Prognostically relevant cluster groups, based on gene expression profiles, have been recently identified for breast cancers, lung cancers, and lymphoma. Our aim was to determine whether hierarchical clustering analysis of multiple immunomarkers (protein expression profiles) improves prognostication in patients with invasive breast cancer. A cohort of 438 sequential cases of invasive breast cancer with median follow-up of 15.4 years was selected for tissue microarray construction. A total of 31 biomarkers were tested by immunohistochemistry on these tissue arrays. The prognostic significance of individual markers was assessed by using Kaplan-Meier survival estimates and log-rank tests. Seventeen of 31 markers showed prognostic significance in univariate analysis (P < 0.05) and 4 markers showed a trend toward significance (P < 0.2). Unsupervised hierarchical clustering analysis was done by using these 21 immunomarkers, and this resulted in identification of three cluster groups with significant differences in clinical outcome. 2 analysis showed that expression of 11 markers significantly correlated with membership in one of the three cluster groups. Unsupervised hierarchical clustering analysis with this set of 11 markers reproduced the same three prognostically significant cluster groups identified by using the larger set of markers. These cluster groups were of prognostic significance independent of lymph node metastasis, tumor size, and tumor grade in multivariate analysis (P ؍ 0.0001). The cluster groups were as powerful a prognostic indicator as lymph node status. This work demonstrates that hierarchical clustering of immunostaining data by using multiple markers can group breast cancers into classes with clinical relevance and is superior to the use of individual prognostic markers.
The RET proto-oncogene encodes a transmembrane receptor with tyrosine kinase activity. Germline mutations in RET are responsible for a number of inherited diseases. These include the dominantly inherited cancer syndromes multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (FMTC), as well as some cases of familial Hirschsprung disease (HSCR1). RET mutations in HSCR1 have been shown to cause a loss of RET function, while the cancer syndromes result in RET oncogenic activation. Occasionally MEN 2A or FMTC occurs in association with HSCR1, albeit with low penetrance. An initial report linked HSCR1 in MEN 2A solely to the C618R and C620R RET mutations. In this study we have analyzed 44 families with MEN 2A. HSCR1 co-segregated with MEN 2A in seven (16%) of the 44 families. The predisposing RET mutation in all seven families had been previously reported in MEN 2A or FMTC and occurred in exon 10 at codons 609, 618 or 620, resulting in C609Y, C618S, C620R or C620W substitution. MEN 2A families with RET exon 10 Cys mutations had a substantially greater risk of developing HSCR1 than those with the more common RET exon 11 Cys634 or exon 14 c804 mutations (P = 0.0005). These findings suggest that expression of HSCR1 in MEN 2A may be peculiar to RET exon 10 Cys mutations . However, HSCR1 in MEN 2A is not exclusive to C618R or C620R RET mutations and can occur with other exon 10 Cys amino acid substitutions. The strong correlation between disease phenotype and position of the MEN 2A RET mutation suggests that oncogenic activation of RET alone is insufficient to account for co-expression of the diseases.
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