Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1997-12-03
2003-09-09
Souaya, Jehanne (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S023100, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06617104
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to the field of human genetics. Specifically, the present invention relates to the discovery that some alleles of the A-T gene cause susceptibility to cancer, in particular breast cancer. More specifically, the present invention relates to germline mutations in the A-T gene and their use in the diagnosis of predisposition to breast cancer. The invention further relates to somatic mutations in the A-T gene in human breast cancer and their use in the diagnosis and prognosis of human breast cancer.
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography.
Breast cancer is a frequent cancer; there are approximately 183,00 new cases and 46,000 deaths from this cancer each year in the United States. It is the second most common cancer among women today, ranking only behind lung cancer. It has been estimated that the lifetime risk for a woman to develop breast cancer is about 1 in 9, although this figure must be interpreted with caution because not every women lives to age 100.
Breast cancer is treated by surgery, radiation therapy, and chemotherapy. New approaches to treatment have improved the survival of women with diagnosed breast cancer. Still, the most reliable approach to reducing mortality from this cancer is to detect it so early that treatment is more effective. It is well established that screening women by mammography beginning at age 50 leads to a substantial reduction in mortality from this cancer.
The concept that women in certain families were more likely to develop breast cancer than women in other families was noted in antiquity, observed several times in the ninteenth century, and established by family studies in the twentieth century. The observation of familial disposition to breast cancer had modest practical consequences because nothing could be done to decrease the risk of breast cancer for women in high risk families and there was no evidence that knowledge about this problem improved survival. Indeed, one could make a case that the awareness of familial predisposition led primarily to increased anxiety while having limited practical benefit.
In general, there are more cases of breast cancer among first and second degree relatives of breast cancer patients than would be expected according to the incidence of breast cancer in the general population. In a minority of families, the incidence of female breast cancer is so high that the pattern appears to follow a Mendelian autosomal dominent pattern of inheritance. Two genes, BRCA1 and BRCA2, have been shown responsible for the breast cancers in about two-thirds of families in which there are four or more cases of breast cancer. These genes have each been cloned and sequenced. A commercial laboratory, Myriad Genetics, now offers to test individuals to see if they carry BRCA1 or BRCA2, based on sequencing of the DNA from the individuals who are tested. Such testing will be valuable to those women—probably less than 1% of the population—who come from families in which the density of breast cancer is high.
The ataxia-telangiectasia (A-T) gene represents another approach to identifying a gene responsible for some breast cancers. This gene was first recognized because it causes a distinctive autosomal recessive syndrome characterized by cerebellar ataxia and oculocutaneous telangiectasia in children who have two copies of this gene (Swift, 1993). A great deal has been learned about the clinical features and laboratory findings in A-T since its description in the late 1950s. One of the most important facts to emerge was that patients with A-T (who will be called A-T homozygotes) developed cancer at a rate approximately 100-fold greater than children of the same age who do not have A-T (Morrell et al., 1986). It also became evident that the A-T gene makes homozygous patients and their cells many-fold more sensitive to the harmful effects of ionizing radiation. Lymphoid cancers predominate in childhood, while epithelial cancers including breast cancer are seen in adolescent and young adult A-T patients (Swift et al., 1990b).
Still, A-T homozygotes are rare and this gene might be of only theoretical interest except for the series of studies that suggested and now have confirmed that A-T heterozygotes, who constitute approximately 1.4% of the population, are also predisposed to cancer. The first evidence for this came from a study in the early 1970s in which it was shown that the cancer mortality in A-T blood relatives exceeded that of spouse controls in the same families by a statistically significant amount (Swift et al., 1976). This hypothesis was confirmed further by the retrospective analysis of 110 Caucasian A-T families in the United States in which there was a highly significant excess of cancer in the blood relatives when the incidence was compared to that in spouse controls. This study, published in 1987, provided the first evidence that the A-T gene predisposed to breast cancer. (Swift et al., 1987) Further support for the hypothesis was provided by a large scale prospective study of cancer incidence in A-T blood relatives and spouse controls published in 1991 (Swift et al., 1991), and by other smaller studies including two independent studies in Europe (Morrell et al., 1990; Peppard et al., 1988; Borresen et al., 1990).
The interpretation of these previous studies is limited by the facts that not all A-T blood relatives carry the A-T gene and by the inevitable question of how well the spouse controls are matched to the blood relatives. Though the study methods were standard, these limitations on interpretation remained. Further, findings from these earlier studies were characterized by several scientists as “a controversial suggestion,” (Kasten, 1995) “a possibility,” (Savitsky et al., 1995; Collins, 1996) or, “just a hypothesis” (Boice, 1995).
Thus, it is important to confirm that the A-T gene is associated with breast cancer using the best available genetic methods and identifying mutations in the A-T gene in families with breast cancer.
SUMMARY OF THE INVENTION
The present invention relates generally to the field of human genetics. Specifically, the present invention relates to the discovery that some alleles of the A-T gene cause susceptibility to cancer, in particular breast cancer. More specifically, the present invention relates to germline mutations in the A-T gene and their use in the diagnosis of predisposition to breast cancer. The invention further relates to somatic mutations in the A-T gene in human breast cancer and their use in the diagnosis and prognosis of human breast cancer.
In accordance with the present invention, the hypothesis that A-T heterozygotes are predisposed to breast cancer has now been confirmed with unassailable rigor by collecting a group of female blood relatives with breast cancer in A-T families and testing DNA from each of these individuals to determine which of them carried the A-T gene. The method utilized highly polymorphic, tightly linked flanking markers (Gatti et al., 1994) and the index-test method (Swift et al., 1990a).
In addition, the association of the A-T gene with breast cancer is conclusively established by the identification of specific germline mutations in the A-T gene in families with breast cancer.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates generally to the field of human genetics. Specifically, the present invention relates to the discovery that some alleles of the A-T gene cause susceptibility to cancer, in particular breast cancer. More specifically, the present invention relates to germline mutations in the A-T gene and their use in the diagnosis of predisposition to breast cancer. The invention further relates to somatic mutations in the A-T gene in human breast cance
McKenna Long & Aldridge LLP
Souaya Jehanne
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