Family history and molecular features of children, adolescents and young adults with colorectal carcinoma

Carol A Durno ^1*, Melyssa Aronson ², Bharati Bapat ², Zane Cohen ² and Steven Gallinger ²

¹ Mount Sinai Hospital and the Hospital for Sick Children, Canada
² Mount Sinai Hospital, Canada

^* To whom correspondence should be addressed. E-mail: carol.durno{at}sickkids.ca.

Accepted 12 April 2005

Abstract

Background: Colorectal cancer is extremely rare in childhood. Published case series reporting children and adolescents with colorectal cancer have not focused on the underlying genetic aspects of the tumour or genetic susceptibility of the families.

Aims: We examined a cohort of patients with early- onset colorectal cancer to determine whether a specific genetic predisposition could be elucidated. In particular we focused on whether, DNA mismatch repair gene deficiency which causes Hereditary Nonpolyposis Colorectal Cancer (HNPCC), could be elucidated.

Methods: Patients with colorectal cancer < 24 years of age were identified from a database at the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital, Toronto. Detailed pedigrees were ascertained from the proband or parents. Tumours were tested for microsatellite instability, a hallmark of HNPCC. Germline mismatch repair gene mutations (MSH2 and MLH1) were sought in some cases. Clinical data were obtained by chart audit.

Results: Among 1382 probands in our registry,16 (1%) colorectal cancer patients were 24 years or younger at the time of diagnosis. Microsatellite instability was identified in tumours from 8 (73%) of 11 evaluated patients. Germline mutations in mismatch-repair genes were identified in 6 of 12 patients including MSH2 (n=3), MLH1 (n=2), and PMS2 (n=1). Ten (63%) of the 16 families met the Amsterdam criteria for HNPCC. Among these, 6 were screened for MMR gene mutations and 3 were found to carry MSH2 or MLH1 germline mutations. Location of the colorectal cancers included rectum/sigmoid (n=9), splenic flexure (n=2), hepatic flexure (n=3), and cecum (n=2). Forty-four percent (7 of 16) of these young cases developed additional malignancies [gastrointestinal (n=8) and extra-intestinal (n=4)] during follow-up (mean 12.8 years, SD +/- 12.4 years (range 0.08-30 years).

Conclusions: Patients with early-onset colorectal carcinoma often have an inherited predisposition to the disease. Tumours with high frequency microsatellite instability and germline mutations of mismatch repair genes are sufficiently common in this patient population that they should be considered, even though family histories may not satisfy the stringent Amsterdam criteria for HNPCC. Young colorectal cancer patients are at increased risk of developing second gastrointestinal and extra-intestinal malignancies.

Keywords: colorectal cancer, germline mutations, hereditary nonpolyposis colorectal cancer, microsatellite instability, pediatric cancer

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