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Focus on 16p13.3 Locus in Colon Cancer.

Mampaey E, Fieuw A, Van Laethem T, Ferdinande L, Claes K, Ceelen W, Van Nieuwenhove Y, Pattyn P, De Man M, De Ruyck K, Van Roy N, Geboes K, Laurent S - PLoS ONE (2015)

Bottom Line: For instance, the benefit of adjuvant chemotherapy has been most clearly demonstrated in stage III disease with an approximately 30 percent relative reduction in the risk of disease recurrence.Most interestingly, above mentioned characteristics were also found in stage II patients, for whom there is a high medical need for the identification of new prognostic biomarkers.In conclusion, copy number variation of the 16p13.3 locus seems to be an important parameter for prediction of disease recurrence in colon cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology-Digestive Oncology, Ghent University Hospital, Ghent, Belgium.

ABSTRACT

Background: With one million new cases of colorectal cancer (CRC) diagnosed annually in the world, CRC is the third most commonly diagnosed cancer in the Western world. Patients with stage I-III CRC can be cured with surgery but are at risk for recurrence. Colorectal cancer is characterized by the presence of chromosomal deletions and gains. Large genomic profiling studies have however not been conducted in this disease. The number of a specific genetic aberration in a tumour sample could correlate with recurrence-free survival or overall survival, possibly leading to its use as biomarker for therapeutic decisions. At this point there are not sufficient markers for prediction of disease recurrence in colorectal cancer, which can be used in the clinic to discriminate between stage II patients who will benefit from adjuvant chemotherapy. For instance, the benefit of adjuvant chemotherapy has been most clearly demonstrated in stage III disease with an approximately 30 percent relative reduction in the risk of disease recurrence. The benefits of adjuvant chemotherapy in stage II disease are less certain, the risk for relapse is much smaller in the overall group and the specific patients at risk are hard to identify.

Materials and methods: In this study, array-comparative genomic hybridization analysis (array-CGH) was applied to study high-resolution DNA copy number alterations in 93 colon carcinoma samples. These genomic data were combined with parameters like KRAS mutation status, microsatellite status and clinicopathological characteristics.

Results: Both large and small chromosomal losses and gains were identified in our sample cohort. Recurrent gains were found for chromosome 1q, 7, 8q, 13 and 20 and losses were mostly found for 1p, 4, 8p, 14, 15, 17p, 18, 21 and 22. Data analysis demonstrated that loss of chromosome 4 is linked to a worse prognosis in our patients series. Besides these alterations, two interesting small regions of overlap were identified, which could be associated with disease recurrence. Gain of the 16p13.3 locus (including the RNA binding protein, fox-1 homolog gene, RBFOX1) was linked with a worse recurrence-free survival in our patient cohort. On the other hand, loss of RBFOX1 was only found in patients without disease recurrence. Most interestingly, above mentioned characteristics were also found in stage II patients, for whom there is a high medical need for the identification of new prognostic biomarkers.

Conclusions: In conclusion, copy number variation of the 16p13.3 locus seems to be an important parameter for prediction of disease recurrence in colon cancer.

No MeSH data available.


Related in: MedlinePlus

Frequency of DNA copy number alterations of all 93 samples for the whole genome.Gains are represented in blue, losses in red.
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pone.0131421.g001: Frequency of DNA copy number alterations of all 93 samples for the whole genome.Gains are represented in blue, losses in red.

Mentions: After scoring of all tumour samples, 93 samples with at least 50% of tumour cells were retained for array-CGH analysis. Ninety out of these 93 colon carcinomas showed genomic alterations (Fig 1). Patients with an increased CEA level had more CNAs than patients with a normal CEA level at diagnosis (*P = 0.023) (Figure A in S3 File). CNAs in our patient cohort were less abundant in MSI patients than in MSS patients, as evaluated by 180K array-CGH (*P = 0.016) (Figure B in S3 File). All the MSI patients had less than ten alterations, whereas the mean number of alterations for the overall patient cohort is 12.98 (± 0.982). When we looked for alterations in the different tumour stages, we found a higher number of alterations for the MSI patient only in stage IV, while in the other tumour stages, MSI patients had less CNAs compared to MSS patients (**P = 0.003) (Figure C in S3 File). Clustering analysis identified no statistically significant relationship between cluster groups (based on one or more specific alteration) and any clinical parameter in our database (S1 Fig).


