Assessment for hereditary colorectal cancer

Kalyani Maganti, M.D

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Chromosomes, DNA, and Genes

CellNucleus

Chromosomes

Gene

Protein

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Disease-Associated MutationsA “mutation” is a change in the normal

coding sequence of a gene

that alters the function of the corresponding protein

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Disease-Associated Mutations Alter Protein Function

Functional protein Nonfunctional or missing protein

“All cancer arises from gene mutations”

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Genes Associated With Cancer Predisposition

Tumor suppressor genes• Control rates of cell division and growth • Cancer arises when both gene copies are mutated

DNA damage-repair genes• Repair errors in DNA replication• Cancer arises when both genes fail, leading to the accumulation of

mutations in other critical genes

Oncogenes• Accelerate cell division• Cancer arises when stuck in “on” mode

Gene mutations – inherited or acquired?

• All cancer is caused by gene mutations• Usually these mutations were not inherited, but

were acquired over time in individual cells• In ~10% of cancers the mutation is inherited –

the person has a “hereditary predisposition” to cancer

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Two normal genes (prevent cancer)

1st mutation (may be inherited (susceptible carrier), or acquired

2nd mutation or loss of gene function (leads to cancer)

Gene mutations – inherited or acquired?

Hereditary cancer “syndromes”

• A mutation in a single gene increases cancer risk in multiple organs or parts of the body

• Increased risk is inherited, not cancer – so the individual may develop cancer in a single, multiple, or no parts of the body

Sporadic or Hereditary?~75% of colon cancer is “sporadic”

~15-20% of colon cancer is “familial”

~5-8% of colon cancer is due to a single gene

causing a “hereditary predisposition”

Characteristics of Hereditary CancersCancer diagnosed at an early age (before age 50)Close family members with same kind of cancer (or genetically related cancers, such as breast and

ovarian)

Bilateral cancer, or multiple primary cancers

Unusual cancers (male breast cancer)

Two kinds of cancer in the same person

(syndrome)

Hereditary Cancer SyndromesSyndrome

Hereditary breast and ovarian

cancer

Lynch syndrome

Familial adenomatous polyposis

Cowden syndrome

Von Hippel-Lindau syndrome

Li-Fraumeni syndrome

Multiple Endocrine Neoplasia (1 or

2)

Associated cancers

Breast and Ovarian (etc.)

Colon, Endometrial, ovarian, (etc.)

Colon, duodenum (etc.)

Breast, thyroid, endometrial (etc.)

Renal cell, hemangioblastomas,

(etc.)

Sarcoma, breast, brain, adrenal,

(etc.)

Thyroid, parathyroid, other endocrine

30 yrs34 yrs

Key:

CRC Breast CA

Cervical CA

BrCa 85 yrsd.87

Colon Ca54 yrs

Cerv.Ca 30 yr

55 58

Cerv.Ca 32 yr

60

d. 58MI

84

56

CRC 79d.82

Clues from the family history

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1st, 2nd-, and 3rd-Degree Relatives22 22

1 1 2

1

2

1

13

Child

BrotherSister

Father Mother Uncle

First cousin

Maternal grandmother

Maternal grandfather

Paternal grandmother

Paternal grandfather

Aunt

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Dominant Inheritance

Each child has 50% chance of inheriting the mutation

No “skipped generations”

Equally transmitted by men and women

Affected

Normal

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Recessive Inheritance

Two germ-line mutations (one from each parent) necessary to develop disease

Equally transmitted by men and women

Noncarrier individual

Non-affected carrier

Affected individual

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Genes aren’t the whole picture

“Penetrance” is often incomplete May appear to “skip” generations Individuals inherit altered cancer susceptibility gene,

not cancer

Normal

Carrier, affected with cancer

Susceptible Carrier

Sporadic cancer

30 yrs34 yrs

Key:

