P-glycoprotein (gp170; encoded by the MDR1 gene [also known as PGY1]) is a membrane protein capable of exporting a variety of anticancer drugs from cells. MDR1/gp170 expression has been studied in breast cancer, but the prevalence of this expression and its role in breast tumor drug resistance are unclear.

Certain polymorphic variants of H-ras-1 and p53 have been investigated for an association between inheritance and cancer risk. The results of a metaanalysis, which reviews studies of H-ras-1 rare alleles and p53 codon 72 allelic variants in breast and lung cancer, are presented. The data constituted evidence for elevated risk of both breast and lung cancer with inheritance of rare H-ras-1 alleles. Calculated population attributable risks are 0.092 and 0.037 for breast and lung cancer, respectively. The frequency of the rare H-ras-1 alleles was observed to be greater in African Americans than in Caucasians, and a specific allele (A3.5) that is common in African Americans was found only at low frequency in Caucasians. For p53 a consensus has yet to be reached. Lung cancer studies conducted in Caucasian and African-American populations have found no evidence of risk associated with the proline variant of codon 72. Two similar studies conducted in Japanese populations suggested an association between p53 genotype distribution and lung cancer risk. However, one implicates the proline allele but the other implicates the arginine allele. The frequency of the proline variant is significantly dependent on race. Frequencies have been reported for control populations of Japanese (0.347 and 0.401), Caucasian (0.295, 0.284, and 0.214), African American (0.628 and 0.527), and Mexican American (0.263).

An increased risk of breast cancer in women with a family history of breast cancer has been demonstrated by many studies using a variety of study designs. However, the extent of this risk varies according to the nature of the family history (type of relative affected, age at which relative developed breast cancer and number of relatives affected) and may also vary according to age of the individual. The aim of our study was to identify all the published studies which have quantified the risk of breast cancer associated with a family history of the disease, and to summarise the evidence from these studies, with particular emphasis on age-specific risks according to subject and relative age. Seventy-four published studies were identified. The pooled estimate of relative risk (RR) associated with various family histories was as follows: any relative, RR = 1.9 (95% CI, 1.7-2.0); a first-degree relative, RR = 2.1 (CI = 2.0, 2.2); mother, RR = 2.0 (CI = 1.8, 2.1); sister, RR = 2.3 (CI = 2.1, 2.4); daughter, RR = 1.8 (CI = 1.6, 2.0); mother and sister, RR = 3.6 (CI = 2.5, 5.0); and a second-degree relative, RR = 1.5 (CI = 1.4, 1.6). Risks were increased in subjects under age 50 and when the relative had been diagnosed before age 50.

Cytogenetic studies over the past few decades have revealed clonal chromosomal aberrations in almost 27,000 human neoplasms. Many of these neoplasia-associated chromosomal abnormalities have been characterised at the molecular level, revealing previously unknown genes that are closely associated with the tumorigenic process. Information on chromosome changes in neoplasia is growing rapidly, making it difficult to identify all recurrent chromosomal aberrations. We have developed a computer program to ascertain, for the first time, all recurrent structural abnormalities in all haematological malignancies and solid tumours published up to June 1996. Out of 26,523 cases, a total of 215 balanced and 1,588 unbalanced recurrent aberrations were identified among 75 different neoplastic disorders. Our compilation of all recurrent balanced and unbalanced neoplasia-associated rearrangements should help in directing future efforts aimed at identifying the molecular mechanisms involved in tumorigenesis.

This article consists of three independent studies regarding Helicobacter pylori-related gastric carcinogenesis. Ammonia, a Helicobacter product, promoted chemically induced gastric carcinogenesis in animals. Moreover, an extract of Helicobacter stimulated inflammatory production of nitric oxide (NO), a potent mutagen that causes G:C-->A:T transition. Meta-analysis of recent studies demonstrated that G:C-->A:T transition is one of the most common mutations in the p53 tumor suppressor gene in early phases of human gastric carcinogenesis. Therefore, bacterial factors such as ammonia and host factors, including inflammatory NO production, might play important roles in H. pylori-induced gastric carcinogenesis.

