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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