Lynch Syndrome and Colorectal

Cancer

Steven G. Proshan, M.D.Annapolis Colon and Rectal Surgeons

Anne Arundel Medical CenterNovember 8, 2014

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Familial Predisposition to Colorectal and other cancers

Autosomal Dominant Henry Lynch, MD 1966 Hereditary Nonpolyposis Colorectal Cancer

(HNPCC)

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Lynch Syndrome (LS)

Cancers more frequently Cancers at younger age (40’s) Right sided cancers Adenoma to carcinoma sequence more rapid Synchronous and Metachronous Cancers Lifetime Risk 10-74% (vs. 5.5% without) Better Prognosis

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Colorectal Cancer in LS

Genetics of CRCGenetics of CRC

Sporadic Sporadic (65(65%–%–85%)85%)

Familial Familial (10(10%–%–30%)30%)

Lynch syndrome Lynch syndrome (3%)(3%)

Familial adenomatous Familial adenomatous polyposis (FAP) (1%)polyposis (FAP) (1%)

Rare CRC Rare CRC syndromes syndromes

(<0.1%)(<0.1%)

MYH associated MYH associated polyposis (MAP) polyposis (MAP) (1%)(1%)

Cancer Incidence (%) Incidence LS (%)

Endometrium 2.7 14-71

Stomach <1 0.2-13

Ovary 1.6 4-20

Hepatobiliary Tract <1 0.02-4

Urinary Tract <1 0.2-25

Small Bowel <1 0.4-12

Brain/CNS <1 1-4

Sebaceous Neoplasm

<1 1-9

Pancreas 1.5 0.4-4

Prostate 16.2 9-30

Breast 12.4 5-18

Other LS Cancers

A Classic HNPCC/Lynch FamilyA Classic HNPCC/Lynch Family

CRCCRCdx 50sdx 50s

CRCCRCdx 45dx 45

CRCCRCdx 61dx 61

CRCCRCdx 75dx 75

OvarianOvarianCa, dx 64Ca, dx 64

CRCCRCdx 48dx 48

CRCCRCdx 52dx 52

EndometrialEndometrialCa, dx 59Ca, dx 59

CRCCRCdx 42dx 42

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1. Three or more relatives with histologically verified colorectal cancer, 1 of which is a first-degree relative of the other two. Familial adenomatous polyposis should be excluded.2. Two or more generations with colorectal cancer.3. One or more colorectal cancer cases diagnosed before the age of 50 years.

Clinical Diagnosis of LSAmsterdam I Criteria (1991)

1. Three or more relatives with histologically verified HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis), 1 of which is a first-degree relative of the other 2. Familial adenomatous polyposis should be excluded.2. Cancer involving at least 2 generations.3. One or more cancer cases diagnosed before the age of 50 years.

Clinical Diagnosis of LSAmsterdam II Criteria (1999)

1. CRC diagnosed at younger than 50 years.2. Presence of synchronous or metachronous CRC or other LS-associated tumors.*

3. CRC with MSI-high pathologic-associated features (Crohn-like lymphocytic reaction, mucinous/signet cell differentiation, or medullary growth pattern) diagnosed in an individual younger than 60 years old.4. Patient with CRC and CRC or LS-associated tumor* diagnosed in at least 1 first-degree relative younger than 50 years old.5. Patient with CRC and CRC or LS-associated tumor* at any age in 2 first-degree or second-degree relatives.

* LS-associated tumors include tumor of the colorectum, endometrium, stomach, ovary, pancreas, ureter, renal pelvis, biliary tract, brain, small bowel, sebaceous glands, and kerotoacanthomas.

