lynch syndrome ppt

1. Genetic changes in endometrial
cancer and HNPCC syndrome
DR.ASHISH POKHARKAR
(Tata memorial hospital)

2. “An
individual doesn't get
cancer…..,A family does ”
TERRY TWMPEST WILLIAMS

3. [CATEGORY
NAME], [PERCENT
AGE]
3rd Qtr
0
0%
[CATEGORY
NAME] 90%

4. Table 1: Clinical And Pathological Features Of Endometrial
Carcinoma.
Type I (EEC)
Type II (NEEC)
Age
Pre- And Perimenopausal
Postmenopausal
Behaviour
Stable
Progressive
Grade
Low( stage I,II)
High(Stage III/IV)
Hyperplasia-precursor
Present
Absent
Unopposed Oestrogen
Present
Absent
Myometrium Invasion
Minimal
Deep
Specific Subtypes
Endometrioid Carcinoma
Non-endometrioid
Carcinoma
Prevalence
70–80%
Risk Factors
Obesity, Anovulation,
10–20%
In Atrophic Endometrium
Nulliparity
And Exogenous Oestrogen Exposure

5. TABLE 2. MOLECULAR FEATURES OF ENDOMETRIAL CARCINOMA
EEC(TYPE I)
NEEC( TYPE II)
GAIN-OF FUNCTION
K-RAS
15–30%
0–5%
HER2/NEU
10–20%
9–30%
B-CATENIN
31–47%
0–3%
PTEN
35–50%
10%
P53
10–20%
90%
20–40%
0-5%
LOSS-OF FUNCTION
GENOMIC INSTABILITY
(MICROSATELLITE)

6. LYNCH SYNDROME

7. HISTORY
 Father of hereditary cancer.
Henry T. Lynch (professor of medicine at Creighton University Medical
Centre) characterized the syndrome in 1966.
The term "Lynch syndrome" was coined in 1984 by other authors, and
Lynch himself coined the term HNPCC in 1985.

8. WHAT IS LYNCH SYNDROME?
 Autosomal dominant inheritance associated with mutation in mismatch
repair genes(MLH1,MSH2,MSH6,PMS2).
 Increased risk of colon cancer and other extra colonic sites. E.g.
endometrium,ovary,stomach,renal pelvis,ureter,small bowel etc.
 Lynch syndrome type I – Familial colon cancer
Lynch syndrome type II – familial colon cancer with cancers of extra
colonic sites
Muir –torre variant – with sebaceous adenoma, sebaceous carcinoma and
multiple keratocanthomas.
Turcot syndrome-colorectal cancer or colorectal adenomas in addition to
tumours of the central nervous system.

9.  SALIENT FEATURES
 Earlier age of onset.( 45 Vs. 63 yrs. for colonic cancers, 47 Vs. 60 yrs. for
endometrial cancer).
 Proximal colonic cancer predisposition ( 75-80%).
 Accelerated carcinogenesis, ( 2-3 yrs. vs. 8-10 yrs.).
High risk of synchronous and metachronous tumors.
Pathology of colonic cancer is more often poorly differentiated with excess of
mucoid and signet cell features with Crohn’s like reaction and lymphocytes
infiltration.

10. CANCER RISKS IN INDIVIDUALS WITH LYNCH
SYNDROME AGE ≤70 YEARS COMPARED TO THE
GENERAL POPULATION
Cancer Type
General Population
Risk
Lynch Syndrome
(MLH1 and MSH2 heterozygotes)
Risk
Mean Age of Onset
Colon
5.5%
52%-82%
44-61 years
Endometrium
2.7%
25%-60%
48-62 years
Stomach
<1%
6%-13%
56 years
Ovary
1.6%
4%-12%
42.5 years
Hepatobiliary tract
<1%
1.4%-4%%
Not reported
Urinary tract
<1%
1%-4%
~55 years
Small bowel
<1%
3%-6%
49 years
Brain/central nervous
system
<1%
1%-3%
~50 years
Sebaceous
neoplasms
<1%
1%-9%
Not reported

11. COLON CANCER
2/3 Cancers in proximal colon.
Better prognosis than sporadic colon cancers.(When matched stage for
stage)
Histologic characteristics: poor differentiation, tumor-infiltrating
lymphocytes, mucin, and signet ring or cribiform histology

13. ENDOMETRIAL CANCER
25%-60% lifetime risk of endometrial cancer.
Average age of diagnosis of appr. 48 years.
Among women with lynch syndrome who develop both colon cancer and
endometrial cancer, approximately 50% present first with endometrial cancer.
The risk for subsequent endometrial cancer for women with lynch syndrome
presenting first with colon cancer has been estimated at 26% within ten years
of the initial colon cancer diagnosis.
According to study by Westin et al 1/3 of lower uterine segment tumors are
associated with lynch syndrome.
Endometroid histology is most common.

14. OVARIAN CANCER
The mean age of diagnosis of Lynch syndrome-associated ovarian cancers is
42.5 years.
Endometroid histology is most common type.
Overall 4-12% lifetime risk.

