BRCA1 and pancreatic cancer: pedigree findings and their causal relationships

Anecdotal reports and series studies indicate that 5-10% of pancreatic cancer (PC) cases are familial. In addition, PC is associated with a variety of hereditary cancer syndromes. PC appears to be an integral cancer in the hereditary breast-ovarian cancer (HBOC) syndrome, with most notice given to the role of BRCA2. Our purpose is to call attention to BRCA1, which also predisposes to PC. Using data from our familial breast cancer registry, we identified 19 BRCA1/2 families that contain PC affecteds in the pedigrees, 15 with BRCA1 mutations and 4 with BRCA2 mutations. The association between BRCA2 and pancreatic cancer is well established; however, a definite link with pancreatic cancer in families carrying a BRCA1 mutation has been far less studied. Thus, the focus of this report is on 9 of the 15 BRCA1 families, in which PC affecteds were either confirmed carriers of the BRCA1 mutation or were inferred as probable obligate BRCA1 mutation carriers. The numbers are small, but nevertheless illustrate the finding of others of an apparent association between PC and BRCA1-mutation-bearing families. Given the dismal prognosis of PC, with the only current hope for survival being through surgical extirpation of the pancreas prior to metastasis, it is prudent that we realize the potential predisposition toward PC via BRCA1, in the hope of early diagnosis and prevention.     

Trisomy 3 in cold agglutinin disease

Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia generally considered to result from an antibody-producing clonal expansion of B lymphocytes. We studied 16 patients with CAD and demonstrated a chromosomally abnormal clone in the peripheral blood (PB) of six. Trisomy 3 was the only abnormality in two patients, trisomy 12 the only abnormality in one, and both trisomy 3 and trisomy 12 were present in three patients. A lymphoma was subsequently diagnosed in two of these six patients and in none of the patients without a karyotypic abnormality. The results suggest that trisomy 3 confers a slight growth advantage in the B-cell lineage, particularly at a relatively late stage of differentiation. The resultant clone may present clinically as CAD and, in some cases, progress to a clinical lymphoma.     

Hematopoietic progenitor cells and cellular microenvironment: behavioral and molecular changes upon interaction

Cell-cell contact between stem cells and cellular determinants of the microenvironment plays an essential role in controlling cell division. Using human hematopoietic progenitor cells (CD34+/CD38-) and a stroma cell line (AFT024) as a model, we have studied the initial behavioral and molecular sequel of this interaction. Time-lapse microscopy showed that CD34+/CD38- cells actively migrated toward and sought contact with stroma cells and 30% of them adhered firmly to AFT024 stroma through the uropod. CD44 and CD34 are colocalized at the site of contact. Gene expression profiles of CD34+/CD38- cells upon cultivation with or without stroma for 16, 20, 48, or 72 hours were analyzed using our human genome cDNA microarray. Chk1, egr1, and cxcl2 were among the first genes upregulated within 16 hours. Genes with the highest upregulation throughout the time course included tubulin genes, ezrin, c1qr1, fos, pcna, mcm6, ung, and dnmt1, genes that play an essential role in reorganization of the cytoskeleton system, stabilization of DNA, and methylation patterns. Our results demonstrate directed migration of CD34+/CD38- cells toward AFT024 and adhesion through the uropod and that upon interaction with supportive stroma, reorganization of the cytoskeleton system, regulation of cell division, and maintenance of genetic stability represent the most essential steps.     

Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites

To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (+/- SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197 +/- 31 vs. 536 +/- 58 nmol per liter; P less than 0.05) and the upright position (131 +/- 27 vs. 343 +/- 39 nmol per liter; P less than 0.05) and after exercise testing (96 +/- 12 vs. 185 +/- 23 nmol per liter; P less than 0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73 +/- 5 vs. 748 +/- 7 nmol per liter; P less than 0.01) and in the upright position (89 +/- 5 vs. 401 +/- 6 nmol per liter; P less than 0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740 +/- 737 vs. 2125 +/- 214 ml per minute; P less than 0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained.     

Two methods of whole-genome amplification enable accurate genotyping across a 2320-SNP linkage panel

Comprehensive genome scans involving many thousands of SNP assays will require significant amounts of genomic DNA from each sample. We report two successful methods for amplifying whole-genomic DNA prior to SNP analysis, multiple displacement amplification, and OmniPlex technology. We determined the coverage of amplification by analyzing a SNP linkage marker set that contained 2320 SNP markers spread across the genome at an average distance of 2.5 cM. We observed a concordance of >99.8% in genotyping results from genomic DNA and amplified DNA, strongly indicating the ability of both methods used to amplify genomic DNA in a highly representative manner. Furthermore, we were able to achieve a SNP call rate of >98% in both genomic and amplified DNA. The combination of whole-genome amplification and comprehensive SNP linkage analysis offers new opportunities for genetic analysis in clinical trials, disease association studies, and archiving of DNA samples.     