Clinical Diagnosis of LSRevised Bathesda Guidelines

(2004)

Microsatellite Instability (MSI) MSI - High MSI - Low MS - Stable

MSI – High Better Prognosis Most MSI Colorectal Cancers are not LS (12%

of sporadic CRC)

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LS Genetic Alterations

Microsatellite InstabilityMicrosatellite Instability

-CG--CG--CGCGCGCG-CGCGCGCG

-CG--CG--CGCGCGCG-CGCGCGCG

-CG--CG--CGCGCGCG-CGCGCGCG

-CG-CG

-CGCGCGCG--CGCGCGCG-

-CG--CG-

-CGCGCGCGCG--CGCGCGCGCG--CG--CG-

-CGCGCG--CGCGCG-

-CG--CG-

-CGCG--CGCG-

-CG--CG--CGCG--CGCG-

-CGCGCG--CGCGCG--CGCGCGCGCG--CGCGCGCGCG-

Normal CellsNormal Cells

Tumor CellsTumor Cells

Microsatellite Instability

Normal Microsatellites

Proofread Replicated DNA Problem will be most obvious in repetitive

sequences Defect in both copies leads to cancer If already carries one defect, at high risk to

develop a second defect – Lynch Syndrome LS is Autosomal Dominant

Mismatch Repair (MMR) Genes and Proteins

Carrier Parent Non-carrier Parent

Autosomal Dominant Inheritance

Aa aa

Aa Aa aa aa

Carrier Carrier Non-carrier Non-carrier

1/2 1/2

MLH1 MSH2 MSH6 PMS2 EPCAM (Promotor for MSH2)

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Mismatch Repair (MMR) Genes

MLH1

MSH2

MSH6

PMS2

MSI Testing Inexpensive Prognostic and Treatment Information

MMR Protein Testing Inexpensive Directs which gene to look at

Confirm Positive Results with Gene Analysis

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Universal Tumor Testing for LS

Genetic Counseling Gene Testing Appropriate Family Members Familial Colorectal Cancer Type X (FCRCTX)

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Followup

Partial Colectomy Risk of Metachronous Cancer 16-19% at 10

years Total or Subtotal Colectomy with

Ileorectal/Ileosigmoid Anastomosis Risk of Metachronous Cancer 0-3.4% at 10

years Diarrhea

Need to consider age and sphincter function18

Treatment of Colon Cancer in LS Patients

Resection of Rectum with Anastomosis Risk of Metachronous Cancer 69% at 30 years

with colonoscopy every 1.6 years Total Proctocolectomy with Ileal Pouch-Anal

Anastomosis (IPAA) Standard of Care for cancer with UC or FAP LS patients older

Total Proctocolectomy with End Ileostomy

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Treatment of Rectal Cancer in LS Patients

Colonoscopy every 1-3 years leads to fewer CRC and at a later age than unscreened

Colonoscopy every 1-3 years leads to similar CRC mortality compared to those without LS, although more CRC diagnosed

More frequent colonoscopy (≤ 2 years) better

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CRC Screening in LS Patients

Guideline: Screening for CRC by colonoscopy is recommended in persons at risk (first-degree relatives of those affected) or affected with LS every 1 to 2 years, beginning between ages 20−25 years or 2−5 years before the youngest age of diagnosis of CRC in the family if diagnosed before age 25 years.

May need to adjust based on exact family history and which gene is mutated.

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CRC Screening in LS Patients

Second most common cancer 75% Stage I and 88% 5 year survival Hard to prove screening helps Annual Pelvic Exam and Endometrial

Sampling Offered Starting at Age 30-35

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Endometrial Cancer in LS

No data as to screening Transvaginal Ultrasound and CA-125

Screening does not seem to help with BRCA1 and BRCA2 patients

Annual Transvaginal Ultrasound Offered Starting at Age 30-35

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Ovarian Cancer in LS

Retrospective analysis of 315 women with MMR mutations 33% Uterine cancer without surgery No uterine cancer with surgery 5.5% Ovarian cancer without surgery No ovarian cancer with surgery

Guideline: Hysterectomy and Oophorectomy after childbearing or at age 40

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Prophylactic Hysterectomy and Oophorectomy in LS

Lifetime Risk 0.2-13% EGD every 2-3 years beginning age 30-35 Treat H.pylori if found Modify based on family history and gene

mutation

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Gastric Cancer in LS

Not much data screening (urinalysis, urine cytology) helps

Inexpensive Noninvasive Easy Consider annually starting age 30-35

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Urinary Cancers in LS

No screening or no increased screening beyond that for usual population Pancreatic Small Intestine Prostate Breast

Either no clear increased risk or no good screening test

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Other Cancers in LS

Questions?

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