Genetic and epigenetic changes in mammary epithelial cells identify a subpopulation of cells involved in early carcinogenesis.

Morphologically normal foci of epithelial cells exhibiting p16 inactivation have been found in several tissues and may be precursors to cancer. Our previous work demonstrates that cells lacking p16(INK4A) activity exhibit phenotypes associated with malignancy (Romanov et al. 2001). The acquisition of genomic instability occurs through the activation of telomeric and centrosomal dysfunction. Additionally, the activation of stress pathways such as COX-2 provides these cells with the mutagenic potential to survive adverse environments as well as the ability to migrate, evade apoptosis and immune surveillance, and summon sustaining vasculature. Examination of archived tissue from women with DCIS (ductal carcinoma in situ) reveals epithelial cells that overexpress markers of premalignant stress activation pathways and mirror the distinctive expression patterns of these markers observed in vitro. These epithelial cells are found within the premalignant lesion as well as in the field of morphologically normal tissue that surrounds the lesion. Here, we show that p16(INK4A)-silenced vHMEC cells exhibit a gene expression profile which is distinct, reproducible, and extends beyond the changes mediated by p16(INK4A) inactivation. The present work suggests that cells lacking p16(INK4A) activity exhibit critical activities which allow cells to evade differentiation processes that would be expected to terminate proliferation. All of these properties are critical to malignancy. These events may be useful biomarkers to detect the earliest events in breast cancer.

Loss of chromosomal integrity in human mammary epithelial cells subsequent to escape from senescence.

The genomic changes that foster cancer can be either genetic or epigenetic in nature. Early studies focused on genetic changes and how mutational events contribute to changes in gene expression. These point mutations, deletions and amplifications are known to activate oncogenes and inactivate tumor suppressor genes. More recently, multiple epigenetic changes that can have a profound effect on carcinogenesis have been identified. These epigenetic events, such as the methylation of promoter sequences in genes, are under active investigation. In this review we will describe a methylation event that occurs during the propagation of human mammary epithelial cells (HMEC) in culture and detail the accompanying genetic alterations that have been observed.

The short-term impact of tailored mammography decision-making interventions.

BACKGROUND: We assessed the short-term impact of decision-making interventions on knowledge about mammography, accuracy of women's breast cancer risk perceptions, attitudes toward mammography, satisfaction with decisions, and mammography use since the intervention. METHODS: The study was conducted among women who were members of Blue Cross Blue Shield of North Carolina and were in their 40s or 50s at the time the study began in 1997. Women were randomly assigned to usual care (UC), tailored print booklets (TP) alone, or TP plus telephone counseling (TP+TC ). RESULTS: 12-month interviews were completed by 1127 women to assess short-term intervention effects. Generally, women who received TP+TC were significantly more knowledgeable about mammography and breast cancer risk and were more accurate in their breast cancer risk perceptions than women in the TP and UC groups. They also were more likely to have had a mammogram since the baseline interview. In multivariable analyses, we found significant benefits of the combination of TP+TC compared to TP and to UC for knowledge, accuracy of risk perceptions, and mammography use. DISCUSSION: For complex decision-making tasks, such as women's decisions about mammography in the face of controversy, the combination of TP and TC may be more effective than TP alone, and certainly more effective than UC. It is critical that investigators determine the topics for which TP is appropriate and the situations that require additional supportive interventions.

Factors associated with repeat mammography screening.

BACKGROUND: Even organizations with differing mammography recommendations agree that regular repeat screening is required for mortality reduction. However, most studies have focused on one-time screening rather than repeat adherence. We compare trends in beliefs and health-related behaviors among women screened and adherent to the National Cancer Institute's screening mammography recommendations (on schedule), those screened at least once and nonadherent (off schedule), and those never screened. METHODS: Our data are from a baseline telephone interview conducted among 1,287 female members of Blue Cross Blue Shield of North Carolina who were aged either 40 to 44 years or 50 to 54 years. RESULTS: The 3 groups differed significantly on beliefs and health-related behaviors, with the off-schedule group almost consistently falling between the on-schedule and never screened groups. Off-schedule women were more likely than on-schedule women, but less likely than those never screened, to not have a clinical breast examination within 12 months, to be ambivalent about screening mammography, to be confused about screening guidelines, and to not be advised by a physician to get a mammogram in the past 2 years. Off-schedule women perceived their breast cancer risk as lower and were less likely to be up to date with other cancer screening tests. CONCLUSIONS: Our findings suggest that women who are off schedule are in need of mammography-promoting interventions, including recommendations from and discussion with their health care providers. Because they are more positive and knowledgeable about mammography than women who have never been screened, they may benefit from brief interventions from health care providers that highlight the importance of repeat screening.

Confusion about mammography: prevalence and consequences.

