Recognition and diagnosis of Lynch syndrome and ESMO guidelines hereditary GI cancer

Prof. Nicoline Hoogerbrugge, MD, PhD

ESMO 2019

Disclosure conflicts of interest speaker

(potential) conflicts of interest No

Relationships with companies AstraZeneca

Research funding MLDS; Dutch cancer society; KIKA; Horizon2020

Hereditary Colorectal Cancer Syndromes

Hereditary CRC:

(Known Genetic Cause)

Lynch Syndrome (=HNPCC)

Various forms of Polyposis:

(e.g.. FAP, MAP, Peutz-Jeghers )

Genetic causes e.g.:

APC, MUTYH

POLE, POLD1, NTHL1

PTEN

SMAD4, BMPR1A

STK11

Familial CRC

Positive Family history

No genetic cause known

Sporadic CRC

Unknown cause

Lynch

Modified from: Lynch & Shaw, Chin Clin Oncol, 2013

Lynch syndrome (HNPCC)

• Caused by a germline mutation in a mismatch repair gene: in particular MLH1, MSH2, MSH6, EPCAM and PMS2.

• Mutation carriers have increased risk for cancer:

Colorectal cancer Life time risk 60-70%Endometrial cancer Life time risk 30-70%

Lynch syndrome associated malignancies < 10% Life time risk:Gastric, hepatobiliary, ovarian, small bowel, ureter or renal pelvis cancer.

Lynch syndrome (HNPCC)

Accounts for up to 5% of all CRC.

Clinical characteristics of Lynch syndrome:

1.Young age at cancer diagnosis (mean 40-45 years)

2.Multiple primary cancers

(23% has a double tumor, Lifetime risk second carcinoma 90%)

3.Positive family history (autosomal dominant inheritance).

4.Mismatch-repair deficiency (dMMR)

5.Very fast progression time from adenoma to cancer!

Important surveillance differences

Lynch syndrome: Rapid progression form adenoma to carcinoma!

Surveillance advice

Lynch syndrome Colonoscopy every 1-2 yr. starting at age 25

(endometrial ca. surveillance annually starting at age 35-40)

Familial CRC Colonoscopy every 5 yr. starting at age 50

Sporadic CRC Population screening or none

ESMO GUIDELINES ANNALS OF ONCOLOGY 2013

cancergenetics.eu

•Information on hereditary CRC•Referral test•Three 2 minutes Video’s for patients preparing their visits for genetic testing

Characteristics of high risk of Lynch syndrome

• Several close relatives with CRC below age 70

• CRC at remarkable young age below age 40

• Two or more primary CRC’s (or Lynch associated cancer) in a single

individual.

• Specific features of the CRC: signs of mismatch repair deficiency:

• MSI: microsatellite instability

• IHC: immuno histochemistry absence of staining MMR proteins.

Microsatellite instability (MSI)

positive negative

Immunohistochemistry MMR protein

Detection of Lynch syndrome needsimprovement

▪ Only 35% of all patients suspected of Lynch syndrome are identified by

their medical specialist because of their family history.

▪ Identification of Lynch syndrome is important because of

▪ Personalized adaptation of CRC treatment (surgery and chemotherapy)

▪ Surveillance of other organs e.g. endometrial cancer.

▪ Life saving benefits of surveillance programs for yet unaffected

relatives.

Recognition of Lynch syndrome

In real life only 30% of the CRC patientsat high risk of Lynch syndrome based on age and family history

is referred for genetic testing *.

They

* Published by our group in Colorectal Dis. 2015 ;17:499-510

Recognition of Lynch syndrome

In real life only 30% of the CRC patientsat high risk of Lynch syndrome based on age and family history

is referred for genetic testing *.

Will this be improved byreflex MSI/IHC (dMMR) testing in all CRC < 70 yr ?

They

* Published by our group in Colorectal Dis. 2015 ;17:499-510

Results reflex dMMR-testing in 19 hospitals

new CRC patients< 70 year:n = 3602

CRC < 40 yr:n = 55

CRC 40 - 70 yr: n = 3547

dMMR-test performedn = 3025 (84%)

Quarterly feedback on inclusion to PATHOLOGY labs increased testing from 71 to 90%

UPTAKE

Age below 50 orPositive Family History

Clinical Geneticist

CRC dMMR analysis

Germline mutation analysis

CRC diagnosedat age < 70 yr

Clinical Geneticist

Pathologist

+ 30%*

84%

69%

* Same Hospitals investigated published by our group in Colorectal Dis. 2015 ;17:499-510

58% = (84% x 69%)

UPTAKE

Age below 40 orPositive Family History

Clinical Geneticist

CRC dMMR analysis

Germline mutation analysis

CRC diagnosedat age < 70 yr

Clinical Geneticist

Pathologist

+ 30%*

84%

69%

* Same Hospitals investigated published by our group in Colorectal Dis. 2015 ;17:499-510

58% = (84% x 69%)

Underlying cause of MSI-high tumors(n=230; mean age at diagnosis 48 yrs)

Mensenkamp et al Gastroenterology 2014

YIELD dMMR in CRC<70: 1% Lynch syndrome

Genetic counseling and diagnostics:

Bi-allelic somaticmutations

n = 20

Lynch syndromen = 26

8 MLH16 MSH2/EPCAM

4 MSH67 PMS2

Somatic mutations MMR mutations causing CRC: Gastroenterology. 2014;146:643-646

Unexplained MMRD (Lynch-like)

n = 1

Conclusion:

• CRC < 40 yrs: > 18% Lynch/CMMRD

• CRC 40 - 70 yrs: 1 - 2% Lynch

• Pathologists are very effective in tracing dMMR-tumours

• Referral for genetic testing still needs extra attention.

• Reflex dMMR testing increases detection of Lynch syndrome families