Exome sequencing in diagnostic evaluation of colorectal cancer predisposition in young patients.

Scand J Gastroenterol 2013 Jun 2;48(6):672-8. Epub 2013 Apr 2.

Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, P.O. Box 63, FIN-00014 University of Helsinki, Helsinki, Finland.

Objective: Early-onset colorectal cancer (CRC), defined here as age of onset less than 40 years, develops frequently in genetically predisposed individuals. Next-generation sequencing is an increasingly available option in the diagnostic workup of suspected hereditary susceptibility, but little is known about the practical feasibility and additional diagnostic yield of the technology in this patient group.

Materials And Methods: We analyzed 38 young CRC patients derived from a set of 1514 CRC cases. All 38 tumors had been tested in our laboratory for microsatellite instability (MSI), and Sanger sequencing had been used to screen for MLH1 and MSH2 mutations in MSI cases. Also, gastrointestinal polyposis had been diagnosed clinically and molecularly. Family histories were acquired from national registries. If inherited syndromes had not been diagnosed in routine diagnostic efforts (n = 23), normal tissue DNA was analyzed for mutations in a comprehensive set of high-penetrance genes (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, SMAD4, BMPR1A, LKB1/STK11, and PTEN) by exome sequencing.

Results: CRC predisposition syndromes were confirmed in 42% (16/38) of early-onset CRC patients. Hereditary nonpolyposis colorectal cancer was diagnosed in 12 (32%) patients, familial adenomatous polyposis in three (7.9%), and juvenile polyposis in one (2.6%) patient. Exome sequencing revealed one additional MLH1 mutation. Over half of the patients had advanced cancers (Dukes C or D, 61%, 23/38). The majority of nonsyndromic patients had unaffected first-degree relatives and microsatellite-stable tumors.

Conclusions: Microsatellite instability positivity or gastrointestinal polyposis characterized all patients with unambiguous highly penetrant germline mutations. In our series, exome sequencing produced little added value in diagnosing the underlying predisposition conditions.

Download full-text PDF

Source
http://dx.doi.org/10.3109/00365521.2013.783102DOI Listing
June 2013
18 Reads

Publication Analysis

Top Keywords

colorectal cancer
12
exome sequencing
12
mlh1 msh2
8
microsatellite instability
8
gastrointestinal polyposis
8
crc patients
8
patients
7
crc
5
mutyh smad4
4
pms2 apc
4
msh6 pms2
4
apc mutyh
4
genes mlh1
4
comprehensive set
4
set high-penetrance
4
high-penetrance genes
4
smad4 bmpr1a
4
msh2 msh6
4
exome sequencingresults
4
confirmed 42%
4

References

(Supplied by CrossRef)

Lynch HT et al.
N Engl J Med 2003

Aaltonen L et al.
Clin Cancer Res 2007

Thibodeau SN et al.
Cancer Res 1996

Aaltonen LA et al.
N Engl J Med 1998

Vasen HF et al.
Dis Colon Rectum 1991

Griffin PM et al.
Gastroenterology 1991

Chang DT et al.
Mod Pathol 2012

O'Connell JB et al.
Am Surg 2003

Similar Publications