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Association of candidate single nucleotide polymorphisms with somatic mutation of the epidermal growth factor receptor pathway.

Wormald S, Milla L, O'Connor L - BMC Med Genomics (2013)

Bottom Line: Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics such as cetuximab extends survival in only 25% of patients who test wild-type for KRAS, while the majority of patients prove resistant (J Clin Oncol 28(7):1254-1261, 2010).Prediction of cetuximab responsiveness for KRAS wild-type colorectal cancers is currently not well defined, and prognostic biomarkers would help tailor treatment to individual patients.We show that allelic variants of rs7736074 and rs4975596 modulate TERT expression levels in multiple cancer types, and exhibit preliminary prognostic value for response to cetuximab.These variants could potentially contribute to a panel of prognostic biomarkers for assessing whether metastatic colorectal cancer patients are likely to derive benefit from cetuximab treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Systems Biology and Personalized Medicine, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. wormald@wehi.edu.au.

ABSTRACT

Background: Tumour growth in colorectal cancer and other solid cancers is frequently supported by activating mutations in the epidermal growth factor receptor (EGFR) signaling pathway (Patholog Res Int 2011:932932, 2011). Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics such as cetuximab extends survival in only 25% of patients who test wild-type for KRAS, while the majority of patients prove resistant (J Clin Oncol 28(7):1254-1261, 2010).Prediction of cetuximab responsiveness for KRAS wild-type colorectal cancers is currently not well defined, and prognostic biomarkers would help tailor treatment to individual patients. Somatic mutation of the EGFR signalling pathway is a prevalent mechanism of resistance to cetuximab (Nature 486(7404):532-536, 2012). If the human genome harbours variants that influence susceptibility of the EGFR pathway to oncogenic mutation, such variants could also be prognostic for cetuximab responsiveness.

Methods: We assessed whether patient genetic variants may associate with somatic mutation of the EGFR signalling pathway. We combined tumour mutation data from the Cancer Genome Atlas with matched patient genetic data, and tested for germline variants that associate with somatic mutation of the EGFR pathway (including EGFR, KRAS, BRAF, PTEN and PIK3CA).

Results: Two single nucleotide polymorphisms (SNPs) located 90 kb upstream of the TERT oncogene associated with somatic mutation of the EGFR pathway beyond the threshold of genome-wide significance: rs7736074 (P = 4.64 × 10-9) and rs4975596 (P = 5.69 × 10-9). We show that allelic variants of rs7736074 and rs4975596 modulate TERT expression levels in multiple cancer types, and exhibit preliminary prognostic value for response to cetuximab.

Conclusions: We have identified two germline SNPs that associate with somatic mutation of the EGFR pathway, and may be prognostic for cetuximab responsiveness. These variants could potentially contribute to a panel of prognostic biomarkers for assessing whether metastatic colorectal cancer patients are likely to derive benefit from cetuximab treatment. Genotyping of a large cohort of cetuximab-treated colorectal cancer patients is called for to further clarify the association.

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Patient genotype numbers and odds ratios for the top five SNPs associated with EGFR pathway status combined across four cancer types (COAD, SKCM, THCA and UCEC). (A) Odds ratios for combined analysis. (B) Odds ratios for individual cancer types. Error bars indicate 95% confidence intervals. +++P < 5 × 10-9; ++P < 5 × 10-7; +P < 5 × 10-6; ***P < 5 × 10-4; **P < 5 × 10-3; *P < 0.05.
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Figure 2: Patient genotype numbers and odds ratios for the top five SNPs associated with EGFR pathway status combined across four cancer types (COAD, SKCM, THCA and UCEC). (A) Odds ratios for combined analysis. (B) Odds ratios for individual cancer types. Error bars indicate 95% confidence intervals. +++P < 5 × 10-9; ++P < 5 × 10-7; +P < 5 × 10-6; ***P < 5 × 10-4; **P < 5 × 10-3; *P < 0.05.

Mentions: We also identified three additional SNPs that appear suggestive based on visual inspection of the quantile distribution for SNP P values, despite failing to achieve genome-wide significance (Figure 1B). Of the top five SNPs identified, four were located on chromosome 5, and one on chromosome 22 (Table 2). Uniform effect sizes were observed both for the combined analysis (Figure 2A) and for individual cancer types (Figure 2B).


