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Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors.

Weber F, Fukino K, Sawada T, Williams N, Sweet K, Brena RM, Plass C, Caldes T, Mutter GL, Villalona-Calero MA, Eng C - Br. J. Cancer (2005)

Bottom Line: Organ-specific differences in epidermal growth factor receptor (EGFR) mutational spectra and frequencies were found in lung cancer and sporadic and BRCA1/2-related breast cancers.Additionally, we found a high frequency of EGFR mutations in the tumour stroma of these invasive breast carcinomas.Those organ-specific mutational spectra and potential targets in the cancer-associated stroma might influence the efficacy of TKI therapy.

View Article: PubMed Central - PubMed

Affiliation: Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

ABSTRACT
Organ-specific differences in epidermal growth factor receptor (EGFR) mutational spectra and frequencies were found in lung cancer and sporadic and BRCA1/2-related breast cancers. Additionally, we found a high frequency of EGFR mutations in the tumour stroma of these invasive breast carcinomas. Those organ-specific mutational spectra and potential targets in the cancer-associated stroma might influence the efficacy of TKI therapy.

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Somatic EGFR mutations in the epithelium or stroma of sporadic and hereditary breast carcinomas. Each of the four columns (A–D, E–H, I–L and M–P) represents one EGFR mutation-positive sample and the corresponding images taken during the LCM process. The sample codes corresponding to Table 1 are indicated below each set of chromatograms. Each set of chromatograms (A, E, I and M) shows the control (wild-type) sequence in the top row, followed by the sequence of the mutation-negative compartment. The heterozygous mutation and surrounding sequences are shown in forward (f) and reverse (r) directions in the bottom two rows. The first column shows sample H2, harbouring a somatic D761N mutation in the tumour epithelium (A, f and r) but not tumour stroma (mut. neg. in A). Image (B) shows an overview of this tumour (H&E, × 100 and × 200) and images (C) and (D) confirm that we accurately captured stroma (C) and epithelium (D). The second column shows the chromatograms (E) and tissue image (F) of sample H9, harbouring the somatic Q791R mutation in the stroma (f and r in (E)) but not epithelium (E, mut. neg.). The corresponding images (G) and (H) depict the captured epithelium (G) and the tissue image after extraction of the epithelial component by LCM (H). The third column represents the sporadic breast adenocarcinoma sample S1 (J) with a somatic T693A mutation in the stromal compartment (I, f and r) but not epithelium (mut. neg. in (I)). Again, images (K) and (L) verify the separation of tumour epithelium (L) and stroma (K). The last column shows sample S13 harbouring a W817X mutation in the tumour epithelium (M, f and r) but not stroma (M, mut. neg.). The neoplastic epithelium is microdissected (O) out of the whole tumour section (N), leaving the stromal compartment (P).
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fig2: Somatic EGFR mutations in the epithelium or stroma of sporadic and hereditary breast carcinomas. Each of the four columns (A–D, E–H, I–L and M–P) represents one EGFR mutation-positive sample and the corresponding images taken during the LCM process. The sample codes corresponding to Table 1 are indicated below each set of chromatograms. Each set of chromatograms (A, E, I and M) shows the control (wild-type) sequence in the top row, followed by the sequence of the mutation-negative compartment. The heterozygous mutation and surrounding sequences are shown in forward (f) and reverse (r) directions in the bottom two rows. The first column shows sample H2, harbouring a somatic D761N mutation in the tumour epithelium (A, f and r) but not tumour stroma (mut. neg. in A). Image (B) shows an overview of this tumour (H&E, × 100 and × 200) and images (C) and (D) confirm that we accurately captured stroma (C) and epithelium (D). The second column shows the chromatograms (E) and tissue image (F) of sample H9, harbouring the somatic Q791R mutation in the stroma (f and r in (E)) but not epithelium (E, mut. neg.). The corresponding images (G) and (H) depict the captured epithelium (G) and the tissue image after extraction of the epithelial component by LCM (H). The third column represents the sporadic breast adenocarcinoma sample S1 (J) with a somatic T693A mutation in the stromal compartment (I, f and r) but not epithelium (mut. neg. in (I)). Again, images (K) and (L) verify the separation of tumour epithelium (L) and stroma (K). The last column shows sample S13 harbouring a W817X mutation in the tumour epithelium (M, f and r) but not stroma (M, mut. neg.). The neoplastic epithelium is microdissected (O) out of the whole tumour section (N), leaving the stromal compartment (P).

