Hereditary Colon Cancer ACP, October 2013 Steve Lanspa MD, FACP.
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Transcript of Hereditary Colon Cancer ACP, October 2013 Steve Lanspa MD, FACP.
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Hereditary Colon Cancer
ACP, October 2013Steve Lanspa MD, FACP
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Magnitude of the Problem• Annual worldwide incidence of CRC is 1,023,152*:
• • Lynch syndrome (LS) accounts for 2-5% • (20,460-51,160 cases).
• • < 1% (10,230 cases) constitute FAP.
• • 20% (204,630 cases) are familial (2 or more first-• degree relatives with CRC.
• • Each family is a cancer prevention target!
• *International Agency for Research on Cancer. Globocan 2002. Available at: http://www-dep.iarc.fr/.
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Magnitude
All CRC worldwide – Approx 1 million per year
LS associated CRC – 21,000 – 50,000 per year
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JAMA 294:2465-2473, 2005.
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Two Hit Hypothesis
Two Hit Hypothesis
HereditaryHereditary SporadicSporadic
1st Hit1st Hit
NormalNormal
MutantMutant
TumorTumor
2nd Hit2nd Hit
TumorTumor
XX XX XX XX XX
XX
XX
XX
XX
Molecular Changes-Cell ProliferationMolecular Changes-Cell Proliferation
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Illustration by Jerry Schoendorf, MAMS. Pages 577-587 (February 2006) GE
Maintenance of DNA integrity
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Molecular Classification of CRC
• Step-wise accumulations of multiple mutations
• Chromosomal Instability (CIN) 85%• Microsatellite Instability (MSI) 5%
• CpG island methylator phenotype (CIMP) 10%
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Chromosomal Instability Pathway (CIN)
• Chromosomal gains and losses (aneuploidy; copy number change)
• Allele losses (LOH)• Is the molecular basis of progression in CRC in
Familial Adenomatous Polyposis
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Microsatellite Instability Pathway (MSI)
• Mononucleotide mutations of tumor suppressor genes
• Arises from defective DNA mismatch repair• Is the molecular basis of progression in CRC in Lynch
Syndrome
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Microsatellite Instability (MSI)• Microsatellites (short nucleotide repeats) are prone
to replication errors, but corrected by MMR genes in normal cells
• In tumor DNA, there are altered lengths (instability) of microsatellites
• MSI is a phenotype that can be used as a surrogate for MMR mutation/inactivation (now also IHC for absence of protein expression)
• Inactivation of one copy of MMR = 1st hit• Subsequent somatic lesion (2nd hit) leads to
mutation rates 1000 times normal
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CpG Island Methylation (CIMP)• Short stretch of DNA with high CG sequences
(phosphodiester bond)• Located at gene promoter • Methylation leads to inactivation of many tumor
suppressor genes• ~200 CpG islands that are methylated have been
identified in tumor DNA• Epigenetic, biallelic silencing of MLH1• Tumors highly correlated with a mutation of the
BRAF-kinase encoding gene (Chr 7)• May be the molecular basis of progression of CRC in
the serrated pathway
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Familial Adenomatous Polyposis
FAP
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Oncogenesis - Familial Adenomatous Polyposis SyndromeOncogenesis - Familial Adenomatous Polyposis Syndrome
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Familial Adenomatous Polyposis Syndrome
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Oncogenesis - Familial Adenomatous Polyposis SyndromeOncogenesis - Familial Adenomatous Polyposis Syndrome
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Familial Adenomatous Polyposis Syndrome
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Oncogenesis - Familial Adenomatous Polyposis SyndromeOncogenesis - Familial Adenomatous Polyposis Syndrome
Familial Adenomatous Polyposis Syndrome
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FAP
• Germline mutation of APC– Autosomal dominant
• Polyps in teens, cancers in 20’s– >100 polyps
• Gene testing, colectomy• Surveillance of UGIT• nccn.org
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Attenuated FAP
aFAP
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Attenuated FAP
Later onset (CRC ~age 50) Few colonic adenomas Not associated with CHRPE UGI lesions Associated with mutations at
extreme 5’, 3' ends of APC gene, & exon 9A
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Multiple Adenomatous Polyposis
• MAP• Biallelic MUTYH mutation
– Autosomal recessive• 10 polyps• CRCS > age 50 years
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Lynch Syndrome(HNPCC)
• H.T. Lynch– Jane Lynch– Patrick Lynch
• Creighton University
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JAMA 2011
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Lynch Syndrome associated tumors
• Colorectal• Endometrial• Ovarian• Genitourinary• Brain• Small bowel• Hepatobiliary
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Diagnosing Lynch Syndrome
• Amsterdam criteria– 3 relatives with cancer– 2 generations involved– 1 patient under age 50 Yeats
• Bethesda criteria– Test familial and synchronous tumors for MSI– MSI+ tumor in a patient under age 60 years
• Test all tumors for MSI+
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Unique Pathology• Carcinoma of Colon
– mucinous carcinomas– signet cell carcinomas– diploid tumors (on flow cytometry)– TILs (tumor infiltrating lymphocytes)
• Adenoma– Found in 20% of colons with CRC– Jass and Stewart (Gut 33:783-786, 1992): adenomas in
LS were larger, more often villous, and had more high grade dysplasia
– Consistent with our hypothesis that adenomas in LS have a greater proclivity for malignant degeneration than sporadic adenomas.
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Colon Cancer Surveillance in LS
• Adenoma removal is important• Surveillance must be at an earlier age and • more frequent than that for the general population• Colonoscopy to the cecum is important• Lesions under 1 cm are important
• Would prophylactic subtotal colectomy be better?
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Do New Technologies Help?
• Narrow band imaging colonoscopy• Magnifying colonoscopy• Chromoendoscopy• Autoflorescence• CT colography (computer-assisted)• MRI colography• Chemoprevention
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Metachronous CRC in LS
• Overall incidence 22-41%• Parry al. Metachronous colorectal cancer risk for mismatch repair
gene mutation carriers: the advantage of more extensive colon surgery. Gut. 2011;60:950–957.
• Cumulative incidence after varying type of resection – Segmental colectomy: 16%– Subtotal colectomy: 2 %
• de Vos tot Nederveen Cappel et al. Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis Colon Rectum. 2002;45:1588–1594.
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DisColRec 2010
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National Comprehensive Cancer Network (http://nccn.org)
• Colonoscopy at age 20-25 or 10 years younger than youngest age of cancer Dx
• Repeat every 1-2 years
• Annual urinalysis with cytology• Endometrial and ovarian cancer screening age 30-
35; every 6-12 months; TAH-BSO
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Serrated Polyposis Syndrome
• “Hyperplastic polyposis”• ? gene, but there is a familial syndrome• Associated with pancreatic cancer• May have rapid adenoma-carcinoma
sequence, similar to LS
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Peutz-Jeghers Syndrome
PJS
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Peutz-Jeghers Syndrome
• Inactivating mutations of tumor suppressor STK gene on chromosome 19p13
• Hyperpigmented macules on buccal mucosa and lips, gastrointestinal (respiratory tract, genitourinary tract) hamartomatous polyps
• Increased risk of Gastrointestinal, breast, thyroid lung, pancreatic, uterine cancer, Ovarian sex cord tumors Sertoli cell testicular tumors
• Lifelong endoscopic, radiologic (SBS), ultrasound incl. testicular surveillance– ? Role of capsule endoscopy surveillance
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Summary
• Complete family history• High index of suspicion• Expert colonoscopy• Hereditary Cancer Institute• nccn.org