CRC Breast CA

Cervical CA

BrCa 85 yrsd.87

Colon Ca54 yrs

Cerv.Ca 30 yr

55 58

Cerv.Ca 32 yr

60

d. 58MI

84

56

CRC 79d.82

“Familial” risk for colon cancer

Typical “hereditary” colon cancer family

CRCdx 50s

CRC dx 45Gastric ca dx 52

CRCdx 61 + 63

CRCdx 75

OvarianCa, dx 64

CRCdx 48

CRCdx 50

EndometrialCa, dx 59

CRCdx 42 + 55

45

“Familial” versus “single gene inheritance” of risk

Key:

Endometrial CA

Colorectal CA

Adenomatous polyps

Dx 38

Dx 50

88 yr

63 yr

4 polyps50 yrs.

CRC Dx 48

61 yr

38 yr

10 yr 8 yr

35 yr

HNPCC:Colon cancer as part of a “syndrome”

HNPCC or “Hereditary Non-polyposis Colorectal Cancer syndrome”

• 3-5% of all colorectal cancer cases

• A cancer “syndrome” caused by a single gene

mutation

• Cancers outside the colon: endometrium

(uterus), ovary, stomach, urinary tract, small

bowel, bile ducts, sebaceous glands

HNPCC:Clinical Diagnostic Criteria

• 3 or more relatives with an HNPCC-related cancer, one of whom is a 1st degree relative of the other two

• 2 or more generations affected• 1 or more cancers diagnosed before age 50• Other syndromes excluded

( Failure to meet these criteria does not exclude HNPCC )

Cancer Risks in HNPCC

Aarnio M et al. Int J Cancer 64:430, 1995

% with

cancer

100

80

60

40

20

020 40 60 800

Age (years)

Colorectal 78%

Endometrial 40-60%

Stomach 13-19%Biliary tract 18%

Urinary tract 10%Ovarian 9%

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The Family History Is Key to Diagnosing HNPCC

CRCdx 50s

CRCdx 45Gastric ca dx 52

CRCdx 61+63

CRCdx 75

OvarianCa, dx 64

CRCdx 48

CRCdx 50

EndometrialCa, dx 59

CRCdx 42+ 55

45

NCCN Surveillance and Prevention Guidelinesfor Lynch syndrome

Colonoscopy at age 20-25, or 2-5 yrs prior to the earliest diagnosis; repeat every year

Prophylactic hysterectomy and bilateral salpingo-oophorectomy is a risk reducing option for women who have completed childbearing

Transvaginal U/S for ovarian and endometrial cancer may be considered at the clinicians’ discretion, but data do not support its efficacy

Consider upper endoscopy for gastric and small bowel cancers, beginning at age 30-35

Consider annual urinalysis for urothelial cancer

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The value of surveillance in HNPCCPercentage of individuals with an altered disease gene who develop the disease

0 20 40 60 800

20

40

60

80

100

HNPCC mutation carriers

General population

Affected with colorectal cancer (%)

Screening for HNPCC

Screening for HNPCC on basis of family history misses ~40% of cases

Screening with combined family history and tumor testing detects ~100% of cases

This combined approach to screening for HNPCC is recommended by current NCCN guidelines

Genetic Features of Lynch syndromeallow us to screen tumors – at the time of surgery(or years later)

Four genes: can cause Lynch syndrome:

(MLH1, MSH2, MSH6, PMS2) = “mismatch repair genes”

Mutation in gene absence of corresponding protein in tumor tissue detected by IHC stains

Mutation in gene microsatellite instability in tumor DNA (caused by the loss of functional mismatch repair protein)

These measurable differences in the tumor itself can be used to screen for Lynch syndrome and justify proceeding to genetic testing (of a blood sample)

Clues from the tumor – does this patient have a genetic mutation?