Association of candidate single nucleotide polymorphisms with somatic mutation of the epidermal growth factor receptor pathway.

Wormald S, Milla L, O'Connor L - BMC Med Genomics (2013)

Patient genotype numbers and odds ratios for the top five SNPs associated with EGFR pathway status combined across four cancer types (COAD, SKCM, THCA and UCEC). (A) Odds ratios for combined analysis. (B) Odds ratios for individual cancer types. Error bars indicate 95% confidence intervals. +++P < 5 × 10-9; ++P < 5 × 10-7; +P < 5 × 10-6; ***P < 5 × 10-4; **P < 5 × 10-3; *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016273&req=5

Figure 2: Patient genotype numbers and odds ratios for the top five SNPs associated with EGFR pathway status combined across four cancer types (COAD, SKCM, THCA and UCEC). (A) Odds ratios for combined analysis. (B) Odds ratios for individual cancer types. Error bars indicate 95% confidence intervals. +++P < 5 × 10-9; ++P < 5 × 10-7; +P < 5 × 10-6; ***P < 5 × 10-4; **P < 5 × 10-3; *P < 0.05.
Mentions: We also identified three additional SNPs that appear suggestive based on visual inspection of the quantile distribution for SNP P values, despite failing to achieve genome-wide significance (Figure 1B). Of the top five SNPs identified, four were located on chromosome 5, and one on chromosome 22 (Table 2). Uniform effect sizes were observed both for the combined analysis (Figure 2A) and for individual cancer types (Figure 2B).

Bottom Line: Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics such as cetuximab extends survival in only 25% of patients who test wild-type for KRAS, while the majority of patients prove resistant (J Clin Oncol 28(7):1254-1261, 2010).Prediction of cetuximab responsiveness for KRAS wild-type colorectal cancers is currently not well defined, and prognostic biomarkers would help tailor treatment to individual patients.We show that allelic variants of rs7736074 and rs4975596 modulate TERT expression levels in multiple cancer types, and exhibit preliminary prognostic value for response to cetuximab.These variants could potentially contribute to a panel of prognostic biomarkers for assessing whether metastatic colorectal cancer patients are likely to derive benefit from cetuximab treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Systems Biology and Personalized Medicine, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. wormald@wehi.edu.au.

ABSTRACT

Background: Tumour growth in colorectal cancer and other solid cancers is frequently supported by activating mutations in the epidermal growth factor receptor (EGFR) signaling pathway (Patholog Res Int 2011:932932, 2011). Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics such as cetuximab extends survival in only 25% of patients who test wild-type for KRAS, while the majority of patients prove resistant (J Clin Oncol 28(7):1254-1261, 2010).Prediction of cetuximab responsiveness for KRAS wild-type colorectal cancers is currently not well defined, and prognostic biomarkers would help tailor treatment to individual patients. Somatic mutation of the EGFR signalling pathway is a prevalent mechanism of resistance to cetuximab (Nature 486(7404):532-536, 2012). If the human genome harbours variants that influence susceptibility of the EGFR pathway to oncogenic mutation, such variants could also be prognostic for cetuximab responsiveness.

Methods: We assessed whether patient genetic variants may associate with somatic mutation of the EGFR signalling pathway. We combined tumour mutation data from the Cancer Genome Atlas with matched patient genetic data, and tested for germline variants that associate with somatic mutation of the EGFR pathway (including EGFR, KRAS, BRAF, PTEN and PIK3CA).

Results: Two single nucleotide polymorphisms (SNPs) located 90 kb upstream of the TERT oncogene associated with somatic mutation of the EGFR pathway beyond the threshold of genome-wide significance: rs7736074 (P = 4.64 × 10-9) and rs4975596 (P = 5.69 × 10-9). We show that allelic variants of rs7736074 and rs4975596 modulate TERT expression levels in multiple cancer types, and exhibit preliminary prognostic value for response to cetuximab.

Conclusions: We have identified two germline SNPs that associate with somatic mutation of the EGFR pathway, and may be prognostic for cetuximab responsiveness. These variants could potentially contribute to a panel of prognostic biomarkers for assessing whether metastatic colorectal cancer patients are likely to derive benefit from cetuximab treatment. Genotyping of a large cohort of cetuximab-treated colorectal cancer patients is called for to further clarify the association.

Show MeSH
Related in: MedlinePlus