Lynch syndrome detection and screening Ondrej Daum Plzen Czech - - PowerPoint PPT Presentation

Lynch syndrome

detection and screening

Ondrej Daum

Plzen Czech Republic

Χ

1 out of 440 people carries a germline mutation causing LS (i. e. 22 730 in Czech Republic) Localisation Cancer risk

large intestine up to 74 % small intestine up to 12 % stomach up to 13 % uterus up to 71 % fallopian tube/ovary up to 20 % urinary system up to 25 %

• adenoma to carcinoma transformation occurs in 2-3 years (x 8-10 years in sporadic CRC)
• average age at the time of diagnosis is 45 let (x 65 years in sporadic CRC)

Pai R. K. et al. (2016) Am J Surg Pathol 40(4): e17-34 Pai R. K. et al. (2016) Am J Surg Pathol 40(4): e17-34

MSH6 MSH2 MLH1 PMS2

Mismatch Repair

DNA

Sporadic MSI-H CRC Lynch Epigenetic inactivation of MLH1

(promoter hypermethylation)

Epigenetic inactivation of MLH1

(promoter hypermethylation)

Germline “loss of function” mutation of an MMR gene Germline “loss of function” mutation of an MMR gene

• 15 % CRC are MSI-H
• 20 % MSI-H CRC are caused by LS

Peltomaki P. et al. (1993) Cancer Res 53(24): 5853-5855 Yuen S.T.et al. (2002) Oncogene 21(49): 7585-7592 Peltomaki P. et al. (1993) Cancer Res 53(24): 5853-5855 Yuen S.T.et al. (2002) Oncogene 21(49): 7585-7592

Possibilities of detection

Molecular genetic testing of all CRC and endometrial ca. for MMR mutations? MSI testing of all CRC and endometrial ca.? IHC MMR staining of all CRC and endometrial ca.? 1. 2. 3.

• MSI-H histology is more sensitive than the

combination of 4 remaining RBG criteria

4.

• Proč to vadí?

MSI - feature Right-sided localisation Dissecting mucin (any volume) Age < 50 years TILs (> 2/HPF or > 10/100 epithelial nuclei) Peritumoral lymphoid cuff Stromal plasma cells (> 25% stromal leukocytes)

MSI-H histology (SemiPREDICT score)

If ≥ 2 signs → MSI susp.

Hyde A. et al. (2010) Am J Surg Pathol 34(12):1820-1829 Hyde A. et al. (2010) Am J Surg Pathol 34(12):1820-1829

BRAF V600E

• Hypermethyl. MLH1

MSI-H IHC deficiency of MLH1 and/or PMS2 IHC deficiency of MSH2 and/or MSH6 Analysis of MLH1 and PMS2 in peripheral blood Analysis of MSH2, MSH6 and EPCAM in peripheral blood

Finish testing

+ + + +

• IHC

MMR def.

IHC:

BRAF V600E Annexin A10

+

• Semi PREDICT

score ≥ 2 Clinical suspicion

?

Lynch like syndrome

wt

LS

mut

LS

mut

wt

* * * Not applicable in EC

Timeline of LS detection in Plzen

2013 2014 2015 2016 2017

SemiPREDICT score investigated by all pathologists in the Sikl´s Institute and in the private Bioptical Laboratory ↓ Positive cases sent to me for further management ↓ Comment on LS suspicion along with request on blood in the report

All CRCs and ECs to investigate by IHC Investigation almost completely banned by clients

• f PBL

No blood received for germline testing Only clinical geneticists can

• rder germline

testing

IHC on all CRCs and ECs in the Sikl´s Institute (**), while only on consult cases in the private Bioptical Laboratory ↓ In case of LS suspicion the patient´s GP is contacted by phone and asked to refer the patient to clinical geneticist

Reason shown later

* * **

• In CRC resection specimens one extra tissue block submitted for

IHC during gross specimen processing, in endoscopical biopsies the IHC performed as a second step

• In EC the IHC performed as a second step

2013 PBL SI CRC 1006 376 MSI-histology 47 (4.7 %) 40 (10.6 %) LS 3 (0.3 %) 4 (1.06 %) Not Finished (NF) 6 1 LS + NF 9 (0.89 %) 5 (1.32 %) Results 2013-2016 CRC 20 endometrium 2 duodenum 1 LS frequency reaches 1.2 % (or 2.4 % for LS+NF)

Possible explanations of the low percentage

• 1. Statistical effect of “low numbers”
• 2. Regional differences of distribution (environmental factors)
• 3. IHC-related errors

Recommendations

• Centralize the detection of suspicious cases
• Choose a powerful but (relatively) cheap method of detection of suspicious cases (IHC)
• Build a stable team:
• Pathologist
• Molecular geneticist
• Clinical geneticist
• Gastroenterologist
• Gynecologist
• Urologist
• Dermatologist
• Create an encrypted network software to share the data within the team
• Persuade health maintenance organization (health insurance company)
• Persuade politicians
• Be patient!

… or authorize someone else to organize the screening … … and to become frustrated.