Microsatellite instability (MSI) testingif MSI- unstable high probability of a

MMR mutation proceed to genetic testing

Immuno-histochemistry (IHC) for MMR proteins – are all four MMR proteins present?If no proceed to genetic testing

Importance of the Pathology Report Colorectal cancer – polyp type and number

indicates which syndrome to test for:

Multiple adenomas test APC gene – for FAP syndromeFew or no adenomas, proximal location of tumor

test for HNPCC syndrome (several genes)Hamartomas

with freckling around mouth test STK11 gene for Peutz-Jeghers

syndrome

with fam.hx. breast, thyroid, uterine cancer test PTEN gene

for Cowden syndrome

HNPCC1

PROTOCOL PRE-SURGERY 7/08

Pre-Admit Nurse__YES___NO Patient < 50 years old___YES___NO Parent, sibling or child has a CANCER history of: colorectal, uterine,

ovarian, stomach, bile duct, urinary tract, small bowel, pancreatic, brain or sweat gland cancer

___YES___NO Patient’s has a previous CANCER history of: colorectal, uterine, ovarian, stomach, bile duct, urinary tract, small bowel, pancreatic, brain or sweat gland cancer

No to all

Pre-op/Pre-Admit Nurse1) Stamp pre-op form with HNPCC ALERT: Send Specimen for IHC2) Notify OR scheduler – note on schedule made3) Patient given information sheet on IHC2 and MSI3 testing

Circulating Nurse 1) Obtain verbal order from Surgeon2) Request for IHC testing filled out on pathology slip3) Place specimen in formalin – follow specimen handling protocol

Yes to Any Questions = Follow the Protocol

All Colorectal and Uterine Cancer Patients

Specimen to Pathology 1 – HNPCC=Hereditary Non-Polyposis Colorectal Cancer syndrome also called Lynch Syndrome2 - IHC = immunohistochemistry3 – MSI = microsatellite instability

For All Colorectal or Uterine Cancer Surgical Patients

PRE-ADMIT NURSE:

___YES___NO Patient < 50 years old

___YES___NO Parent, sibling or child has a CANCER history of: colorectal, uterine, ovarian, stomach, bile duct, urinary tract, small bowel, pancreatic, brain or sweat gland cancer

___YES___NO Patient has a previous CANCER history of: colorectal, uterine, ovarian, stomach, bile duct, urinary tract, small bowel, pancreatic, brain or sweat gland cancer

PRE-OP/ PRE-ADMIT NURSE:

___ Pre-Op form stamped with

___OR Scheduler notified – note on schedule made

___ Patient given education sheet on IHC (immunohistochemistry) and MSI (microsatellite instability) testing

OR CIRCULATING NURSE: ____ Obtain verbal order from Surgeon for IHC and MSI testing

____ Request for IHC and MSI testing filled out on Pathology Slip

____ Place specimen in formalin - follow specimen handling protocol

RN Signature_______________________________________________Initials___________Date___________Time_______

RN Signature_______________________________________________Initials___________Date___________Time_______

RN Signature_______________________________________________Initials___________Date___________Time_______

At Completion RETURN THIS FORM to: Walnut Creek OR - Keep in Surgical Pack Concord OR - Return to Clinical Coordinator Mailbox FAX to 941-2004 *Hereditary Non-Polyposis Colorectal Cancer

HNPCC PROTOCOL CHECKLIST (06/09)

SURGICAL SERVICES

YES TO ANY OF THESE QUESTIONS = FOLLOW HNPCC* PROTOCOL BELOW

HNPCC ALERT

Clinical Features of FAP (Familial adenomatosis polyposis)

• Early onset of colon polyps in teens or childhood • Untreated polyposis leads to 100% risk of colon cancer

FAP is associated with: Malignant tumors:periampullary carcinomagastric carcinomathyroid tumorsbrain tumors (medulloblastoma)

Non-malignant features:CHRPEsosteomas of the jaw(>90%)duodenal polyps (70%)epidermoid cysts (67%)desmoid tumors

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MYH-associated Polyposis (MAP)

Multiple polyps (15-100) Recessive inheritance Two mutations (one from each parent) necessary to develop disease

