Writing and Publishing Scientific Articles
5-16
Example of a Poorly Written Discussion (Basic Science Study)
Previous data suggested that BRCA1/2 mutation status influences the clinical characteristics and outcome in breast and ovarian cancers. However, mutations in these genes alone are unlikely to account for all of the variation observed; tumor formation results from an accumulation of somatic genetic alterations in several different genes, of which many may influence tumor phenotype. In support of this, some studies have shown associations between the clinical characteristics of tumors and multiple differences in gene expression (14). Previously, we determined the BRCA1 and BRCA2 mutation status in 288 epithelial ovarian cancer families (Ref. 3; unpublished data). The purpose of the study reported here was to establish whether the spectrum of somatic genetic events that may influence tumor phenotype during ovarian cancer development differs with respect to BRCA1/2 mutation status and/or a family history of the disease. To do this, we have compared the frequencies of genomic alterations identified using metaphase comparative genomic hybridization (CGH) between ovarian tumors from BRCA1 and BRCA2 mutation carriers, familial cases in which no BRCA1/2 mutation could be identified, and sporadic cases. Table 1 summarizes the frequencies with which genetic alterations were identified for each chromosome arm. Several alterations occurred with a particularly high frequency (in 42 – 76% of all tumors); these were losses on chromosomes 4q, 5q, 6q, 13q, 18q, and X and gains on chromosomes 1, 3q, 6p, 7q, 8q, 19q, and 20q. Several regions of relatively frequent loss or gains (in >30% of all tumors) were also identified. For most alterations, we were able to define single critical regions in common between tumors. In some cases, it was possible to define more than 1 region of interest (Table 1). High levels of amplifications were identified at several sites throughout the genome. In some instances, the same region of high-level amplification was common to multiple tumors, which possibly indicates the location of a single gene target. In general, high-level amplifications were not frequent events. However, they tended to occur in regions that also showed frequent gain, which may suggest a shared target (Table 2). We used 2 different approaches to determine whether the pattern of somatic genetic alterations during tumor development differs between BRCA1, BRCA2, familial non-BRCA1/2, and sporadic ovarian cancers. Firstly, we performed a systematic comparison of the frequency of genetic alterations between the 4 tumor groups. Secondly, we performed hierarchical cluster analysis to identify alterations that tended to occur together during tumor development. For the purpose of these analyses, we divided the genome into 100 nonoverlapping regions of similar size based on the 4´,6-diamidino-2-phenylindole banding on the CGH profile and recorded the presence of loss or gain at every region for each tumor. Significant differences in the frequency of loss or gain between 1 or more groups of tumors were identified at 20 different chromosome regions; in total, 41 significant differences were observed between the 4 groups (Table 3). Notably, deletions of the region containing the BRCA1 gene (17q12 – 21) were significantly more frequent in tumors from BRCA1 mutation carriers than in non-BRCA1 tumors (P = 0.014). Similarly, deletions of the region containing the BRCA2 gene (13q12 – 13) were significantly more frequent in tumors from BRCA2 mutation carriers than in non-BRCA2 tumors (P = 0.006). This is consistent with data from loss of heterozygosity studies, which indicate that deletion of the wild-type BRCA1 or BRCA2 allele is a frequent and nonrandom event in tumors from mutation carriers.
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