastrinosF, Uno H, UkaegbuC, et al. Development and Validation of the PREMM model for Comprehensive Risk Assessment of Lynch Syndrome. J. Clin Oncol.
2017; 35(19):2165-72
http://premm.dfci.harvard.edu/COPYRIGHT COPYRIGHT

18. CASE 4
Amsterdam Ct+
→X –PREMM5 Score ≥ 50%
PREMM5 Score Specificity (1)
Universal Screening
(1) KastrinosFCOPYRIGHT COPYRIGHT

19. Testing strategy when patient is
clinically affected and the family
mutation is unknownCOPYRIGHT COPYRIGHT

20. COPYRIGHT COPYRIGHT