Mr Christopher WakemanGeneral and Colorectal Surgeon

Christchurch

16:30 - 17:30 WS #133: Does a Family History Matter in Bowel Cancer?

Does a family history matter in

bowel cancer?

Chris Wakeman

Medical advisor and Colorectal surgeon

Malcolm Marshall

Sam Simon (Simpsons)

Audrey Hepburn Bobby Moore

Charles M. Schulz

Queen Elizabeth The Queen

Mother

Robin Gibb Harold WilsonVince Lombardi

Elizabeth

Montgomery

(bewitched)

Bowel cancer kills as many Kiwi lives every

year as breast and prostate cancer combined

Age-Standardized Colorectal Cancer Incidence Rates by Sex and World

Area.Global Cancer Statistics A CANCER J CLIN 2011;61:69–90

<50• Incidence increasing – supports hypothesis

– 0.05531 (0.02141, 0.08920) p = 0.0032

50-80• Incidence decreasing

– -3.066 (-3.520, -2.612) p <0.0001

80+• Incidence increasing

– 3.342 (1.431, 5.252) p = 0.0019

What happening with the incidence

What is the Average Risk for individuals in

NZ?• 55 yrs:

– Overall risk 0.6%

• 75 yrs

– Overall risk 5.6%

– Men: 1 in 18

– Women 1 in 23

Am J Med genetics Vol 129C Aug 15th 2004

Colorectal Cancer

NZ familial GI cancer service -Who We Are

• Ministry of Health funded, multidisciplinary service

specialising in familial gastrointestinal cancer.

• We are a national service with offices in Auckland,

Wellington and Christchurch

• Teresa Chalmers Watson, Chris Wakeman in

Christchurch

Who Is Referred

• Patients may have a history of a number of family members over two or three generations being affected with bowel or other gastrointestinal cancers eg stomach, pancreas

• Patients or a close family member have been diagnosed with bowel or other gastrointestinal cancer at a young age

• There is concern that they or their family may have a genetic bowel or gastrointestinal cancer syndrome

• There is a known genetic gastrointestinal cancer syndrome in a family

What conditions

• We look after FAP, lynch , HNPCC, familial gastric

cancer, MYH, familial gastric cancer

• We advice on the other polyposis syndromes such as

Peutz jeghers, Hyperplasic polyposis, familial

pancreatic cancer, Familial syndrome X

What We Do

• Offer assessment of bowel cancer risk for people with a family history of GI cancer

• Facilitate the diagnosis of hereditary cancer by confirming the family history

• Offer surveillance recommendations

• Co-ordinate surveillance for high-risk families

• Offer specialist management advice

• Provide information for families on familial GI cancer

What do we want to know?

• Who had the cancer ? Colon v extra colonic

• Age of the cancer? Synchronous v metchronous

• Where? So we can track medical other information

• Previous diagnosis?

NZFGICS:

• 689 families registered

– Lynch 146

– HNPCC 304

– 78 Syndrome X

– 66 FAP

– 21 MYH associated polyposis

– 84 Serrated Polyposis

Inherited colorectal cancer syndromes

Polyposis Non polyposis

Adenomas

Serated

Hamartoma

lynch

Syndrome

x

Early onset

CRC

ClusterNew polyposis

disorders

Genetics and cancer

• Germline mutation

– Refers to alterations in an individuals DNA at embryogenes

– Can be passed onto the offspring

• Somatic mutation

– Alteration that occur in the DNA of a particular tissue type

– E.g. colon cancer leading to colon cancer

Adenoma to carcinoma sequence

• The majority of colorectal cancers begin as adenomas

• Multi steps with somatic alteration occur and led to the

development of cancer

• Vogelstein observed that a APC mutation in 25% of all

adenomas

Adenoma to Carcinoma Pathway

Normal CancerAdenoma

• Most cancers develop from adenomatous polyps

Inherited cancer syndromes

• Autosomal recessive

– Need both maternal and paternal allele

– If both parents carriers then a 25% chance of transmission

to next generation

• Autosomal dominant

– Only one altered allele required

– 50% chance of transmission to next generation

Other genetic key concepts

• Penetrance

– Proportion of individuals with a given genotype who

express the phenotype

• Genetic pleiotrophy

– Multiple phenotypes from mutations of a single gene (

PTEN)

• Variable expressivity

– Extent of disease expression

• Genetic heterogeneity

– Multiple genetic ways to inherit a phenotype eg lynch

Possible results from genetic testing

• Positive

– Medical management recommendations made to the

patient

– Family members can be tested

• Negative

– Does not absolutely mean cancers not hereditary

– Does not negate family history

• ?