Focus on 16p13.3 Locus in Colon Cancer.

Mampaey E, Fieuw A, Van Laethem T, Ferdinande L, Claes K, Ceelen W, Van Nieuwenhove Y, Pattyn P, De Man M, De Ruyck K, Van Roy N, Geboes K, Laurent S - PLoS ONE (2015)

Frequency of DNA copy number alterations of all 93 samples for the whole genome.Gains are represented in blue, losses in red.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519182&req=5

pone.0131421.g001: Frequency of DNA copy number alterations of all 93 samples for the whole genome.Gains are represented in blue, losses in red.
Mentions: After scoring of all tumour samples, 93 samples with at least 50% of tumour cells were retained for array-CGH analysis. Ninety out of these 93 colon carcinomas showed genomic alterations (Fig 1). Patients with an increased CEA level had more CNAs than patients with a normal CEA level at diagnosis (*P = 0.023) (Figure A in S3 File). CNAs in our patient cohort were less abundant in MSI patients than in MSS patients, as evaluated by 180K array-CGH (*P = 0.016) (Figure B in S3 File). All the MSI patients had less than ten alterations, whereas the mean number of alterations for the overall patient cohort is 12.98 (± 0.982). When we looked for alterations in the different tumour stages, we found a higher number of alterations for the MSI patient only in stage IV, while in the other tumour stages, MSI patients had less CNAs compared to MSS patients (**P = 0.003) (Figure C in S3 File). Clustering analysis identified no statistically significant relationship between cluster groups (based on one or more specific alteration) and any clinical parameter in our database (S1 Fig).

Bottom Line: For instance, the benefit of adjuvant chemotherapy has been most clearly demonstrated in stage III disease with an approximately 30 percent relative reduction in the risk of disease recurrence.Most interestingly, above mentioned characteristics were also found in stage II patients, for whom there is a high medical need for the identification of new prognostic biomarkers.In conclusion, copy number variation of the 16p13.3 locus seems to be an important parameter for prediction of disease recurrence in colon cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology-Digestive Oncology, Ghent University Hospital, Ghent, Belgium.

ABSTRACT

Background: With one million new cases of colorectal cancer (CRC) diagnosed annually in the world, CRC is the third most commonly diagnosed cancer in the Western world. Patients with stage I-III CRC can be cured with surgery but are at risk for recurrence. Colorectal cancer is characterized by the presence of chromosomal deletions and gains. Large genomic profiling studies have however not been conducted in this disease. The number of a specific genetic aberration in a tumour sample could correlate with recurrence-free survival or overall survival, possibly leading to its use as biomarker for therapeutic decisions. At this point there are not sufficient markers for prediction of disease recurrence in colorectal cancer, which can be used in the clinic to discriminate between stage II patients who will benefit from adjuvant chemotherapy. For instance, the benefit of adjuvant chemotherapy has been most clearly demonstrated in stage III disease with an approximately 30 percent relative reduction in the risk of disease recurrence. The benefits of adjuvant chemotherapy in stage II disease are less certain, the risk for relapse is much smaller in the overall group and the specific patients at risk are hard to identify.

Materials and methods: In this study, array-comparative genomic hybridization analysis (array-CGH) was applied to study high-resolution DNA copy number alterations in 93 colon carcinoma samples. These genomic data were combined with parameters like KRAS mutation status, microsatellite status and clinicopathological characteristics.

Results: Both large and small chromosomal losses and gains were identified in our sample cohort. Recurrent gains were found for chromosome 1q, 7, 8q, 13 and 20 and losses were mostly found for 1p, 4, 8p, 14, 15, 17p, 18, 21 and 22. Data analysis demonstrated that loss of chromosome 4 is linked to a worse prognosis in our patients series. Besides these alterations, two interesting small regions of overlap were identified, which could be associated with disease recurrence. Gain of the 16p13.3 locus (including the RNA binding protein, fox-1 homolog gene, RBFOX1) was linked with a worse recurrence-free survival in our patient cohort. On the other hand, loss of RBFOX1 was only found in patients without disease recurrence. Most interestingly, above mentioned characteristics were also found in stage II patients, for whom there is a high medical need for the identification of new prognostic biomarkers.

Conclusions: In conclusion, copy number variation of the 16p13.3 locus seems to be an important parameter for prediction of disease recurrence in colon cancer.

No MeSH data available.


Related in: MedlinePlus