To examine the association between the sparteine/debrisoquine (CYP2D6) oxidation polymorphism and the risk of lung cancer.

The biology of AML is reflected through several prognostic factors. Until now there has been no general agreement about these factors. In most studies therapy is not stratified according to risk factors with the exception of age. Since 1976 the FAB classification has been the basis for the diagnosis in AML. But only for the AML M3 is this important for the choice of treatment. Therefore, it is unclear if the FAB classification is the best way to describe the individual biology in AML. We are able to verify that significant differences in remission rates and event-tree survival are much better reflected by the cytogenetic results. With data from the AML cooperative group on one hand and in a kind of meta-analysis with cytogenetic date from different studies on the other hand, we are able to conclude that cytogenetics are much more feasible to describe the biological entity in AML patients. Further studies should focus more on this individual prognostic factor.

The association between glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk has been controversial in the published literature. To examine this controversy, 12 case-control studies of GSTM1 status and lung cancer risk were identified in the published English literature. These studies included a total of 1593 cases and 2135 controls. We conclude that GSTM1 deficiency is a moderate risk factor for lung cancer development with an odds ratio of 1.41 (95% confidence interval = 1.23-1.61; P < 0.0001) by using Mantel-Haenszel methods for stratified analysis. This increased risk is evident for all the major histological subtypes of lung cancer. Although the increased risk is small, GSTM1 deficiency accounts for approximately 17% of lung cancer cases because of the high prevalence of GSTM1 deficiency.

Statistical analysis of published data on the age of onset of germ cell tumours of the testis and of the prevalence of bilateral disease in familial and general cases suggest the following: 1. Patients with bilateral disease carry the same genetic predisposition as familial cases. 2. Males with the hereditary predisposition develop none, unilateral or bilateral tumours in the proportions 55%, 38% and 7% respectively. 3. One-third of all testis cancer patients are genetically predisposed to the disease. 4. The 2.2% risk to brothers of cases as reported elsewhere can be accounted for by the homozygous (recessive) inheritance of a single predisposing gene.

Risk of trisomy 18 in a fetus with ultrasonographic diagnosis of choroid plexus cysts and no other anomalies is controversial. Using our data and current literature, we performed a meta-analysis and estimated the positive predictive value of isolated choroid plexus cysts for trisomy 18.

While the value of hormone replacement therapy appears now to be accepted, it is above all a prophylactic technique requiring evaluation of its benefit/risk ratio. The possible increased risk of breast cancer linked to this type of treatment remains a preoccupation which probably limits its more widespread use. The natural history of this cancer and inherent biases in the various types of study are such that analysis of the literature is often difficult and any definite conclusion is prevented. Certain trends nevertheless appear to emerge from the principal studies. While there is indeed an increased risk of onset of breast cancer, it is slight, other than with the use of high doses of estrogens for prolonged periods in women with a family history of breast cancer. Decreased overall mortality rate in women on replacement therapy and the improvement in their comfort tend to suggest that it is now legitimate to offer such treatment, provided its contra-indications are strictly observed and regular monitoring is ensured.

The role of mutations in protooncogenes and their regulatory sequences in the pathogenesis of cancer is under close scrutiny. Minisatellites are unstable repetitive sequences of DNA that are present throughout the human genome. The highly polymorphic HRAS1 minisatellite locus just downstream from the protooncogene H-ras-1 consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. We previously observed an association of the rare mutant alleles with many forms of cancer, and we undertook the present study to pursue this observation further.

