Hereditary Colon Cancer ACP, October 2013 Steve Lanspa MD, FACP.

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Hereditary Colon Cancer ACP, October 2013 Steve Lanspa MD, FACP

Transcript of Hereditary Colon Cancer ACP, October 2013 Steve Lanspa MD, FACP.

Page 1: Hereditary Colon Cancer ACP, October 2013 Steve Lanspa MD, FACP.

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

212212

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