Mentions: In total, seven somatic missense mutations were detected in seven (14.6%) of 48 sporadic breast cancer samples. No correlation was detected between tumour grade and mutation status. We identified 14 missense mutations in 11 (45.8%) of 24 breast cancers from BRCA1/2 mutation carriers (Figures 1 and 2, Table 1). Thus, the frequency of EGFR mutations was significantly higher in BRCA1/2-related breast cancers compared to that in sporadic ones (P=0.0079). In addition, three silent mutations that did not alter the amino acid were identified in three hereditary breast cancer samples, of which two also harboured other missense mutations. There was no difference in the frequency of EGFR mutations between BRCA1- (eight out of 17, 47%) and BRCA2- (three out of seven, 43%) related breast cancers (P=1.0). It is noteworthy that, among the 11 BRCA1/2-related breast cancers with EGFR somatic mutations, eight (72.7%) were located exclusively in the stroma (Table 2, Figure 1). Similarly, of the seven sporadic breast cancers with somatic EGFR mutations, four (57.1%) had mutations only in the stroma (Table 2, Figures 1 and 2). Furthermore, 57% (eight out of 14 hereditary, four out of seven sporadic) of all mutations were located in exon 20. In addition, we identified 10 somatic intronic single-nucleotide variants (ISNV) in seven of 24 (29.2%) hereditary breast cancers and nine ISNV in seven out of 48 (14.6%) sporadic breast cancers. Finally, nonsense mutations were identified in one hereditary breast cancer and two sporadic breast cancers. No in-frame deletions as reported for NSCLC were identified in either hereditary or sporadic breast cancer samples.


Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors.

Weber F, Fukino K, Sawada T, Williams N, Sweet K, Brena RM, Plass C, Caldes T, Mutter GL, Villalona-Calero MA, Eng C - Br. J. Cancer (2005)