Using literature data on cytogenetic abnormalities in 3,612 cases of acute myeloid leukemia (AML) and 1,551-cases of acute lymphocytic leukemia (ALL), we have attempted to quantify the information value of finding the typical ALL- and AML-associated chromosome aberrations. Sensitivity, specificity, and predictive value of finding or not finding a given aberration were calculated for several diagnostic scenarios: for the differential diagnosis between ALL and AML when the patient is known to have acute leukemia, for the differential diagnosis among AML FAB subtypes in a patient with known AML, and for the differential diagnosis between ALL FAB subtypes in a patient with known ALL. The specificities were generally high, close to 1. The highest sensitivities in AML were found for +8, t(15;17)(q22;q11), t(8;21)(q22;q22), and -7 (all greater than 0.1), and in ALL for t(9;22)(q34;q11), t(4;11)(q21;q23), and +21 (again all greater than 0.1). In the AML subtypes, the highest sensitivities were 0.89 for t(15;17)(q22;q11) in M3, followed by 0.40 for t(8;21)(q22;q22) in M2, 0.30 for inv(16)(p13q22)/del(16)(q22)/t(16;16)(p13;q22) in M4, and 0.16 for t(9;11)(p21;q23) in M5. In the ALL subtypes, the highest sensitivities were 0.71 and 0.11 for t(8;14)(q24;q32) and t(8;22)(q24;q11), respectively, in L3, 0.23 for t(9;22)(q34;q11) in L2, and 0.18 and 0.13 for +21 and t(4;11)(q21;q23), respectively, in L1. The highest (1.0) positive predictive values in the AML versus ALL comparison were found for t(1;3)(p36;q21), inv(3)(q21q26), t(6;9)(p23;q34), t(7;11)(p15;p15), t(8;16)(p11;p13), t(8;21)(q22;q22), t(15;17)(q22;q11), and, as sole anomalies, for +4, +9, and +11. In the reverse comparison, ALL versus AML, positive predictive values of 1.0 were found for t(1;14)(p32-34;q11), dup(I)(q12-21q31-32), t(2;8)(p12;q24), t(8;14)(q24;q32), t/dic(9;12)(p11-12;p11-13), t(10;14)(q24;q11), and t(11;14)(p13;q11). Among the AML subgroups, the highest predictive values were: 1.0 for M3 if t(15;17), 0.91 for M2 if t(8;21), 0.86 for M4 if inv/del(16)/t(16;16), and 0.82 for M5 if t(9;11). Among the ALL subtypes, positive predictive values of greater than 0.8 were reached only for the L3-associated aberrations t(2;8) (1.0), t(8;14) (0.95), t(8;22) (0.87), and dup(I) (0.80). The highest negative predictive values were in AML 0.98 that the disease is not M3 if t(15;17) is not found, and in ALL 0.96 that the patient does not have L3 if a t(8;14) is not detected.

The metabolism of estrone (E1) or estradiol-17 beta (E2) to catechols seldom has been investigated in biochemical studies related to the risk of development of human breast cancer, as a result of the extreme lability and reactivity of these hormones. A method of indirect calculation was developed in which estimated catechol estrogen excretion (ECE) from urinary excretion of E1, E2, and estriol (E3) was used, based on the obligate reciprocal relation between 16 alpha-hydroxylase activity (r3) and estrogen 2/4 hydroxylase function (r2). This relationship is expressed by r2 x r3 = K, the estrogen oxidative constant. From published data relating chiefly to 2-OH estrone excretion, K = 12.4 +/- 0.8 (standard error of the mean). Urinary E1 + E2 excretion rates reflect nonprotein-bound plasma ovarian estrogen concentrations available for cell metabolism, which influence the value of K. The equation: r2 = [E1 + E2] K/[E3 + 16 alpha OH E1] = ECE gives a median correlation coefficient between actual catechol estrogen excretion and ECE in micrograms/24 hours of +0.88 (range, 0.61 to 0.97). When tested against the best product isolation analysis of catechol estrogen excretion, ECE was 95% accurate. Using this method a metaanalysis was conducted of published fractional estrogen excretion collected from 2846 healthy women worldwide aged 15 to 59 years, with a risk of breast cancer varying fivefold. Overall ECE was 78% to 97% higher in high-risk women of all ages and menstrual cycle phases (P less than 0.001, by Wilcoxon test). With increasing cancer risk (as estimated by the authors), ECE rose linearly exponentially with a slope of 0.149 (follicular phase) and 0.136 (luteal phase). The correlation coefficient (R2) between the two variables was 0.77 and 0.57, respectively (P less than 0.05). These data derived from calculations of ECE in healthy women confirmed recent analytic results of a twofold increase in the ratio of 2-OH E1/4-OH E1 in healthy Finnish women compared with recent Japanese migrants to Hawaii. In Finnish women with breast cancer, this ratio increased further (almost twofold). Metaanalysis supported the conclusion that increased rates of oxidation of estradiol 17-beta to 2-OH catechols supply the principal proximal human mammary carcinogens active after menarche.

