Epidermal growth factor receptor in non small cell lung cancer: Gene copy number and mutational study

Colomer A1, Erill N1, Verdú M2, Román R 1, Górriz M2, Ibáñez R1, Menoyo A1, Cordon-Cardo C3, Puig X 1,2.

1BIOPAT, Grup Assistència, 2HISTOPAT Laboratoris, Barcelona, Spain; and 3Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, United States.

Background: Activating mutations of the EGFR gene were identified in tumors from patients with non small cell lung cancer (NSCLC) that responded to therapy with tyrosine kinase inhibitors (TKIs). More recently, survival has been reported to significantly increase amongst patients carrying a high number of copies of EGFR gene after treatment with erlotinib in comparison with those receiving placebo. Thus, there is a need to tailor individual treatments based on EGFR molecular profile.

Design: For this retrospective study, characterization of the EGFR gene was performed on formalin-fixed, paraffin-embedded specimens. The series included 83 tumors obtained from patients with NSCLC (72 men and 11 women). Concerning histopathology, lesions were classified as adenocarcinoma (AC), bronchioloalveolar carcinoma (BAC), adenosquamous carcinoma, squamous cell carcinoma, or large cell undifferentiated carcinoma. Gene copy number was assessed by dual-color FISH using both a centromeric probe (CEP7) and a locus specific probe (EGFR LSI). Mutational study was conducted by PCR followed by bidirectional sequencing of exons 18 to 21.

Results: By FISH, 42 out of 76 evaluable cases (55%) were found to carry a high copy gene number of EGFR (ratio LSI/CEP7 ≥2 or gene copies ≥4 per tumoral nuclei). Of those, 9 (21%) were found to be amplified while 33 (79%) exhibited high polysomy (in ≥40% of tumoral nuclei). Out of 34 cases with a low copy gene number, 14 (41%) had disomy and the other 20 (59%) had trisomy or low polysomy (in <40% of tumoral nuclei). Neither histologic type (AC including BAC versus others) nor gender did significantly correlate with gene copy number of EGFR. By sequencing, 3 activating mutations were detected out of 71 evaluable cases (4%) corresponding to large exon 19 deletions previously described (2 cases with delE746-A750 and 1 case with delL747-P753insS). Mutated cases were 2 AC and 1 BAC, all them from women who carried a high copy number of EGFR (2 with high polysomy and 1 with amplification).

Conclusion: In our series, FISH allowed identifying 55% of patients likely to benefit from TKIs therapies. Our results suggest that FISH is a better choice than sequencing to assist in discerning EGFR molecular profile of NSCLC. Further studies should be conducted to elucidate the role of EGFR alterations in the prognosis of NSCLC.

Texto completo

Abstract exhibited at the:

95th ANNUAL MEETING OF THE UNITED STATES AND CANADIAN ACADEMY OF PATHOLOGY.

11-17 February, 2006. Atlanta-USA.

Abstract in:

Modern Pathology 2006; 19: 1424-25

2006-02-23T17:52:21+00:00