Inherited colorectal cancer syndromes

Polyposis Non polyposis

Adenomas

Serated

Hamartoma

lynch

Syndrome

x

Early onset

CRC

ClusterNew polyposis

disorders

Inherited Non polyposis disorders

• Lynch syndrome

• Lynch Syndrome predisposes to

colorectal, endometrial and a variety of

other cancers.

• Inheritance is autosomal dominant, but

with gene-dependent age-related

penetrance, variable expressivity, and sex

limitation.

Hereditary Non Polyposis Colorectal Cancer

HNPCC• First described by Dr Scott

Warthin

• Published family pedigree that meets HNPCC criteria in 1913

• His seamstress predicted her death from gynaecological or CRC…. and was correct

• Henry Lynch followed up on this and other Nebraskan families in 1960’s

• Condition termed HNPCC - to distinguish it from FAP with multiple polyps

Lynch Syndrome - Genetics

• Autosomal dominant familial cancer syndrome– 50:50 chance of passing it on

• The prevalence of mutations causing LS due to each gene is about 1/1000, so total prevalence of LS may be up to 1/250, which makes LS probably the most common form of predisposition to cancer.

• Caused by germline mutation in DNA mismatch repair (MMR) genes

– Tumours have microsatellite instability (MSI)

– Loss of protein expression of the 4 genes can be shown with IHC (immunohistochemistry)

• MLH1 and MSH2 – 70- 80% - ‘classic form’

• MSH6 - 5-10% –’attenuated’ later onset

• PMS2 – 2-5% - ‘attenuated’ - reduced penetrance

Risks of Colorectal and

other Cancers in Lynch

Syndrome Cancer MLH1

to age 70 yrs 1,2

MSH2

to age 70 yrs 1,2

MSH6

to age 70 yrs 3,2

PMS2

to age 70 yrs4

Lynch syndrome

to age 70 yrs*

General population to

age85 yrs

Colorectal (male) 34% 47% 22% 20% 38% 10%**

Colorectal (female) 36% 37% 10% 15% 31% 6.6%**

Endometrial 18% 30% 25% 15% 33% 2 - 3%

Gastric 6% 0.2% 0 - 6% 1%

Ovarian 8-15% 8-15% Low - 9% 1 - 2%

Urothelial 0.2% 2.2% 0.7% - <3% 1%

Small Bowel 0.4% 1.1% 0 - <3% 0.01%

*This data does not take into account the impact of surveillance.

Data Source: NSW Central Cancer Registry 2008 final dataset and NSW Health Outcomes Information Statistical Toolkit (HOIST).

• Lynch Syndrome families – where a mutation has

been found in the family by genetic testing

• Families where criteria are met and special tests

suggest the involvement of the MMR genes but

genetic testing has not found a mutation- Presumed

Lynch Syndrome.

• Families where Amsterdam criteria are met and

special tests DO NOT suggest the involvement of the

MMR genes – Familial Colorectal Cancer

Syndrome X

• Those who meet criteria but no testing possible-

currently still HNPCC

Families previously called HNPCC now

divided up

Lynch Syndrome : management

Colorectal Cancer

• Intensive colonoscopicsurveillance• 1-2 yrly from 25 years.

• 43% reduction in incidence of CRC

• Significant decrease in mortality from CRC (detected at earlier stage)Balance of metachronousCRC risk with quality of life

Surveillance for extra-colonic tumours

• Urinary Tract tumours– value unknown– Urine cytology may be

undertaken 1-2yearly from 35yrs

• Endometrial Cancer – value unknown– Annual surveillance by

examination, transvaginal ultrasound and aspiration biopsy

– from age 35yrs may be beneficial– Hysterectomy may be an option

• Lancet 2011; 378: 2081–87

• Published Online

• October 28, 2011

• DOI:10.1016/S0140-

• 6736(11)61049-0

• See Comment page 2051

CAPP2

• Randomised 2 by 2 trial

• 600mg aspirin or aspirin placebo or 30g of resistant starch in lynch syndrome

• Primary endpoint was colorectal cancer

• Interpretation 600 mg aspirin per day for a mean of 25 months substantially reduces cancer incidence after 55.7 months

Aspirin and bowel cancer in Lynch Syndrome

• Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomisedcontrolled trial

• 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55.7 months in carriers of hereditary colorectal cancer.