Somatic EGFR mutations in the epithelium or stroma of sporadic and hereditary breast carcinomas. Each of the four columns (A–D, E–H, I–L and M–P) represents one EGFR mutation-positive sample and the corresponding images taken during the LCM process. The sample codes corresponding to Table 1 are indicated below each set of chromatograms. Each set of chromatograms (A, E, I and M) shows the control (wild-type) sequence in the top row, followed by the sequence of the mutation-negative compartment. The heterozygous mutation and surrounding sequences are shown in forward (f) and reverse (r) directions in the bottom two rows. The first column shows sample H2, harbouring a somatic D761N mutation in the tumour epithelium (A, f and r) but not tumour stroma (mut. neg. in A). Image (B) shows an overview of this tumour (H&E, × 100 and × 200) and images (C) and (D) confirm that we accurately captured stroma (C) and epithelium (D). The second column shows the chromatograms (E) and tissue image (F) of sample H9, harbouring the somatic Q791R mutation in the stroma (f and r in (E)) but not epithelium (E, mut. neg.). The corresponding images (G) and (H) depict the captured epithelium (G) and the tissue image after extraction of the epithelial component by LCM (H). The third column represents the sporadic breast adenocarcinoma sample S1 (J) with a somatic T693A mutation in the stromal compartment (I, f and r) but not epithelium (mut. neg. in (I)). Again, images (K) and (L) verify the separation of tumour epithelium (L) and stroma (K). The last column shows sample S13 harbouring a W817X mutation in the tumour epithelium (M, f and r) but not stroma (M, mut. neg.). The neoplastic epithelium is microdissected (O) out of the whole tumour section (N), leaving the stromal compartment (P).
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fig2: Somatic EGFR mutations in the epithelium or stroma of sporadic and hereditary breast carcinomas. Each of the four columns (A–D, E–H, I–L and M–P) represents one EGFR mutation-positive sample and the corresponding images taken during the LCM process. The sample codes corresponding to Table 1 are indicated below each set of chromatograms. Each set of chromatograms (A, E, I and M) shows the control (wild-type) sequence in the top row, followed by the sequence of the mutation-negative compartment. The heterozygous mutation and surrounding sequences are shown in forward (f) and reverse (r) directions in the bottom two rows. The first column shows sample H2, harbouring a somatic D761N mutation in the tumour epithelium (A, f and r) but not tumour stroma (mut. neg. in A). Image (B) shows an overview of this tumour (H&E, × 100 and × 200) and images (C) and (D) confirm that we accurately captured stroma (C) and epithelium (D). The second column shows the chromatograms (E) and tissue image (F) of sample H9, harbouring the somatic Q791R mutation in the stroma (f and r in (E)) but not epithelium (E, mut. neg.). The corresponding images (G) and (H) depict the captured epithelium (G) and the tissue image after extraction of the epithelial component by LCM (H). The third column represents the sporadic breast adenocarcinoma sample S1 (J) with a somatic T693A mutation in the stromal compartment (I, f and r) but not epithelium (mut. neg. in (I)). Again, images (K) and (L) verify the separation of tumour epithelium (L) and stroma (K). The last column shows sample S13 harbouring a W817X mutation in the tumour epithelium (M, f and r) but not stroma (M, mut. neg.). The neoplastic epithelium is microdissected (O) out of the whole tumour section (N), leaving the stromal compartment (P).
Mentions: In total, seven somatic missense mutations were detected in seven (14.6%) of 48 sporadic breast cancer samples. No correlation was detected between tumour grade and mutation status. We identified 14 missense mutations in 11 (45.8%) of 24 breast cancers from BRCA1/2 mutation carriers (Figures 1 and 2, Table 1). Thus, the frequency of EGFR mutations was significantly higher in BRCA1/2-related breast cancers compared to that in sporadic ones (P=0.0079). In addition, three silent mutations that did not alter the amino acid were identified in three hereditary breast cancer samples, of which two also harboured other missense mutations. There was no difference in the frequency of EGFR mutations between BRCA1- (eight out of 17, 47%) and BRCA2- (three out of seven, 43%) related breast cancers (P=1.0). It is noteworthy that, among the 11 BRCA1/2-related breast cancers with EGFR somatic mutations, eight (72.7%) were located exclusively in the stroma (Table 2, Figure 1). Similarly, of the seven sporadic breast cancers with somatic EGFR mutations, four (57.1%) had mutations only in the stroma (Table 2, Figures 1 and 2). Furthermore, 57% (eight out of 14 hereditary, four out of seven sporadic) of all mutations were located in exon 20. In addition, we identified 10 somatic intronic single-nucleotide variants (ISNV) in seven of 24 (29.2%) hereditary breast cancers and nine ISNV in seven out of 48 (14.6%) sporadic breast cancers. Finally, nonsense mutations were identified in one hereditary breast cancer and two sporadic breast cancers. No in-frame deletions as reported for NSCLC were identified in either hereditary or sporadic breast cancer samples.

Bottom Line: Organ-specific differences in epidermal growth factor receptor (EGFR) mutational spectra and frequencies were found in lung cancer and sporadic and BRCA1/2-related breast cancers.Additionally, we found a high frequency of EGFR mutations in the tumour stroma of these invasive breast carcinomas.Those organ-specific mutational spectra and potential targets in the cancer-associated stroma might influence the efficacy of TKI therapy.

View Article: PubMed Central - PubMed

Affiliation: Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

ABSTRACT
Organ-specific differences in epidermal growth factor receptor (EGFR) mutational spectra and frequencies were found in lung cancer and sporadic and BRCA1/2-related breast cancers. Additionally, we found a high frequency of EGFR mutations in the tumour stroma of these invasive breast carcinomas. Those organ-specific mutational spectra and potential targets in the cancer-associated stroma might influence the efficacy of TKI therapy.

Show MeSH
Related in: MedlinePlus