Over the last decade, there has been significant controversy about the schedule on which women, particularly women in their 40s, should have mammograms. The purpose of the analysis reported here was to assess whether women in their 40s and 50s were confused as a result of the controversy following the January 1997 National Institutes of Health Consensus Development Conference on Breast Cancer Screening For Women Ages 40-49. We also examined if confusion was related to being off schedule for mammography. The study sample included 1287 women recruited from a random sample of 2165 Blue Cross/Blue Shield of North Carolina members. The data described in this analysis were derived from a baseline telephone interview conducted as part of a larger intervention trial. Study measures included a variety of sociodemographic, medical, belief, and behavioral variables. Overall, 28% of women were confused, and 35% were off schedule. Although a higher proportion of women in their 40s than 50s were confused, more women in their 50s were off schedule. Confusion was a significant predictor for the outcome being off schedule. Predictors of confusion included several belief variables, risk perceptions, age (40s), whether the woman had a regular physician, and whether she had enough information about mammography. Healthcare providers should ask some simple questions to determine if women are confused and then seek to meet their information needs.

Testing different formats for communicating colorectal cancer risk.

This study assessed the extent to which different formats of informing men and women age 50 and over of the risks of colorectal cancer (CRC) affected their perceptions of their absolute and comparative (self versus other) 10-year and lifetime risks; emotional reactions about getting CRC; and screening intentions. Forty-four men and 78 women received information about the absolute lifetime risk of getting CRC. In addition, participants either did or did not receive information about (1) lifetime risk of getting CRC compared with other cancers, and (2) risk factors for CRC (age and polyps). Participants who received risk factors information were more likely to increase their perceived absolute 10-year and lifetime risks of getting CRC compared with participants who did not receive risk factors information. In addition, participants who received risk factors information were more likely to believe age was related to getting CRC and felt at greater risk for having polyps compared with participants who did not receive this information. None of the experimental conditions affected how worried, anxious, and fearful participants felt about getting CRC, nor did they affect screening intentions. Independent of experimental condition, participants tended to increase their intentions to get screened for CRC in the next year or two. Intention to be screened was more pronounced among participants who had been screened via a fecal occult blood test (FOBT) or sigmoidoscopy (SIG). Implications for the design of interventions involving the communication of CRC risks are discussed.

Direct analysis of CYP21B genes in 21-hydroxylase deficiency using polymerase chain reaction amplification.

Steroid 21-hydroxylase deficiency is the leading cause of impaired cortisol synthesis in congenital adrenal hyperplasia (CAH). We have studied the structure of the CYP21B gene in 30 unrelated CAH patients using the polymerase chain reaction (PCR) to differentiate the active CYP21B gene from its highly related CYP21A pseudogene. The PCR approach obviates the need to distinguish the CYP21A and CYP21B genes by restriction endonuclease digestion and electrophoresis before analysis with labeled probes. Furthermore, direct nucleotide sequence analysis of CYP21B genes is demonstrated on the PCR-amplified DNA. Gene deletion of CYP21B, gene conversion of the entire CYP21B gene to CYP21A, frame shift mutations in exon 3, an intron 2 mutation that causes abnormal RNA splicing, and a mutation leading to a stop codon in exon 8 appear to be the major abnormalities of the CYP21B gene in our patients. These mutations appear to account for 21-hydroxylase deficiency in 22 of 26 of our salt-wasting CAH patients.

A longitudinal study of Mycoplasma pneumoniae: infections in Navy recruits by isolation and seroepidemiology.

A longitudinal serologic study of M. pneumoniae infections in two recruit training centers with grossly different climates showed that the frequency of this infection peaks in the late summer-early fall and to a lesser degree in the spring at both training centers. Seroconversions (four-fold or greater increase in titer) were as high as 45-57% in some recruit companies during the late summer peak. M. pneumoniae isolations from men admitted to the dispensary or hospital with pneumonia during the major peak season were as high as 32%. While M. pneumoniae infections are not generally life-threatening, the high incidence of infections observed in personnel during recruit training is of major concern and warrants consideration of effective control measures.

Hemagglutinin from the L phase of Neisseria meningitidis group B, with observations on a serum inhibitor.

A hemagglutinin extracted from the L-phase of Neisseria meningitidis group B directly agglutinated rabbit and rooster erythrocytes but did not react with human, sheep, or guinea pig erythrocytes. Virtually all animal, chicken, and human sera tested showed inhibitory titers. In a significant number of Navy recruits, who became carriers of N. meningitidis, the titer of serum inhibitor began to decline 2 weeks before the bacterial infection was first detected. Titers of this serum inhibitor ranged from 256 to 4,096 in patients with meningitis. The hemagglutinin failed to boost the preexisting titers of serum inhibitor when injected into animals, although roosters showed a minimal but transitory response.