• Further studies are needed to establish the optimum dose and duration of aspirin treatment.

Burn et al Lancet ;378 December 2011

Inherited colorectal cancer syndromes

Polyposis Non polyposis

Adenomas

Serated

Hamartoma

lynch

Syndrome

x

Early onset

CRC

ClusterNew polyposis

disorders

Polyposis disorders

FAP Inheritance

• APC gene on Chromosome 5

• 20 % have no family history

• In 10% cases unable to identify APC gene mutation

• Penetrance is virtually 100%

• Onset of polyposis is in teenage years.

• Most patients are asymptomatic

• Age of onset for colorectal cancer is late 30’s - early 40’s

Surgical specimen of colon with FAP

Surgery

• Mainstay of treatment is removing the large bowel

before the adenoma have a opportunity to become

malignant

• 3 options

– Total colectomy and ileal rectal anastomois (IRA)

– Proctocolectomy and ileostomy

– Pan proctocolectomy and ileal anal pouch ( IPAA)

MAP - Genetics

• MYH located on Chromosome 1 and one of 3 genes involved in base-excision-repair (BER)

• Autosomal recessive

• The two most common MYH gene mutations found in MAP in the Caucasian population are Y165C and G382D

• But…20 % of cases with bi-allelic mutations do not have either of these mutations

• 1% of population are heterozygote

• mono-allelic – sl. increased risk

Sampson Lancet 2003, Sieber NEJM 2003

MAP – Clinical

• Unlike FAP where strong genotype –

phenotype correlation, in MAP

phenotype very variable…

• <10 polyps to widespread /

indistinguishable from FAP

• 2/3 of CRC’s are right-sided and the

mean age at diagnosis is approximately

45 years.

Hamartomatous

polyposisRare syndrome of autosomal dominate conditions characterized by

the presence of hamartomatous polyps

Peutz-Jeghers syndrome characterized by mucocutanoeus

pigmentation , small bowel polyps and a increased risk of intestinal

and extra intestinal malignancies. Mutations in STK11 causal.

Juvenile polyposis is caused by the SMAD4,BMPR1A and ENG1

mutation. Increased risk of GI track malignances

PTEN hamartoma tumour syndrome is composed of cowdens,

Bannayan-Riely-Ruvalcava syndrome and Proteus syndrome

Each of these has unique risks and requires tailored medical

management

Serrated polyposis

• Serrated polyposis syndrome (SPS)(previously

hyperplastic polyposis) is defined by number and size

of serrated polyps in the colon and rectum, but the

definition is purely arbitrary and there is no known

genotype.

• Serrated polyps of the colon and rectum can be found

in approximately 20% of average risk patientscoming

to screening colonoscopy and comprise:

• Hyperplastic polyps – by far the most common. They are small and pale,

usually left sided, and act more as a marker of significant proximal

serrated lesions than being premalignant in themselves.

• Sessile serrated adenoma/polyps (SSA/P) – larger, right sided lesions

that are difficult to see endoscopically and can progress to cancer

relatively rapidly.

• Traditional serrated adenomas (TSA) – endoscopically more like

adenomas, usually left sided and are premalignant in the same way as

adenomas.

Diagnostic criteria The ‘WHO Criteria’ for the Serrated

Polyposis Syndrome (SPS) include any of the following

• At least five serrated polyps proximal to the sigmoid

colon, two of which are greater than 10mm in

diameter.

• Any number of serrated polyps occurring proximal to

the sigmoid colon in an individual who has a first-

degree relative with serrated polyposis

• More than 20 serrated polyps of any size distributed

throughout the colon.

Serrated cancer pathway

• Typically, the molecular basis of serrated lesions begins with an

activating mutation in KRAS or BRAFoncogenes.

• On the left side of the colon this leads to hyperplastic polyps and

sometimes TSA.

• On the right side of the colon DNA hypermethylation adds to the

proliferative effect of a BRAF mutation to produce SSA/P.

• The hypermethylation shuts down expression of many genes, including

the DNA mismatch repair gene MLH1. This event promotes

microsatellite instability in SSA/P, leading to adenomatous

dysplasia. Cancer may follow. Biologically these are usually CIMP high

cancers.

