12/4/2014

1

COLON CANCER &

GENETICSVERMONT COLORECTAL CANCER

SUMMIT

NOVEMBER 15, 2014

WENDY MCKINNON, MS, CGC

CERTIFIED GENETIC COUNSELOR

FAMILIAL CANCER PROGRAM

UNIVERSITY OF VERMONT MEDICAL CENTER

12/4/2014

2

� Multiple relatives with colorectal cancer on same side of the family (maternal or paternal lineage)

� Early age at diagnosis of colon cancer (<50)

� Multiple primary tumors in same individual

� Multiple colon polyps

� Other benign and/or malignant tumors in the family known to be associated with inherited CRC

CHARACTERISTICS OF HEREDITARY

COLORECTAL CANCER

�Lynch syndrome / HNPCC� Autosomal dominant

� Variants: Turcot, Muir-Torre

� Genes: MLH1, MSH2 (EPCAM), MSH6, PMS2

�Familial adenomatous polyposis (FAP)� Autosomal dominant

� Variants: AFAP, Gardner, Turcot

� Gene: APC

�Multiple adenomatous polyposis (MAP)� Autosomal recessive

� Gene: MUTYH

INHERITED CRC: ADENOMATOUS

12/4/2014

3

� Peutz-Jegher syndrome (PJS)

�Gene: STK11

� Juvenile Polyposis (JP)

�Genes: SMAD4, BMPR1A

�Mutations in SMAD4 also associated with HHT

� Cowden syndrome (CS)

�Variant: Bannayan-Ruvalcaba-Riley (BRR)

�Gene: PTEN

INHERITED CRC: HAMARTOMATOUS

* All are autosomal dominant

�Accounts for at least 3% all colon

cancers

�Characteristics:

�Early age onset

�Proximal tumors

�Pathologic characteristics

�Extra-colonic cancers

� LS accounts for at least 3% all endometrial cancers

� Gastric, small intestine, urinary tract, ovarian, hepatobiliary,

sebaceous skin tumors, and glioblastomas

LYNCH SYNDROME

12/4/2014

4

LIFETIME CANCER RISKS FOR LS

Cancer siteCancer siteCancer siteCancer site MLH1MLH1MLH1MLH1 MSH2MSH2MSH2MSH2 MSH6MSH6MSH6MSH6 PMS2PMS2PMS2PMS2

Any Lynch

cancer

44-79% 38-78% 25-65% 16-53%

ColorectalColorectalColorectalColorectalMenMenMenMen

WomenWomenWomenWomen

58585858----65%65%65%65%

50505050----53%53%53%53%

54545454----63%63%63%63%

39393939----68%68%68%68%

36363636----69%69%69%69%

18181818----30%30%30%30%

20%20%20%20%

15%15%15%15%

Endometrial 57-66% 21% 17-44%

15%

Lynch syndrome Surveillance Options

Lindor et al, 2006; Vasen et al, 2007; Lu 2007

Intervention Recommendation

Colonoscopy Every 1-2 y beginning at age 20-25 (MLH1

& MSH2), or age 30 (MSH6 & PMS2).

Annual after age 40.

Endometrial sampling

Transvaginal US

Upper endoscopy

Annual beginning at age 30-35

Consideration of TAH/BSO

Urinalysis Every 1-2 y beginning at age 25-35

History & Exam w/

review of systems

Annual beginning at age 21

Periodic

12/4/2014

5

�Family history / clinical criteria

�Tumor based testing

�Molecular / DNA based testing

�Multi-gene panels

�Tumor genomics

APPROACHES TO DIAGNOSING LYNCH

SYNDROME

THE FAMILY HISTORY AND

DIAGNOSING LYNCH SYNDROME

CRCdx 50s

CRCdx 45

CRCdx 61

CRCdx 75

OvarianCa, dx

64

CRCdx 48

CRCdx 52

EndometrialCa, dx 59

CRCdx 42

45

12/4/2014

6

�Many families do not meet current clinical criteria for Lynch syndrome

�Amsterdam Criteria I and II

�Bethesda Criteria, original and revised

�Hampel, et al NEJM, 2005

�Screened 1500 CRC; 44 LS mutation carriers

�50% CRC diagnosed after age 50

�25% did not meet AC or BC

CLINICAL CRITERIA

� Genes belong to DNA mismatch repair (MMR)

family

� Mutations in MMR genes lead to microsatellite

instability (repetitive sequences of DNA)

