1. Hereditary Gastrointestinal Cancers
John Quillin
07 Nov 2017

2. Objectives Recognize features that warrant referral
Focus on Lynch Syndrome
Interpret tumor screening results
Surgical and chemotherapy implications of Lynch Syndrome

3. How Much is Genetic?
Mucci et al. JAMA 2016;315(1):68-76

4. How Much is Genetic?
Jasperson et al., Gastroenterol 2010;183:

5. CRC 20s
CRC 12 YO
seer.cancer.gov
MLH1 del exon 12

6. MSH2 c.1783_1875del Stomach 30s Breast 40 YO RCC 40s CRC 34 YO
Endo 47 YO
Trans cell bladder 57
Renal pelvis 59
Breast 62
Sebaceous 61 YO
Ovarian 57
Leuk 40s
MSH2 c.1783_1875del

7. Autosomal Dominant Inheritance

8. MUTYH c.1145G>A / c.1172C>T
52 YO
~70 polyps
MUTYH c.1145G>A / c.1172C>T

9. Autosomal Recessive Inheritance

10. Key Characteristics of Hereditary Cancer
Early-onset
Multiple Primary Cancers
Mendelian Inheritance
Autosomal dominant (most common)
Autosomal recessive

11. When to Refer
Hampel et al. Genet Med 2015;17(1):70-87

12. Healthy People 2020 Genet Med 2009;11(1):35-41 Objective G-1:
Increase the proportion of persons with newly diagnosed colorectal cancer who receive genetic testing to identify Lynch syndrome (or familial colorectal cancer syndromes)

13. Microsatellite Instability and Immunohistochemistry

15. Panc or Liver Ca 89
CRC 43 YO
MLH-1
MSH-2
MSH-6
PMS-2
CRC 65 YO

18. Surgical Management
NCCN “Genetic/Familial High-Risk Assessment: Colorectal v3.2017

19. Chemotherapy
NCCN “Genetic/Familial High-Risk Assessment: Colorectal v3.2017

20. For the Future and the Family
Screening
Primary Prevention
Chemoprevention
Aspirin
Risk-reducing surgery
Lifestyle
Targeted/Informative Testing

21. CRC 50s
CRC 68 YO
MLH1
MSH2
MSH6
PMS2
(diagnostic biopsy)

23. Meanwhile…
MLH1
MSH2
MSH6
PMS2
(resection)

25. MLH1 Promoter Hypermethylation
Somatic BRAF Mutation
(usually p.V600E)
MLH1 Promoter Hypermethylation
Absent MLH1/PMS2

27. Medical Management Surgery – treat as usual
Chemotherapy – potential immunotherapy candidate
Family
No genetic testing
Colonoscopy at 40 YO, q 5 to 10 years

28. Summary Small – but significant! – proportion of CRC is hereditary
Universal screening is standard of care
IHC/MSI
Patient/family history
Assessment affects:
patient treatment
screening/prevention for patient and family