•

GeneticsSPS is commonly grouped with the hereditary polyposes

even though it is not associated with a single gene

mutation and it does not appear to be inherited in a

simple Mendelian fashion.

Phenotypic overlap with MUTYH associated polyposis

(MAP) is documented in some individuals with

SPS where adenomas are also present, and with Lynch

syndrome, so patients with SPS are potential candidates

for panel testing as there may be germline mutations in

unexpected genes.

The new polyposis disorders

Other causes of adenomatous polyposis

• NTHL1-associated polyposis (NAP)

• NTHL1 is a counterpart of MUTYH in oxidative DNA

damage repair, and mutations in NTHL1 can also

cause a recessive form of adenomatous polyposis.

Consitutional mismatch repair disorder

(CMMR-D)• Individuals with CMMR-D can develop multiple

colorectal adenomas, and so in this way resemble

MAP and NAP patients. However, CMMR-D patients

also develop a host of other malignancies and clinical

abnormalities, often at a much younger age.

Polymerase proofreading-associated

polyposis (PPAP)

• Individuals with dominantly inherited mutations in the

DNA polymerases POLD1 and POLE can also

develop adenomatous polyposis, but they are also at

risk of endometrial and possibly other LS-related

cancers.

MSH3-associated polyposis

• Most recently, recessive inheritance of mutations

in MSH3 has been found in patients with adenomatous

polyposis. Interestingly, tumours in such patients

exhibit instability at microsatellites with tetranucleotide

but not mono- or di-nucleotide repeats, and thus this

sort of instability will not be detected in standard tests

for MSI, as used to diagnose LS.

Genetic panels

• Although hereditary cancer panels vary, they typically

include both highly penetrant as well as moderately

penetrant genes 6. For highly penetrant genes, clinical

guidelines exist for the prevention or early detection of

cancers 7. In other words, these are ‘actionable genes’

with known clinical utility 8. In contrast, the utility of

moderately penetrant genes is less certain.

• Despite the potential for panel-based testing to identify

more mutations, this testing is also expected to

increase the complexity of results interpretation

because of factors such as questionable or uncertain

clinical utility of testing for moderate penetrance genes

and the higher rate of inconclusive results because of

an increase in the number of variants of uncertain

significance (VUS)

Ethical issues

• Ethical and legal aspects complex

• Family history essential

• Investigation of one family member may mean

recording information about others and identifying

them as being at risk without their knowledge

• Confidentiality amongst family members

• When to test Children

NZ Guidelines Group Categories for CRC risk

based on family history

Category 1: Slightly increased risk

Category 2: Moderately increased risk

Category 3: Potentially high risk

(risk above that of the general population)

Category 1. Individuals with a slight

increase in risk of colorectal cancer

• Familial risk

• Recommendations

• Individuals with a slight increase in risk of colorectal

cancer due to family history.

• One first-degree relative with colorectal cancer

diagnosed over the age of 55 years

Category 2. Individuals with a moderate

increase in risk of colorectal cancer • Individuals with a moderately increased risk of

colorectal cancer have one or more of the

following:

• one first-degree relative with colorectal cancer

diagnosed under the age of 55 years

• two first-degree relatives on the same side of

the family with colorectal cancer diagnosed at any

age.

Category 3: Potential High Risk of Colorectal Cancer

➢ A family history of Familial Adenomatous Polyposis (FAP), Lynch Syndrome or other familial CRC syndrome

➢ One FDR plus two or more 2nd degree relatives (SDR) on same side of family diagnosed CRC at any age

➢ Two FDRs or one FDR and one or more SDRs on same side of family with CRC and one of them

➢ - diagnosed under 55

➢ - developed multiple bowel cancers

➢ - developed an extracolonic cancer suggestive of Lynch Syndrome (uterine, ovarian, stomach,small

bowel, renal pelvis, pancreas, brain)

➢ At least one FDR or SDR diagnosed with CRC in association with multiple bowel polyps

➢ Personal history of or one FDR with CRC diagnosed CRC under age 50 particularly where tumour

immunohistochemistry revealed loss of expression of mismatch repair genes . Personal history of or one

FDR with multiple bowel polyps

Five times as many Kiwis die as a result of

Bowel Cancer than road traffic accidents

Does a family history matter in

bowel cancer?

Chris Wakeman

Medical advisor and Colorectal surgeon

Does a family history matter in

bowel cancer?

YES it is does