FACET - European Journal of Cancer Care March 2004

FACET - European Journal of Cancer CareMarch 2004

slides available at: www.blackwellpublishing.com/journals/ecc

Genetics of colorectal cancerRafi, I.1

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*Click on “View”; “Notes Page” for explanatory notes

Ascertainment

• Good family history

• Use of computers

• Questionnaire



Genetics of colorectal cancer(continued)

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Primary-Secondary Care

Communication between primary care and secondary care is important in the management of families at high genetic risk.

• Filter low risk families

• CMO report 1996

• GP’s may overestimate

risk




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Epidemiology In England and Wales, colorectal cancer is the second most common cause of cancer death.

• Rising incidence

The age-standardised incidence rates for colon cancer are:

• 17.1 per 100,000 for males

• 13.2 per 100,000 for females

• Ethnic variation

• Social class influence




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Aetiology

15-20% of cases of colorectal cancer are accounted for by genetic causes whilst 80-85% of cases of colorectal cancer are sporadic, arising from pre-malignant adenomatous polyps.

• Pre-existing adenomas

• Several genetic

abnormalities and genes

involved

• Environment-genetic

interplay




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Screening

• Do relatives of an

affected individual with

colorectal cancer have a

greater lifetime risk

compared to normal

population?



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Screening/outcomes

• Mortality

• Type of screening

• Evidence base

• Targeted v general

population




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Genetic Families at Risk

• Familial Adenomatous

Polyposis (FAP)

• Hereditary Non-Polyposis

Coli (HNPCC)

• Familial Colorectal Cancer

(FCC)




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Familial Adenomatous

Poylposis

• Germ-line mutations in

the APC gene

• Undifferentiated growth of

adenomas

• Extra-colonic

manifestations




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HNPCC

• Mutation in genes

essential for DNA

mismatch repair

• Right sided colonic

tumours

• Extra colonic cancers

such as endometrial,

ovarian, bladder and

renal tumours




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Familial

Families have an increased

lifetime risk of developing

colorectal cancer where there

is a first-degree relative with

colorectal cancer.

Risk stratification based on:

• Number of first degree

relatives affected

• Early age of cancers




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Genetic epidemiology

Lovett’s incidence and

cancer mortality study

elicited family histories of

patients admitted to St

Mark’s Hospital (London) for

treatment for colorectal

cancer.

• Life tables method

• Identifying risks to

members of colorectal

cancer families



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Genetic Studies

• Burt (1996)

• St John et al (1993)

• Utah population data

(1994)




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Lifetime risk

Houlston et al (1990) estimated the risks to relatives of patients with colorectal cancer using Lovett’s pedigrees of families.

• Population risk – 1 in 50

• One relative affected – 1 in 17

• One first degree/one second degree – 1 in 12

• One relative under 45 – 1 in 10

• Two first degree relatives




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Screening methods (1)

• FAP

• Sigmoidoscopy (starting

in adolescence)

• Gastro-duodenoscopy

• Gene testing for the APC

gene



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Screening methods (2)

• HNPCC

• Colonoscopy

• ? Pelvic Ultrasound



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Screening by genetic testing

• Genetic counselling

• The role of genetic testing in patients with suspected hereditary colorectal cancer is to:

• Determine if affected patient is carrier of germ-line mutation of one of the colorectal genes

• Allow screening of other family members through genetic testing alone



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Conclusion

• Evidence that screening

affects mortality is

sparse

• Further research

• Need for clear referral

criteria



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References • Bodmer WF, Failey CJ, Bodmer J, et al.

(1987) Localisation of the gene for familial adenomatous polyposis on chromosome 5. Nature, 328:614-616.

• Burt R. (1996) Familial risk and colon cancer. International Journal of Cancer 69:44-46.

• Department of Health. (1996) Genetics and Cancer Services Report of a working group for the Chief Medical officer. DOH.

• Department of Health. (1995b) Report of the genetics research advisory group (first report of the NHS central research and development committee on the new genetics).

• Emery J, Walton R, Murphy M, et al. (2000) Computer support for interpreting family histories of breast and ovarian cancer in primary care : comparative study with simulated cases. British Medical Journal, 321:28-32.

• Emery J, Watson E, Rose P, et al. (1999) A systematic review of the literature exploring the role of primary care in genetic services. Family Practice, 16, No 4:426-445.



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References (continued)• Houlston RS, Murday V, Harocopes C, et al.

(1990) Screening and genetic counselling for relatives of patients with colorectal cancer in a family cancer clinic. British Medical Journal, 301:366-368.

• House W, Sharp D and Sheridan E. (1999) Identifying and screening patients at high risk of colo-rectal cancer in general practice. Journal of Medical Screening, 6(4):205-208.

• Leggat V, Mackay J, Marteau T, et al. (2000) The psychological impact of a cancer family history questionnaire completed in general practice. Journal of Medical Genetics, 37:470-472.

• Leggat V, Mackay J, and Yates JRW. (1999) Evaluation of questionnaire on cancer family history in identifying patients at increased genetic risk in general practice. British Medical Journal, 319:757-758.

• Lovett E. (1976a) Familial cancer of the gastro-intestinal tract. British Journal of Surgery, 63:19-22.



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References (continued)• Lovett E. (1976b) Family studies in cancer

of the colon and rectum. British Journal of Surgery, 63:13-18.

• Lynch HT, Smyrk T and Lynch JF. (1996) Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome). International Journal of Cancer, 69:38-43.

• Lynch PM. (1999) Clinical challenges in management of familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. Cancer, 86:1713-1719.

• Lynch T and Smyrk TC. (1999) Hereditary Colorectal Cancer. Seminars in Oncology, 5:478-484.

• Peckham CS and Dezateux C. (1998) Screening. The Royal Society of Medicine Press Limited, London.

• Petersen GM. (1996) Genetic counselling and predictive testing for colorectal cancer risk. International Journal of Cancer, 69:53-54.



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References (continued)• Petersen GM, Brensinger JD, Johnson KA, et

al. (1999) Genetic testing and counselling for hereditary forms of colorectal cancer. Cancer, 86:1720-1730.

• Potter JD, Slattery ML, Bostick RM, et al. (1993) Colon Cancer: A review of the epidemiology. Epidemiologic Reviews, 15, No 2:499-545.

• Slattery ML and Kerber RA. (1994) Family history of Cancer and colon cancer risk: the Utah population database. Journal of the National Cancer Institute, 86:1618-1625.

• St.John DJB, McDermott FT, Hopper AL, et al. (1993) Cancer risk in relatives of patients with common colorectal cancer. Annals of internal medicine, 118:785-790.

• Toribara NW and Sleisenger MH. (1995) Screening for colo-rectal cancer. New England Journal of Medicine, 332:861-867.

• Vogelstein B, Fearon ER, Hamilton SR, et al. (1988) Genetic alterations during colo-rectal tumour development. New England Journal of Medicine, 319:525-532.



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References (continued)• Westman J, Hampel H and Bradley T.

(2000) Efficacy of a touchscreen computer based family cancer history questionnaire and subsequent cancer risk assessment. Journal of Medical Genetics, 37:354-360.

• Wilmink ABM. (1997) Overview of the epidemiology of colorectal cancer. Diseases of the Colon and Rectum, 40, 4:483-493.

• Winawer SJ, Zauber AG, O'Brien MJ, et al. (1993) Prevention of colo-rectal cancer by colonoscopic polypectomy. New England Journal of Medicine, 329:1977-1981.

FACET - European Journal of Cancer Care March 2004

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