� MMR proteins are missing in the tumor tissue

GENETIC FEATURES OF LYNCH

12/4/2014

7

� Identify MMR proteins normally present

� If protein is absent, gene is not being expressed (mutation or methylation)

� Helps direct gene testing by predicting likely involved gene

IMMUNOHISTOCHEMISTRY

MSH2MLH1

MSH6PMS2

ABNORMAL – MLH1 & PMS2 ABSENT

�15% of the

time

�80% acquired

methylation of

MLH1

�20% will be LS

MLH1 MSH2

MSH6PMS2

12/4/2014

8

ABNORMAL – MSH2 & MSH6 ABSENT

�3% of the time

�Most likely LS due to either MSH2 or MSH6gene mutation

�Refer to Genetics for GC and GT

MLH1 MSH2

PMS2MSH6

ABNORMAL – MSH6 OR PMS2 ABSENT

�2% of the time

�Most likely LS due to an MSH6 or PMS2 gene mutation

�Refer to Genetics for GC and GT

MLH1MSH2

MSH6 PMS2

12/4/2014

9

� Columbus-area HNPCC studies◦ NEJM 2005;352:1851-60; J Clin Oncol 2008;26:5783-88

� EGAPP Recommendations◦ All CRC be screened for LS; Genet Med, 2009,11:35-41

� Cost-effectiveness evaluations◦ Genet Med, 2010, 12:93-104; Ann Int Med, 2011, 155:69-79

� Healthy People 2020; www.healthypeople.gov

� Institutions adopting universal screening◦ 71% NCI Cancer Centers

◦ 28% COC Accredited Cancer Centers

◦ 15% Community Cancer Centers

EVIDENCE FOR UNIVERSAL SCREENING

POTENTIAL IMPACT

�146,970 new cases of CRC in the US

�4,115 have Lynch syndrome (2.8%)

�12,345 of their relatives have LS (~3 per

proband)

�Total of 16,460 individuals who could be

diagnosed with LS by universal screening on

colon cancers

12/4/2014

10

�For cancer patient with LS diagnosis:

� Increased risk of second primary cancer

� 50% after 20 years

�Guidelines differ for cancer patients with/without LS

�For relatives:

� Individualize screening for relatives with/without LS

�Early diagnosis / prevention

IMPLICATIONS OF DIAGNOSIS OF LYNCH

SYNDROME

�2010-11, a targeted approach was used

�Jan 2012, all colon cancers tested for Lynch

syndrome

�colon resections

�biopsies under age 50

�September 2014, switched to testing all

biopsies containing cancer regardless of age

� IHC is screening tool used

UNIVERSAL SCREENING FOR LYNCH

SYNDROME AT FAHC/UVMC

12/4/2014

11

IHC LETTER

�Genetic Counselor notified by pathology of all

results

�For abnormal results, GC asks permission of

ordering physician to contact patient

�Patient contacted and GC appointment

scheduled

�All results entered into database housed in

the EMR

�All patients with normal results sent letter

COMMUNICATION OF RESULTS

12/4/2014

12

PRISM (EPIC) Document Flowsheet

NORMAL IHC RESULT LETTER

12/4/2014

13

Established Guidelines

� MLH1

� MSH2

� MSH6

� EPCAM

� PMS2

� APC

� MUTYH

� SMAD4

� BMPR1A

� TP53

� STK11

Newer genes; no

established guidelines

� CHEK2

� GREM1

� GALNT12

� POLE

� POLD1

GENES ASSOCIATED WITH INCREASED COLON

CANCER RISK

12/4/2014

14

� Family history is key component

� Thanksgiving is National Family History Day

� Access the My Family Health Portrait Web

tool at https://familyhistory.hhs.gov/

FAMILY HISTORY

Contact Information:

Familial Cancer Program

(802) 847-4495

wendy.mckinnon@vtmednet.org

THANK YOU!