Term Paper on "Biochemistry the Effect of BRCA1 in Sporadic"

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In the second study, by a group in the Netherlands, on breast cancers from carriers of BRCA1 mutations and sporadic controls, van der Groep and his cohorts found that though 5% of all breast cancer cases are attributable to germline mutations in BRCA1 or BRCA2 genes, BRCA mutations in suspected carriers, may be missed. But breast carcinomas can be determined "with a high level of certainty as sporadic or related to BRCA1 germline mutations by using a decision tree with age, Ki67 and EGFR" (van der Groep, et al. 611).

In this study, in which 22 breast cancers from carriers of proved BRCA1 mutations out of 604 from sporadic controls evaluated, a 75% chance of BRCA1-related breast cancer was shown by the "probably BRCA1-related" class, with 82% of the BRCA1-related cases but only 1.4% of the sporadic cases (van der Groep 611).

The third study, in Korea, investigated the role of BRCA1 and BRCA2 mutations with sporadic breast cancer in 793 breast cancer patients who were analyzed by denaturing high performance liquid chromatography and direct sequencing. The 793 breast cancer patients enrolled in this study by Han, et al., had no family history or first-or second-degree relatives with breast cancer.

Han, et al. identified seventy-nine different sequence variations, of which 34 were novel. Eleven frameshift mutations and 4 nonsense mutations (seven in BRCA1 and eight in BRCA2 out of fifteen deleterious mutations were detected in 20 out of 793 patients (2.5%). There were no recurrent or founder mutations in BRCA mutation screening. Of 793 patients, the clinicopathological information was obtained in 135 patients, including 20 deleterious mutation-positive and 115 deleterious mutation-negative groups (Han, et al. 496).

When age at diagnosis, histologic type, histologic grade and T. stage were evaluated, there was no statistical difference between the groups. While BRCA-mutation-associated tumors showed lower estrogen receptor, progesterone receptor, and HER-2/neu but higher p53 expression, poor prognostic features were noted in BRCA-associated tumors (496). The prevalence of germline deleterious mutations and a lower prevalence of BRCA mutations (2.5%) were similar to previous studies on BRCA1 and BRCA2 mutations in Korean patients with sporadic breast cancer (500).

The peak age of Korean women diagnosed with breast cancer is 15-20 years, quite a bit younger than those in the United States, suggesting racial differences and genetic variations may play a role in the frequency of breast cancer found (496). This study revealed other racially-marked deleterious mutations, 34 of which have not been reported previously and may be of Korean-specific origin (501).

In each study, detailed description of the findings were recorded and compared to other like finding in similar studies. In each, the DNA columns were subjected to tests in controlled environments and compared to other profiles, such as the Breast Cancer Information Core. Tables of values of features found in the breast cancers were evaluated and put into tables, according to Sporadic, Intermediate risk, High risk, BRCA1 mutation and BRCA2 mutations. Probability studies according to each category were also created.

Surprisingly, closely similar findings were described in each of the three studies, though scientists doing the studies expected to find these results. In the Netherlands study, they described for the first time the high expression of EGFR in breast cancers related to BRCA1 or BRCA2 mutations (van der Groep, et al. 615). In the Korean study, BRCA-associated tumors showed lower ER, PR, and HER-2/neu and higher p53 expression, findings in accordance with previous studies, though the ages of the subjects were found to be younger than those of other studies. Also, in the Korean study, BRCA1 and BRCA2 mutations did not identify any of the founder mutations common to western populations, though they admit that more population-based studies need to be done. They found that the BRCA1 anomaly had characteristics indicating either higher mitotic activity or no tubule formation, often with lymphocytic infiltration. In all cases, BRCA2 mutations were invasively cancerous. There were other factors that each study admitted had influences on analysis, such as sporadic carcinogenetic pathways, age, family history and estrogen and progesterone receptors. The Netherlands study added that the expression of Ki57 and EGFR was found to be related to sporadic cancer. The Icelandic study found phenotypic similarities between BRCA1 methylated and familial BRCA1 breast tumors (Birgisdotter, et al. 9).

In conclusion in all studies, in the "probably sporadic" cancers it was highly probable that they were related to BRCA1. There were differing variables for each study, but the Netherlands study found that in the high-risk group EGFR expression was similar to the heredity cases (12/15, 80%) (van der Groep 614)

Each study found that with increasing risk of hereditary disease, age, estrogen and progesterone receptor expression decreased, whereas other variables, such as MAI, grade and Ki67, p53, and cyclin a expression increased.

In the Netherlands study it was found that significant (p,0.0001) increase in the frequency of EGFR expression in cancers was associated with BRCA1 (14/21, 67%) and BRCA2 mutations (5/5, 100%), than in sporadic cancers (70/430, 16%). EGFR expression remained steady. They found no relationship between tumor size and HER-2/neu, p27, p21 and cyclin D1 expression (van der Groep 613). All cases with BRCA2 mutations showed very low p53 expression, whereas cases with sporadic cancer and BRCA1 mutations showed an average of 11% and 46% of positive nuclei, respectively (van der Groep, et al. 614).

The Korean study found that BRCA-associated tumors showed lower ER, PR, and HER-2/neu and higher p53 expression, as did the other studies, with poor prognostic features were noted in BRCA-associated tumors. They determined that neither hormone receptors nor HER-2/neu stimulation suggest important differences in the pathogenesis of cancers arising in mutation carriers. "A reasonable explanation for these results is that p53 loss rescues the proliferative deficiency of BRCA mutant cells at the expense of genetic instability" (Han, et al. 500).

While the BRCA1 mutation plays a key role in the incidence of sporadic breast cancer, as the Korean and Netherland studies found, the Icelandic study results also implied that methylation of the BRCA1 gene is genomically rearranged at the BRCA1 locus, "resulting in loss of genetic material containing nonmethylated BRCA1 alleles and retention of methylated BRCA1 alleles" (Birgisdottir 9). They also found the variable that a higher number of TP53 mutations were… READ MORE