Chemicals classified by the IARC to its groups 1, 2A, 2B and 3 were examined in an attempt to identify characteristics of their behaviour in experimental studies of carcinogenicity, genotoxicity and acute mammalian toxicity that correlate with those categories. Only those agents for which information on carcinogenic potency was available were studied. In both mice and rats, more chemicals were potent carcinogens if they had been categorized in Group 1 (human carcinogens) than if they had been put into one of the other categories. Not surprisingly, there was a weak association between carcinogenic potency and acute toxicity. Mice were especially sensitive to tumour induction by halides; the lower sensitivity of rats to any carcinogenic effect of halides could be due in part to their higher systemic toxicity in this species: a reduced differential of toxic and carcinogenic doses decreases the dose window in which carcinogenic effects may be demonstrated. It was notable that the human carcinogens were active in those genotoxicity tests with higher specificity for identifying rodent carcinogens. Predictive assays for carcinogenicity that were considered to be highly specific were tests for cytogenetic effects in vivo, unscheduled DNA synthesis in hepatocytes, mutation in any of the five commonly used strains of Salmonella typhimurium and mutation at the hprt locus in mammalian cells. None of the relationships was strong enough to form the basis of a simple categorization, but they could serve to alert investigators to chemicals of special toxicological interest and importance.

I reexamined the relations of family history of breast cancer in first-degree relatives, mammographic features of breast tissue, and breast cancer risk, using data from three case-control studies. Subjects included 1,047 cases with newly diagnosed breast cancer and 2,329 controls. Family history of breast cancer showed only a weak relation to mammographic features. In addition, while family history and mammographic features were each related to breast cancer risk, associations of these two factors with risk appeared additive. In contrast to previous reports, these data suggest that, to a large extent, family history and mammographic features have independent effects on breast cancer development.

A statistical overview of published results on correlations between various prognostic factors in breast cancer was undertaken. A distinction was made between clinical (or anatomical) prognostic factors--namely, axillary lymph node status and tumour size--and eight different biological prognostic factors. The latter included: tumour grade, oestrogen and progesterone receptor status, thymidine labelling index, DNA ploidy, S-phase fraction, epidermal growth factor receptor expression and c-erbB-2 gene amplification (or overexpression). 139 articles were eligible for review which reported a total of 432 individual correlations. A simple form of meta-analysis was employed: the counting method, in which the number of studies achieving a statistically significant correlation or not were counted. For each possible correlation examined, the proportion of studies showing a statistically significant correlation was calculated and an exact binomial 99% confidence interval determined for that proportion. If the 99% confidence interval included 5% (the proportion of correlations that would be expected to be statistically significant if the null hypothesis was true), it was taken as failing to exclude the null hypothesis of a zero correlation, while if it excluded 5% it was taken as rejecting the null hypothesis of a zero correlation. A broad agreement was found among published reports on the existence of a statistically significant correlation between the various biological prognostic factors in breast cancer. Of the 20 correlations examined, 18 had a 99% confidence interval excluding 5%, thus rejecting the null hypothesis of a zero correlation. On the other hand, a completely different result was obtained when reports on possible correlations between lymph node status and tumour size on the one hand and the eight biological prognostic factors on the other were analysed. Of the 16 correlations examined, 13 had a 99% confidence interval including 5%, failing to reject the null hypothesis of a zero correlation. These observations suggest the hypothesis that the prognostic influence of node status and tumour size cannot be explained by an analysis of the biology of breast cancer; and is compatible with the contention that axillary node status is merely a reflection of the relative chronological age of breast cancer.