SURVEILLANCE FOR A FAMILY HISTORY OF

COLORECTAL CANCER

Andrew Luck

Northern Adelaide Colorectal NetworkLyell McEwin Hospital

South Australia

NATURE OR NURTURE?

• Early studies (cancer mortality) showed CRC in any first degree relative increased risk 3-4 fold

• Woolf Am J Hum Genet 1958

• Lovett Br J Surg 1976

– ? Genetic predisposition– ? Shared environment

• Diet • Exercise• External factors

NATURE OR NURTURE?

• Later studies (cancer incidence with matched control groups and accurate collection of family history data)– Australia RR 1.8 St John et al Ann Intern Med 1993

– Denmark RR Men 1.9 Women 1.6 Sondergaard et al Int J Cancer 1991

– USA RR 1.7 Fuchs et al N Engl J Med 1994

• Differences at least in part explained by non genetic factors

AVERAGE RISK

If aged Risk over 5 years

Risk over 10 years

Risk over 15 years

Risk over 20 years

30 1 in 7000 1 in 2000 1 in 700 1 in 350

40 1 in 1200 1 in 400 1 in 200 1 in 90

50 1 in 300 1 in 100 1 in 50 1 in30

60 1 in 100 1 in 50 1 in 30 1 in 20

70 1 in 65 1 in 30 1 in 20 1 in 15

80 1 in 50 1 in 25

CATEGORY 1

• Those at or slightly above average risk

– No personal history of bowel cancer, advanced adenoma or chronic ulcerative or Crohn’s colitis

– Either no close relatives with bowel cancer or one first or second degreee relative with CRC diagnosed at age 55 or older

CATEGORY 1

• Screening recommendations

– Confirm asymptomatic

– Faecal occult blood testing every second year from the age of 50 years

MODERATELY INCREASED RISK

• First degree relative with CRC diagnosed at an early age (below 55)

• Two first degree relatives (or one first and one second degree relative that are related to each other)

• RR 3-6

• Category 2

AVERAGE RISK

If aged Risk over 5 years

Risk over 10 years

Risk over 15 years

Risk over 20 years

30 1 in 7000 1 in 2000 1 in 700 1 in 350

40 1 in 1200 1 in 400 1 in 200 1 in 90

50 1 in 300 1 in 100 1 in 50 1 in30

60 1 in 100 1 in 50 1 in 30 1 in 20

70 1 in 65 1 in 30 1 in 20 1 in 15

80 1 in 50 1 in 25

CATEGORY 2

• Screening recommendations

– Complete family history

– Confirm asymptomatic

– Colonoscopy every 5 years, starting at age 50 or at an age 10 years younger than the age of first diagnosis of CRC in the family, whichever comes first

FH ADENOMA

• Some studies have shown FH sporadic colorectal adenoma can be a marker for CRC risk– Esp if detected at a young age– Esp if advanced features

• >1cm• High grade dysplasia• Villous change

• Insufficient data to advise relatives

CATEGORY 3• Those at potentially high risk (RR 15)– Three or more first degree relatives (or a

combination of first and second degree relatives from the same side of the family (?HNPCC)

– Two or more relatives as above with high risk features (?HNPCC)• Multiple bowel cancers in the same person

• CRC before age 50

• A relative with cancer of the endometrium, ovary, stomach, small bowel, renal pelvis, ureter, biliary tract or brain

CATEGORY 3

• Those at potentially high risk

– At least one first degree relative with a large number or colorectal adenomas (suspected FAP)

– A relative in whom the presence of a high risk mutation in the APC gene (FAP) or one of the mismatch repair genes (HNPCC) has been identified

CATEGORY 3• Screening recommendations– Complex– Individualised – ? Genetic testing– Extraintestinal tumours

• FAP - Periampullary carcinoma, intra-abdominal fibromatosis (desmoids), papillary cancer of thyroid

• HNPCC – tumours of endometrium, ovary, stomach, small bowel, renal pelvis, ureter, biliary tract and brain

FAMILIAL ADENOMATOUS POLYPOSIS (FAP)