Noncarrier individual

Non-affected carrier

Affected individual

MYH gene - normally functions to repair mistakes in DNA (mistakes can lead to cancer)

1-2% of the population carries a single MYH mutation –> ~ 10,000 have two MYH mutations, and develop MYH-associated polyposis)

Multiple colorectal adenomas (~15-100 polyps) – with onset in 30-50’s

Progression of polyps to colon cancerusually by age 50

MYH-associated polyposismay be suspected if:

Individual has multiple colon polyps (and possibly colon cancer), and no family history of polyposis or colon cancer

Individual has multiple colon polyps (and possible colon cancer, and the only affected family members are siblings

Genetic Counseling for hereditary cancersGenetic counseling is an interactive process that allows

people to:

Address their concerns about hereditary risk for cancer

Learn basic genetic principles

Look at their personal and family history in the context of

these genetic principles

Learn if their perception of risk is realistic or not

Learn about the process and the implications of genetic

testing

Find out what kinds of pro-active steps they could take to

lower their cancer risks if they do carry a genetic mutation

Who should consider genetic counseling?(characteristics of hereditary cancers)

Cancer diagnosed at an early age (before age 50)Close family members with same kind of cancer (or genetically related cancers, such as breast and

ovarian) Bilateral cancer, or multiple primary cancersAshkenazi Jewish ancestry and breast or ovary ca.Unusual cancers (male breast cancer) in the

familyTwo kinds of cancer in the same person

(syndrome)

30 yrs34 yrs

Key:

CRC Breast CA

Cervical CA

BrCa 85 yrsd.87

Colon Ca54 yrs

Cerv.Ca 30 yr

55 58

Cerv.Ca 32 yr

60

d. 58MI

84

56

CRC 79d.82

Should everyone with a family history of colon cancer have genetic testing?

Using family history to screen for Lynch syndrome

Key:

Endometrial CA

Colorectal CA

Colon polyps

Dx 38

Dx 50

88 yr

63 yr

4 polypsat 50 yrs.

CRC Dx 48

61 yr

38 yr

10 yr 8 yr

35 yrDetects 60% Misses 40%

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Ideally, Begin Testing With an Affected Person

If a mutation is found in an affected person, testing will be more informative for other family members

Colon Ca, 42

Colon Ca, 38d.45

Colon Ca, 45 Person seeking

counseling (proband)

Test first, if possible

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Interpreting a Negative Result

No identified mutation in family

Colon Ca, 52

Endometrial Ca, 47

Colon Ca, 45

37 MSH2 -

Inconclusive

Family with known mutation

True negative

Colon Ca, 52

Endometrial Ca, 47

Colon Ca, 45MSH2 + 37

MSH2 -

Does this family have HNPCC ?

CRCdx 50s

CRCdx 45Gastric ca dx 52

CRCdx 61+63

CRCdx 75

OvarianCa, dx 64

CRCdx 48

CRCdx 50

EndometrialCa, dx 59

CRCdx 42+ 55

45

Genetic Counseling for hereditary cancers“Informed consent” for genetic testing includes

discussing:the benefits and limitations of genetic testingwhat’s involved in the testing processpossible results and their interpretationhow one might respond to a positive test result

(what are the emotional issues?)Risk management options for those found to carry a

mutation (using the information in a pro-active way)Implications to other family members

Genetic testing for hereditary cancer syndromesBenefits

1. Genetic testing can identify individuals at high risk of developing specific cancers

2. Those at high risk have the opportunity to be pro-active in making medical and lifestyle choices to lower risk

3. Medical options include increased surveillance, chemoprevention, and/or prophylactic surgery

4. Patients who are not high risk can be spared anxiety and the need for increased surveillance

Limitations5. A negative result may not give any useful

information6. Some genetic variants are of unknown clinical

significance

Assessment for hereditary colorectal cancer

Kalyani Maganti, M.D