15. PATHOGENESIS & MOLECULAR GENETICS
Mutations in the genes of mismatch repair pathways.
MSH2
2p21
DNA mismatch repair protein Msh2
PMS1
2q32​.2
PMS1 protein homolog 1
PMS2
7p22​.1
Mismatch repair endonuclease PMS2
MSH6
2p16​.3
DNA mismatch repair protein Msh6
MLH1
3p22​.2
DNA mismatch repair protein mlh1
EPCAM 2p21
Epithelial cell adhesion molecule

17. MICROSATELLITE INSTABILITY

18. DIAGNOSIS
How can we improve identification of LS??
 Adequate education of general population.
Adequate family history.
Use of surveillance criteria.
Amsterdam criteria
Amsterdam II criteria
Revised bethesda guidelines.

19. AMSTERDAM CRITERIA
Amsterdam Criteria
Amsterdam II Criteria
Three or more family members, one of whom
is a first-degree relative of the other two, with
a confirmed diagnosis of colorectal cancer
Three or more family members, one of whom
is a first-degree relative of the other two, with
HNPCC-related cancers
Two successive affected generations
Two successive affected generations
One or more colon cancers diagnosed before
age 50 years
One or more of the HNPCC-related cancers
diagnosed before age 50 years
Exclusion of familial adenomatous
polyposis (FAP)
Exclusion of familial adenomatous
polyposis (FAP)

20. REVISED BETHESDA GUIDELINES
Tumours from individuals should be tested for microsatellite instability in the
following situations:
1. Colorectal cancer diagnosed under the age of 50 years of age.
2. Presence of synchronous, metachronous colorectal, or other HNPCC associated
tumours, regardless of age.
3. Colorectal cancer with the MSI-H histology diagnosed in a patient who is
less than 60 years of age.
4. Colorectal cancer diagnosed with one or more first-degree relatives with an
HNPCC-related tumour, with one of the cancers being diagnosed under age 50
years.
5. Colorectal cancer diagnosed in two or more first or second degree relatives

21. RECENT GUIDELINES BY MALLOCRA GROUP
Testing all CRC and all EC (or individuals <70yrs) by IHC or MSI is useful for the
identification of patients with LS (category of evidence IIb).
1) Recommends investigation of all CRC (or individuals with CRC<70 years) by IHC
of the four MMR proteins or MSI (grade of recommendation C).
These tests should be accompanied by methods that identify MLH1 promoter
methylation.
2) Investigation of all EC in individuals less than 70 years by IHC or MSI can be
considered to improve identification (grade of recommendation C).
(Revised Guidelines for the Clinical Management of Lynch Syndrome (HNPCC) Recommendations by a
Group of European Experts Hans F A Vasen, Ignacio Blanco, Katja Aktan-Collan, Jessica P Gopie, Angel Alonso, Stefan
Aretz, Inge Bernstein, Lucio Bertario, John Burn, Gabriel Capella, Chrystelle Colas, Christoph Engel, Ian M Frayling, Maurizio
Genuardi, Karl Heinimann, Frederik J Hes, Shirley V Hodgson, John A Karagiannis, Fiona Lalloo, Annika Lindblom, Jukka-Pekka
Mecklin, Pal Møller, Torben Myrhoj, Fokko M Nagengast, , Yann Parc, Maurizio Ponz de Leon, Laura Renkonen-Sinisalo, Julian R
Sampson, Astrid Stormorken, Rolf H Sijmons, Sabine Tejpar, Huw J W Thomas, Nils Rahner, Juul T Wijnen, Heikki Juhani
Järvinen, Gabriela Möslein Gut. 2013;62(6):812-823)

22. TESTS USED FOR SCREENING AND DIAGNOSIS

23. TESTS USED ON TUMOR TISSUE
Used to establish probability of lynch syndrome.
Tissue type: Generally done on colorectal tumor tissue, polyp can be used.
Testing can be done on endometrial cancer tissue.
 Two types of tests: 1) Immunohistochemistry (IHC)
2) Microsatellite instability (MSI) testing

24. IMMUNOHISTOCHEMISTRY
IHC detects the presence or absence of the protein products expressed by mismatch repair
genes.
The MMR gene products work in dimers:
MSH2 complexes MSH6 / MSH3 protein,
MLH1 complexes with PMS2/ PMS1 protein.
MSH6 and PMS2 proteins are unstable when not paired in a complex;
thus, a germline mutation in
MSH2 typically results in loss of expression of the proteins MSH2/MSH6
MLH1 results in loss of expression of the proteins MLH1/PMS2.
However, germline mutations in MSH6 and PMS2 typically do not result in loss of MSH2 or
MLH1 expression because these proteins are still present in other pairings.

25. ADVANTAGES OF IHC TESTING :
Antibodies for MSH2, MLH1, MSH6, and PMS2 have demonstrated 92%
sensitivity for identifying tumors that arise in individuals with a germline mutation .
Readily available at most centres and is technically easy to perform.
IHC testing identifies in most individuals the MMR gene in which either a germline
mutation or a somatic alteration that silences gene expression is most likely to be
found thus significantly reducing the cost of molecular genetic testing.
DISADVANTAGES OF IHC TESTING:
Variation in tissue fixation and other technical issues can result in weak or
equivocal staining patterns.
It is possible that some missense germline mutations will not result in the absence
of a detectable protein product.
It may be less reliable when performed on small tissue samples.

