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Functional Pathway Characterized by Gene Expression Analysis of Supraclavicular Lymph Node Metastasis-Positive Breast Cancer

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Functional Pathway Characterized by Gene Expression Analysis of Supraclavicular Lymph Node Metastasis-Positive Breast Cancer J Hum Genet (2007) 52:271–279 DOI 10.1007/s10038-007-0111-z ORIGINAL ARTICLE Functional pathway characterized by gene expression analysis of supraclavicular lymph node metastasis-positive breast cancer Yoko Oishi Æ Koichi Nagasaki Æ Satoshi Miyata Æ Masaaki Matsuura Æ Sei-ichiro Nishimura Æ Futoshi Akiyama Æ Takehisa Iwai Æ Yoshio Miki Received: 25 November 2006 / Accepted: 22 December 2006 / Published online: 7 February 2007 Ó The Japan Society of Human Genetics and Springer 2007 Abstract The outcome of breast cancer patients with breast cancer patients with supraclavicular lymph node supraclavicular lymph node metastasis is generally metastasis by profiling cDNA microarrays. Thirty-one poor, but some patients do survive for a long time. breast cancer patients with supraclavicular lymph node Consequently, the ability to predict the outcome is metastasis without distant metastasis comprised the important in terms of choosing the appropriate therapy study cohort; these were divided into three groups for breast cancer patients with supraclavicular lymph based on prognosis – poor, intermediate, and good. node metastasis. In this study, we attempted to identify Two functional pathways, the Wnt signaling pathway functional pathways that determine the outcome of and the mitochondrial apoptosis pathway, were con- structed using six genes (DVL1, VDAC2, BIRC5, Stathmin1, PARP1, and RAD21) that were differently Electronic supplementary material The online version of this expressed between the good and poor outcome groups. article (doi:10.1007/s10038-007-0111-z) contains supplementary Our results indicate that these two functional pathways material, which is available to authorized users. may play an important role in determining the outcome Y. Oishi Á Y. Miki of breast cancer patients with supraclavicular lymph Department of Molecular Diagnosis, Cancer Institute, node metastasis. We also determined that immunohis- Japanese Foundation for Cancer Research, Tokyo, Japan tostaining for the Stathmin1 gene product is a potential tool for predicting the outcome of breast cancer K. Nagasaki Á S. Miyata Á M. Matsuura Á Y. Miki Genome Center, Japanese Foundation for Cancer Research, patients with supraclavicular lymph node metastasis. Tokyo, Japan Keywords Breast cancer Á Gene expression profiles Á F. Akiyama Functional pathway Á Poor outcome Á Supraclavicular Department Pathology, Cancer Institute, Japanese Foundation for Cancer Research, lymph node metastasis Tokyo, Japan Abbreviations S. Nishimura Sc Supraclavicular lymph node metastasis Department of Breast surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan DMFS Distant metastasis-free survival OS Overall survival Y. Oishi Á T. Iwai Department of Vascular Surgery, Tokyo Medical and Dental University, Tokyo, Japan Introduction Y. Miki (&) Breast cancer is the most frequently occurring type of Medical Research Institute, cancer among all of the gynecological cancers. Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan According to the 2003 vital statistics records on the e-mail: [email protected] Japanese population, the mortality rate from breast 123 272 J Hum Genet (2007) 52:271–279 cancer (15.2%) is increasing. There are many prog- new possibilities for the molecular characterization of nostic factors for breast cancer, such as lymph node cancer. There have been several reports related to the metastasis, hormone receptors, tumor size, pathologi- prediction of outcomes, such as the likelihood of cal grade, age, vascular invasion, and HER2/neu metastasis, using the gene expression pattern of the (Goldhirch et al. 2005); however, these clinicopatho- breast cancer primary lesion. Perou et al. (2000) car- logical factors do not enable an accurate prediction of ried out microarray analysis on samples collected from the outcome. the breast cancer primary lesion and lymph node In the search for a prognostic factor(s) using clinical metastasis lesion before and after preoperative che- samples, patients under consistent clinical conditions motherapy and found that the gene expression pattern are first selected and the factor(s) related to these pa- was similar in any one patient compared to the pattern tients’ prognosis is searched for. However, the clinical found in other patients. This suggests that common condition of any one patient, such as occurrence and ‘molecular portraits’ are present in individual cases of places of recurrence and the choice of therapeutic primary breast cancer and the metastatic lesion and methods and their effect on recurrence, differs greatly that the molecular portraits of primary lesions repre- from that of another patient. Therefore,in most of the sent the characteristics of the cancer, such as the like- earlier studies reported, factors responsible for regu- lihood of metastasis. lating prognosis were searched for by comparing the The aim of the present study