Fibrodysplasia ossificans progressiva: Still turning into wood after 300 years?

Fibrodysplasia ossificans progressiva (FOP), a rare autosomal dominant disorder, is characterized by symmetrical congenital skeletal abnormalities and progressive heterotopic ossification of the connective tissues. At present, more than 300 years after the first report by Patin in 1648 in which he described the woman who turned to wood, its pathogenesis remains largely unknown and its therapy is limited to symptom-modifying trials. However, significant progress has been recently made and new data on the molecular organization and regulation of normal and disordered bone induction are likely to lead to a more specific therapy. FOP is believed to be a genetic disorder characterized by a disturbed expression of the endochondral osteogenesis programme, and the remarkable clues from the fly reported by Kaplan et al. [8] in 1990 suggest a gain-of-function mutation in the genetic regulation of bone morphogenetic proteins.     

Sex hormones and headache

The normal female life cycle is associated with a number of hormonal milestones: menarche, pregnancy, contraceptive use, menopause, and the use of replacement sex hormones. Menarche marks the onset of menses and cyclic changes in hormone levels. Pregnancy is associated with rising noncyclic levels of sex hormones, and menopause with declining noncyclic levels. Hormonal contraceptive use during the reproductive years and hormone replacement in menopause are therapeutic hormonal interventions that alter the levels and cycling of sex hormones. These events and interventions may cause a change in the prevalence or intensity of headache. The menstrual cycle is the result of a carefully orchestrated sequence of interactions between the hypothalamus, pituitary, ovary, and endometrium, with the sex hormones acting as modulators and effectors at each level. Estrogen and progestins have potent effects on central serotonergic and opioid neurons, modulating both neuronal activity and receptor density. The primary trigger of Menstrually-related migraine (MM) appears to be the withdrawal of estrogen rather than the maintenance of sustained high or low estrogen levels. However, changes in the sustained estrogen levels with pregnancy (increased) and menopause (decreased) appear to affect headaches. Headaches associated with OC use or menopausal hormonal replacement therapy may be related, in part, to periodic discontinuation of oral sex hormone preparations. The treatment of migraine associated with changes in sex hormone levels is frequently difficult and the patients are often refractory to therapy. Based on what is known of the pathophysiology of migraine, we have attempted to provide a logical approach to the treatment of headaches that are associated with menses, menopause, and OCs using abortive and preventive medications and hormonal manipulations. Considerable evidence suggests a link between estrogen and progesterone, the female sex hormones, and migraine. (Silberstein and Merriam, 1997; Lipton and Stewart, 1993; Epstein et al., 1975; Goldstein and Chen, 1982; Selby and Lance, 1960) Although no gender difference is apparent in prepubertal children, with migraine occurring equally in 4p. 100 of boys and girls, (Goldstein and Chen, 1982, Waters and O'Connor, 1971) migraine occurs more frequently in adult women (18p. 100) than in men (6p. 100). (Lipton and Stewart, 1993) Migraine develops most frequently in the second decade, with the peak incidence occurring with adolescence. (Selby and Lance, 1960; Epstein et al., 1975) Menstrually-related migraine (MM) begins at menarche in 33p. 100 of affected women (Epstein et al. , 1975). MM occurs mainly at the time of menses in many migrainous women, and exclusively with menses (true menstrual migraine [TMM]) in some (Epstein et al., 1975). Menstrual migraine can be associated with other somatic complaints arising before and often persisting into menses, such as nausea, backache, breast tenderness, and cramps and like them appears to be the result of falling sex hormone levels (Silberstein and Merriam, 1997; American Psychiatric Association, 1994). In addition, premenstrual migraine can be associated with premenstrual dysphoric disorder (PDD), also called "premenstrual syndrome" (PMS), which is distinct from the physical symptoms of the perimenstrual period and is probably not directly driven by declining progesterone levels (Mortola, 1998). Migraine occurring during (rather than prior to) menstruation is usually not associated with PMS (Silberstein and Merriam, 1997). Migraine may worsen during the first trimester of pregnancy and, although many women become headache-free during the last two trimesters, 25p. 100 have no change in their migraine (Silberstein, 1997). MM typically improves with pregnancy, perhaps due to sustained high estrogen levels (Silberstein, 1997). Hormonal replacement with estrogens can exacerbate migraine and oral contraceptives (OCs) can change its character and frequency