27. MSI TESTING
For MSI analysis, DNA is usually extracted from paraffin-embedded tumor
tissue and normal tissue or peripheral blood.
 Reliable demonstration of MSI requires that at least 30% of the tumor
specimen is composed of tumor cells.
PCR is used to amplify the region containing the microsatellite, and the
products are then separated on the basis of size. A microsatellite is considered
unstable if the distribution of the fragments from the tumor sample differs
from that of the normal tissue
A 1997 NCI consensus meeting recommended a core panel of five markers:
BAT25, BAT26, D2S123, D5S346, and .D17S250.
MSI-high if more than two (or >30%) of the markers show instability.
MSI-low if one (or <30%) of the markers show instability.
MSI-stable if 0 (or 0%) of the markers show instability.

28. ADVANTAGES:
Effective method, sensitivity 93 %.
MSI testing may be positive (i.e., Identify a tumor as arising from MMR
deficiency) when the IHC studies have given a false negative result
(e.g., Because the appropriate antibody was not included in the test; the
protein is present, but non-functional).
Can be done with very little tissue.
Highly reproducible.
Disadvantages:
May not be readily available.
It does not reduce the cost of molecular testing because it does not help
identify the gene which is most likely mutated.

29. MOLECULAR GENETIC TESTING.
Once a tumor is determined to be MSI-H and/or demonstrates loss of MMR
protein expression by IHC, the individual can, after appropriate genetic
counselling, elect to have molecular genetic testing to identify a germline
mutation in one of the MMR genes.

31. SURVEILLANCE PROTOCOL FOR COLON
CANCER.
Regular colonoscopy leads to a reduction of CRC-related mortality and also
to a significant reduction of overall mortality in contrast with CRC screening
in the general population.
Colonoscopy is recommended rather than flexible sigmoidoscopy because
of the predominance of proximal colon cancers in lynch syndrome.
Current recommendations are to have colonoscopy every one to two years
beginning between ages 20 and 25 years or ten years before the earliest
diagnosis in the family, whichever is earlier.

32. SURVEILLANCE PROTOCOL FOR
ENDOMETRIAL AND OVARIAN CANCERS.
No proven screening strategy.
Patient should be aware that abnormal vaginal bleeding warrant evaluation.
Can consider screening with annual endometrial biopsy and transvaginal
ultrasound beginning at age 30.

33. SURVEILLANCE PROTOCOL FOR STOMACH
AND SMALL BOWEL CANCERS.
Currently the NCCN recommends beginning upper endoscopy with a sideviewing scope and extended duodenoscopy between ages 30 and 35 years and
repeating them every two to three years depending on the findings.
At this time data are limited regarding screening for cancer development in
the distal small bowel. Capsule endoscopy every two to three years beginning
between ages 30 and 35 years can be considered.

34. SURVEILLANCE PROTOCOL FOR UROTHELIAL
CANCERS
NCCN recommends consideration of annual urine analysis starting at age
25-30.

35. RISK REDUCING STRATEGIES:
Prophylactic removal of the uterus and ovaries (prior to the development of
cancer) can be considered after childbearing is completed.
Can consider chemoprevention with OCP and progestins.
Because routine colonoscopy is an effective preventive measure for colon
cancer, prophylactic colectomy is generally not recommended for individuals
with Lynch syndrome.
Regular aspirin significantly reduces the incidence of cancer in LS.

36. MANAGEMENT:
 If colon cancer is detected, full colectomy with ileorectal anastomosis is
recommended rather than a segmental/partial colonic resection because of the
high risk for metachronous cancers.
The other tumors seen in Lynch syndrome are managed as in the general
population.

37. EVALUATION OF RELATIVES AT RISK
When an MMR gene mutation has been identified in a family with Lynch
syndrome, molecular genetic testing for the mutation should be offered to all
first-degree relatives (parents, sibs, and children).

38. GENETIC COUNSELLING
Genetic counselling is the process of providing individuals
and families with information on the nature, inheritance,
and implications of genetic disorders to help them make
informed medical and personal decisions.

39. RISK TO FAMILY MEMBERS
Not all individuals with a Lynch syndrome-causing MMR gene mutation
have a parent who had cancer.
if clinical and family history cannot identify from which parent the proband
inherited the MMR gene mutation, molecular genetic testing should be
offered to both parents to determine which one has the mutation identified in
the proband.
Molecular genetic testing for the mutation identified in the family should be
offered to all sibs.
Each child of an individual with Lynch syndrome has a 50% chance of
inheriting the mutation.

40. GENETIC COUNSELLING ISSUES
Family planning: It is appropriate to offer genetic counselling (including
discussion of potential risks to offspring and reproductive options) to young
adults who are affected or at risk.
Molecular genetic testing of asymptomatic individuals younger than age 18
years should not be advised.
Prenatal Testing

41. THANK YOU