Trial Information

Colonoscopy Screening in Siblings of Patients With Advanced Neoplasm: A Concurrent Case-Control Study (Sibling AN Study)

The incidence of colorectal cancer (CRC) is rising rapidly in Hong Kong. It is the second
commonest cancer in Hong Kong with more than 4000 new cases diagnosed in 2007, and it is
also the second commonest cause of cancer death accounting for approximately 1,700 deaths
per year. It has been estimated that 1 in 20 (5%) and 1 in 33 (3%) Hong Kong males and
females, respectively, will develop CRC in their life time. (1) Data from the Hong Kong
cancer registry showed that almost half of the cancer cases were stage III or IV disease at
diagnosis which was associated with a worse prognosis(1), suggesting that earlier detection
of CRC is important.

Genetic factors play an important role in the development of CRC. Approximately one fifth of
CRC are associated with familial clustering(2), whilst hereditary syndromes including
hereditary non- polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP)
account for approximately six percent of CRC cases (3;4)

Individuals with a family history of CRC have an increased risk of developing colonic
neoplasm (cancer and adenoma). Meta-analyses of epidemiological studies showed that FDR of
patients with CRC have an approximately two to three-fold increase risk of developing CRC
compared with the general population (5-9). [Table 1]. The frequency of adenomas (12-69%) is
also higher in relatives of patients with CRC although most of the earlier data have been
derived from cohort studies (10-16). In the recent two case-control studies, the choice of
the control population has been questionable (17;18) [Table 2]. Our own case-control study
of screening colonoscopy in FDR with CRC, compared with FDR of patients with a normal
colonoscopy ( published in abstract form) showed that the prevalence of colonic adenomas was
significantly higher in cases compared with controls (25.3% versus 15.6%) (19).

Colorectal adenomas are precursors of CRC, and FDR of individuals with colonic adenomas also
have an increased risk of CRC as well as colonic adenomas (20;21) The risk of developing
colorectal neoplasia in FDR of patients with adenoma is likely be influenced by the
characteristics of the adenoma in the index case. Colonic adenomas have a higher malignancy
potential when they are greater than 10mm in size, and / or contains a villous component or
severe dysplasia (22). In one study, relative risk of CRC for FDR was higher in relatives of
patients with large adenomas (>10mm) than in those with small adenomas (OR 2.1 and 1.2
respectively) (23). These findings have been reproduced in a recent study from France, which
in addition showed that the risk was particularly high if the index case was younger than 60
years at diagnosis of a large adenoma, male or if they had a large adenoma in the left colon
(24). In a separate study, relatives of patients with advanced neoplasm (OR1.62), but not
those with small tubular adenomas (OR 1.26), have an increased risk of CRC (25).

Little is known about the prevalence of CRC and adenomas among siblings of individuals with
advanced neoplasm in Hong Kong. Furthermore screening procedure for relatives of patients
with high risk adenomas are not as well established as screening strategies for relatives of
patients with CRC. This information is of important relevance in the formulation of an
effective CRC screening strategy in Hong Kong (26). In a pilot screening project in 2001
among asymptomatic subjects of greater than 50 years old, the investigator have demonstrated
an approximately 12% rate of advanced neoplasms using colonoscopy as a tool. Since 2008,
asymptomatic subjects greater than 50 years old have been invited to undergo colonoscopy
screening for CRC in PWH and AHNH hospital. To date about 1800 asymptomatic subjects have
completed colonoscopy screening. This project provides the investigators with the
opportunity to use an original design to determine the prevalence of colorectal neoplasia in
siblings of patients with advanced neoplasm, compared with siblings of asymptomatic
individuals who have had a negative screening colonoscopy during the same period of time.

The molecular pathways leading to tumour development in familial colorectal neoplasms are
likely to be different from sporadic cases. Development of new molecular based methods for
early detection, prevention or treatment relies heavily on the understanding of the
differences between sporadic and familial neoplasms. Identification of genetic mutations can
also improve genetic diagnosis and screening protocol of an at risk population.

The investigators hypothesize that siblings of patients with advanced neoplasm have an
increased risk of both CRC and adenomas. The investigator aim to quantify this risk, and to
identify other individual patient or neoplasm characteristics that may contribute to this
increased risk. In addition, the investigator aim to determine molecular alteration profiles
of colonic adenoma in siblings of patients with advanced neoplasm.