Week 5: Lynch Syndrome

Lynch Syndrome

AKA Hereditary Non-polyposis Colorectal Cancer (HNPCC)

MLH1, MSH2/EPCAM, MSH6, PMS2

AD

Constitutional Mismatch Repair Deficiency

What percent of people with CRC have lynch syndrome?

2-4%

__in__ americans are Lynch +

1 in 279

95% dont know it

__in__ endometrial cancers is attributable to lynch

1 in 50

What is the function of the lynch associated gnes?

Mismatch repair genes

What are the most common genes that P/LP variants most often found in:

MSH2 and MLH1

What is the NCCN Lynch criteria

with Personal hx of a LS related cancer:

dx <50

A synchronous or metachronous LS regardless of age

1 FDR or SDR with LS <50y

>2 FDR or SDR with a LS related cancer, relgardless of age

without phx:

>1 FDR with CRC or dx <50

> 2 FDR or SDR with LS related cancer including >1 dx <50y

Amsterdam criteria

3 affected relatives w CRC

1 FDR and the other 2

CRC in at least 2 generations

1 member diagnosed with CRC ,50y

AND

polyposis excluded

Does everyone who has lynch meet amsterdam and bethesda guidelines?

no ~68%

Gene with the highest ovarian risk?

MSH2 and EPCAM (8-38%)

what are some risk reducing agents that can reduce endometrial risk?

oral contraceptive pills and progestin IUD

Colonoscopy for MLH1 and MSH2

20-25y repeat every 1-2 years

Colonoscopy for MSH6 and PMS2

30-35y repeat 1-3 years

What is recommended for ppl w lynch to reduce CRC ?

daily aspirin to reduce future risk of CRC

Lynch surveillance for Gi risks?

upper Gi surveillance w high-quality EGD starting at age 30-40y and repeat 2-4 years + colonoscopy

Urothelial risk and management for lynch?

no clear evidence to support surveillance for urothelial cancers in LS

-consider urinalysis starting at 30-35y

Prostate risk managment?

reasonable to consider screening at 40y at annual intervals

Skin manifestations risk manifestations

skin test 1-2 years

Lynch syndrome tumor testing

MLH1 methylation

BRAF V600E

Microsatellite instability

immunohistochemical testing

NCCn recommends screening for MMR deficiency for which cancers?

CRC and endometrial tumors + stomach , pancreas, billary tract, brain, bladder

about ___ of CRC and EC will screen positive for deficient MMR but only ___ will be lynch syndrome

10-20% but only 1 in 5

Microsatellite

repeated sequences of DNA of the same lengths

microsatellite instability

inconsistent length in these repeated DNA fragments

MSi for majority of tumors

normal or stable

MSi for lynch syndrome

MSI is high bc MMR mechanism not fixing replication errors

10-15% of ___ cancers exhibit abnormal IHC and MSI-H

Sporadic colon cancers

IHC

method of staining where antibodies bind to MMR genes

Abnormal IHC occurs when one of the proteins is not detected in the tumor tissue

IHC for ppl with Lynch

likely to demonstrate loss of MMR protein expression

pattern of loss can provide informatio about genes not functioning properly

---

__ of LS tumors are MSI-H and/ or lack expression of MMR proteins by IHC

90%

MLH1 hypermethylation

Hypermethylation of the MLH1 promoter region silences gene transcription and produces and MSI tumor phenotypes

-epigenetic

BRAF testing

tests for V-600E mutation in the BRAF gene

leads to continous activation of BRAF

positive MLH1 methylation and BRAF testing

Most likely sporadic

Which 2 forms heterodimers?

MLH1 and PMS2 and MSH2 and MSH6

WHat will have if MLH1 stops working?

automatic loss of PMS2

What happens if PMS2 stops working

MLH1 not impacted

What happens if MHS2 stops working?

Loss of MSH6

WHat happens if MSH6 stops working?

MSH2 not impacted

Absent MLH1 and PMS2

further testingneeded

BRAF and MLH1

What happens if MSH2 and MSH6 absent?

MSH2 lynch

Absent PMS2

Likely lynch - PMS2 or MLH1

Absent MSH6

lynch MSH6

Absent MSH2

likely lynch MSH2

Clinical variants

Muir-torre Syndrome and Turcot syndrome

Muir-torre

1 sebaceous tumor in addition t one visceral malignancy