Transcript genetics

Hereditary Colon Cancer
ACP, October 2013
Steve Lanspa MD, FACP
Magnitude of the Problem
• Annual worldwide incidence of CRC is 1,023,152*:
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• Lynch syndrome (LS) accounts for  2-5%
(20,460-51,160 cases).
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• < 1% (10,230 cases) constitute FAP.
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•  20% (204,630 cases) are familial (2 or more firstdegree relatives with CRC.
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• 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
JAMA 294:2465-2473, 2005.
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Two Hit Hypothesis
Molecular Changes-Cell Proliferation
Two Hit Hypothesis
Sporadic
Hereditary
Normal
1stst Hit X
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Mutant
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X
nd Hit
2nd
Tumor
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Tumor
Maintenance of DNA integrity
Illustration by Jerry Schoendorf, MAMS.
Pages 577-587 (February 2006) GE
Molecular Classification of CRC
• Step-wise accumulations of multiple mutations
• Chromosomal Instability (CIN) 85%
• Microsatellite Instability (MSI) 5%
• CpG island methylator phenotype (CIMP) 10%
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
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
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
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
Familial Adenomatous Polyposis
FAP
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Familial Adenomatous Polyposis Syndrome
Oncogenesis - Familial Adenomatous Polyposis Syndrome
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Familial Adenomatous Polyposis Syndrome
Oncogenesis
Oncogenesis -- Familial
Familial Adenomatous
Adenomatous Polyposis
Polyposis Syndrome
Syndrome
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Familial Adenomatous Polyposis Syndrome
Oncogenesis - 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
Attenuated FAP
aFAP
Attenuated FAP
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Later onset (CRC ~age 50)
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Few colonic adenomas
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Not associated with CHRPE
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UGI lesions
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Associated with mutations at
extreme 5’, 3' ends of APC
gene, & exon 9A
Multiple Adenomatous Polyposis
• MAP
• Biallelic MUTYH mutation
– Autosomal recessive
• 10 polyps
• CRCS > age 50 years
Lynch Syndrome
(HNPCC)
• H.T. Lynch
– Jane Lynch
– Patrick Lynch
• Creighton University
JAMA 2011
Lynch Syndrome associated tumors
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Colorectal
Endometrial
Ovarian
Genitourinary
Brain
Small bowel
Hepatobiliary
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+
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.
Colon Cancer Surveillance in LS
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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?
Do New Technologies Help?
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Narrow band imaging colonoscopy
Magnifying colonoscopy
Chromoendoscopy
Autoflorescence
CT colography (computer-assisted)
MRI colography
Chemoprevention
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.
DisColRec 2010
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 3035; every 6-12 months; TAH-BSO
Serrated Polyposis Syndrome
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“Hyperplastic polyposis”
? gene, but there is a familial syndrome
Associated with pancreatic cancer
May have rapid adenoma-carcinoma
sequence, similar to LS
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
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Complete family history
High index of suspicion
Expert colonoscopy
Hereditary Cancer Institute
nccn.org