Hereditary Gastrointestinal Cancers John Quillin 07 Nov 2017
Objectives Recognize features that warrant referral Focus on Lynch Syndrome Interpret tumor screening results Surgical and chemotherapy implications of Lynch Syndrome
How Much is Genetic? Mucci et al. JAMA 2016;315(1):68-76
How Much is Genetic? Jasperson et al., Gastroenterol 2010;183:2044-2058
CRC 20s CRC 12 YO seer.cancer.gov MLH1 del exon 12
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
Autosomal Dominant Inheritance
MUTYH c.1145G>A / c.1172C>T 52 YO ~70 polyps MUTYH c.1145G>A / c.1172C>T
Autosomal Recessive Inheritance
Key Characteristics of Hereditary Cancer Early-onset Multiple Primary Cancers Mendelian Inheritance Autosomal dominant (most common) Autosomal recessive
When to Refer Hampel et al. Genet Med 2015;17(1):70-87
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)
Microsatellite Instability and Immunohistochemistry
Panc or Liver Ca 89 CRC 43 YO MLH-1 MSH-2 MSH-6 PMS-2 CRC 65 YO
Surgical Management NCCN “Genetic/Familial High-Risk Assessment: Colorectal v3.2017
Chemotherapy NCCN “Genetic/Familial High-Risk Assessment: Colorectal v3.2017
For the Future and the Family Screening Primary Prevention Chemoprevention Aspirin Risk-reducing surgery Lifestyle Targeted/Informative Testing
CRC 50s CRC 68 YO MLH1 MSH2 MSH6 PMS2 (diagnostic biopsy)
Meanwhile… MLH1 MSH2 MSH6 PMS2 (resection)
MLH1 Promoter Hypermethylation Somatic BRAF Mutation (usually p.V600E) MLH1 Promoter Hypermethylation Absent MLH1/PMS2
Medical Management Surgery – treat as usual Chemotherapy – potential immunotherapy candidate Family No genetic testing Colonoscopy at 40 YO, q 5 to 10 years
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