• Autosomal dominant

• APC gene (Chromosome 5)

• Phenotype influenced by the site of the mutation– Attenuated FAP• Less than 100 polyps, often only in proximal

colon

FAMILIAL ADENOMATOUS POLYPOSIS (FAP)

• Screening recommendations– If no mutation identified

• Flexible sigmoidoscopy annually from age 12-15 to age 35 or until polyps develop

• Dye spray chromo-endoscopy or narrow band imaging

• Attenuated FAP families need colonoscopic surveillance

– If mutation identified• Offer genetic testing to distinguish mutation

positive and mutation negative family members

FAMILIAL ADENOMATOUS POLYPOSIS (FAP)

• If mutation negative– Same risk as Category 1

• If mutation positive or diagnosis confirmed – Total colectomy/ileorectal anastomosis or

proctocolectomy in late teenage years• Annual flexible sigmoidoscopy if TC/IRA

– Duodenoscopy from age 25

HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (hnpcc)

• Autosomal dominant– Germline mutation in one of the mismatch

repair genes, usually MLH1, MSH2, MSH6 or PMS2

• Early age of onset• Proximal colonic malignancy• Multiple colorectal cancers• Extracolonic malignancy

HNPCC

• Amsterdam criteria 1991

• Amsterdam II criteria1999

• Bethesda guidelines 2001

• Revised Bethesda guidelines 2004

• Allows selection of patients for MSI assessment (or immunohistochemistry) to determine who should be tested for germline mutation

BETHESDA GUIDELINES• Colorectal cancer diagnosed in a patient who is less

than 50 years of age• Presence of synchronous CRC, metachronous CRC or

other HNPCC associated cancers• CRC with MSI-H type histology in a patient under 60

years of age• Tumour infiltrating leucoctes• Crohn’s like lymphocytic reaction• Mucinous/signet ring differentiation• Medullary growth pattern

• CRC in a patient under 60 with at least one first degree relative with an HNPCC associated cancer

• CRC in a patient of any age with 2 or more first or second degree relatives with HNPCC associated cancers

MICROSATELLITE INSTABILITY

• Microsatellites are tandem repeats of short (1-5 bases) sequences of DNA.

• If errors are made during mitosis there is a change in the size of the microsatellite in the daughter cells – so called microsatellite instability (MSI)

• This should be corrected by mismatch repair genes, but if these are defective, as in HNPCC, MSI-H (high) status remains.

• MSI-H is thus a marker of HNPCC

MSI-H• Almost all HNPCC cancers are MSI-H

• 70% of adenomas in HNPCC are MSI-H

• 10-15% of sporadic cancers are MSI-H– Must consider MSI-H status in the context of

the family history and the age of the patients before diagnosing HNPCC

– Patients who fit Bethesda criteria and have MSI-H tumours should be considered for genetic testing for germ line mutation in MLH1, MSH2, MSH6 and PMS2

HNPCC

• Screening recommendations

– Proven germline mutation or HNPCC tumours that fit Bethesda/Amsterdam• Colonoscopy (and gastroscopy) annually (or at

least 2 yearly) beginning at age 25 or 5 years younger than the age of diagnosis of the youngest member of the family• Annual transvaginal ultrasound from age 30• Annual urinary cytology and renal ultrasound

HNPCC

• Screening recommendations

– First degree relatives with unknown mutation status• As above• 2 yearly rather than annual

– Relatives negative for known germ line mutation• Category 1 recommendations

SUMMARY

• Category 1

– At or just above average risk• No FH or single first degree relative with CRC

over 55

• FOBT ever 2 years from age of 50

SUMMARY

• Category 2

–Moderately increased risk• One first degree relative CRC under age 55• Two first or second degree relatives on same

side of family with CRC

– 5 yearly colonoscopy from age 50 or 10 years younger than the age of diagnosis of the youngest family member

SUMMARY

• Category 3

• At potentially high risk– Features of FAP or HNPCC

– Complex– Individualised– Genetic testing– Extensive - often annual testing