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/.

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.

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

Illustration by Jerry Schoendorf, MAMS. Pages 577-587 (February 2006) GE

Maintenance of DNA integrity

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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Oncogenesis - Familial Adenomatous Polyposis SyndromeOncogenesis - Familial Adenomatous Polyposis Syndrome

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Familial Adenomatous Polyposis Syndrome

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 SyndromeFamilial Adenomatous Polyposis Syndrome

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

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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

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

• 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

• 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?

• 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 30-

35; every 6-12 months; TAH-BSO

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

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

Summary

• Complete family history• High index of suspicion• Expert colonoscopy• Hereditary Cancer Institute• nccn.org