was to carry out a prognosis of patients who had actually received dif- highly accurate search for a factor(s) predicting the ferent treatments. outcome of breast cancer with Sc(+). We therefore In the present study, we focused on breast cancer only used Sc(+)-positive tissue samples without dis- patients with supraclavicular lymph node metastasis tant metastasis, although this criterion severely lim- [Sc(+)]in order to avoid – or reduce as much as pos- ited the number of samples that could be obtained. sible – any influence of a difference in clinical condi- We then identified genes and functional pathways tion among the study cohort. Most breast cancer related to prognosis by profiling the gene expression patients diagnosed as Sc(+)-positive also have distant and pathway construction method in breast cancer metastasis and, consequently, a poor outcome. On the accompanied by Sc(+). Clarification of the gene other hand, the outcome of Sc(+)-positive breast can- expression patterns related to outcomes may reveal cer patients without distant metastasis varies from the direction to be taken for choosing individual relatively good, such as postoperative relapse in local therapeutic strategies. lymph nodes and bone, to poor, with a relapse in the lung, liver, and pleura. However, all Sc(+)-positive patients without distant metastasis are considered to be Materials and methods similar in terms of distribution of the cancer, and the difference between treatments of this patient popula- Patients and tissue samples tion is small. Of 35 patients diagnosed as Sc(+)-positive without distant metastasis at the Cancer Institute Primary breast cancers from 31 patients who under- Hospital (Tokyo, Japan) in the period 1996–2000, dis- went surgery at the Department of Breast Surgery, tant metastasis-free survival (DMFS) was shorter than Cancer Institute Hospital, Tokyo, between 1996 and 2 years and overall survival (OS) was shorter than 2002 were obtained and frozen immediately. Core 3 years in 13 patients (37.14%; poor outcome group). needle biopsy samples were obtained from the patients DMFS was longer than 2 years and OS was longer than with neoadjuvant therapy before treatment, and tissue 5 years in 12 patients (34.29%; good outcome group). samples from the patients without neoadjuvant therapy Because the mechanism of cancer development, pro- were excised at surgery. The samples were embedded gression, and metastasis involves the interaction of in O.C.T. compound (Sakura Finetek, Torrance, Calif.) many genes in a complex manner, the prognosis of and stored at –80°C. All patients were cytologically or each Sc(+)-positive patient is different; consequently, pathologically diagnosed with supraclavicular lymph the therapy of recurrent breast cancer should be dealt node metastasis. Patients diagnosed with a DMFS of with on an individual basis. Therefore, searching fac- longer than 2 years and an OS of longer than 5 years tors which characterize breast cancer with Sc(+) is very were grouped together as the ‘good outcome’ group important for choosing an individualized therapy. (11/31); patients with a predicted DMFS of shorter DNA microarray analysis is a revolutionary experi- than 2 years and an OS of shorter than 3 years were mental tool for analyzing gene expression compre- grouped together as the ‘poor outcome’ group (12/31); hensively, and gene expression profiling has created patients who did not meet these conditions were 123 J Hum Genet (2007) 52:271–279 273 Breast cancers with supraclavicular lymph node Table 1 Clinical and biological characteristics of 31 breast can- metastasis without distant metastasis(31 cases) cer patients with supraclavicular lymph node metastasis without distant metastasis Clinical/biological Good Poor Intermediate characteristics outcome outcome outcome DMFS<24M DMFS>24M of patientsa (15 cases) (16 cases) Ageb (years) 43–73 40–71 (55.3) 40–70 (57.8) (54.9) DMFSb 61–96 1–10 (8.5) 12–58 (34) OS<36M OS>36M OS<36M OS>36M OS>60M (12 cases) (3 cases) (1 cases) (4 cases) (11 cases) (70) <24 months – 12 3 Poor outcome Intermediate outcome Good outcome >24 months 11 – 5 OSb 61–96 10–17 (17.5) 35–58 (42) Fig. 1 The selection of patients included in the study. DMFS (78) Distant metastasis-free survival, OS overall survival. Patients <36 months – 12 1 with a DMFS of longer than 24 months and an OS of longer than >36 months 11 – 7 60 months were included in the ‘good outcome’ group; patients T1 0 1 3 with a DMFS of shorter than 24 months and an OS shorter than T2 10 8 3 36 months were included in the ‘poor outcome’ group; patients T3 1 3 1 who did not meet these conditions were included in the T4 0 0 1 ’intermediate outcome’ group Non-invasive ductal 000 carcinoma Invasive ductal 11 12 7 grouped together as the ‘intermediate outcome’ group carcinoma (8/31) (Fig. 1). The clinical backgrounds of the patients Other 0 0 1 ER are shown in Table 1 and Supplementary Table S1. Negative 4 6 3 Informed consent was obtained from all patients who Positive 7 6 5 provided samples. All of the procedures followed were PgR examined and approved by the Institutional Review Negative 6 7 4 Positive 5 5 4 Board of Cancer Institutional Hospital.
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