[DNA microarrays and prediction of clinical outcome in ovarian carcinoma patients]. / Puces à ADN et prédiction de l'évolution clinique des cancers ovariens.

Despite debulking surgery and taxane/platinum-based chemotherapy, ovarian cancer is the most lethal pelvic gynaecological cancer in western countries, with a 25% 5-years survival. Current histo-clinical prognostic factors are insufficient to capture the heterogeneous clinical outcome of patients. A better molecular characterization of the disease is crucial to refine the prognostic classifications and to identify new therapeutic targets. DNA microarrays, which allow the quantitative measurement of expression level of the whole genome simultaneously in a single tumor sample, have been recently used towards this objective with promising results. Here, we present and discuss the main published studies and the issues to address in the future to allow the expected transfer to clinical practice.

Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases.

The t(8;16)(p11;p13) is a rare translocation involved in de novo and therapy-related myelomonocytic and monocytic acute leukemia. It fuses two genes encoding histone acetyltransferases (HATs), MYST3 located at 8p11 to CREBBP located at 16p13. Variant translocations involve other HAT-encoding genes such as EP300, MYST4, NCOA2 or NCOA3. MYST3-linked acute myeloid leukemias (AMLs) share specific clinical and biological features and a poor prognosis. Because of its rarity, the molecular biology of MYST3-linked AMLs remains poorly understood. We have established the genome and gene expression profiles of a multicentric series of 61 M4/M5 AMLs including 18 MYST3-linked AMLs by using array comparative genome hybridization (aCGH) (n=52) and DNA microarrays (n=44), respectively. We show that M4/5 AMLs have a variety of rare genomic alterations. One alteration, a gain of the MYB locus, was found recurrently and only in the MYST3-linked AMLs (7/18 vs 0/34). MYST3-AMLs have also a specific a gene expression profile, which includes overexpression of MYB, CD4 and HOXA genes. These features, reminiscent of T-cell acute lymphoid leukemia (ALL), suggest the targeting of a common T-myeloid progenitor.

Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q.

Chromosome 1 is involved in quantitative anomalies in 50-60% of breast tumours. However, the structure of these anomalies and the identity of the affected genes remain to be determined. To characterise these anomalies and define their consequences on gene expression, we undertook a study combining array-CGH analysis and expression profiling using specialised arrays. Array-CGH data showed that 1p was predominantly involved in losses and 1q almost exclusively in gains. Noticeably, high magnitude amplification was infrequent. In an attempt to fine map regions of copy number changes, we defined 19 shortest regions of overlap (SROs) for gains (one at 1p and 18 at 1q) and of 20 SROs for losses (all at 1p). These SROs, whose sizes ranged from 170 kb to 3.2 Mb, represented the smallest genomic intervals possible based on the resolution of our array. The elevated incidence of gains at 1q, added to the well-established concordance between DNA copy increase and augmented RNA expression, made us focus on gene expression changes at this chromosomal arm. To identify candidate oncogenes, we studied the RNA expression profiles of 307 genes located at 1q using a home-made built cDNA array. We identified 30 candidate genes showing significant overexpression correlated to copy number increase. In order to substantiate their involvement, RNA expression levels of these candidate genes were measured by quantitative (Q)-RT-PCR in a panel of 25 breast cancer cell lines previously typed by array-CGH. Q-PCR showed that 11 genes were significantly overexpressed in the presence of a genomic gain in these cell lines, and 20 overexpressed when compared to normal breast.

Gene expression profiling of breast cell lines identifies potential new basal markers.

A better molecular characterization of breast cell lines (BCL) may help discover new markers to apply to tumour samples. We performed gene and protein expression profiling of 31 BCL using whole-genome DNA microarrays and immunohistochemistry (IHC) on 'cell microarrays' (CMA), respectively. Global hierarchical clustering discriminated two groups of BCL: group I corresponded to luminal cell lines, group II to basal and mesenchymal cell lines. Correlations with centroids calculated from a published 'intrinsic 500-gene set' assigned 15 cell lines as luminal, eight as basal and four as mesenchymal. A set of 1.233 genes was differentially expressed between basal and luminal samples. Mesenchymal and basal subtypes were rather similar and discriminated by only 227 genes. The expression of 10 proteins (CAV1, CD44, EGFR, MET, ETS1, GATA3, luminal cytokeratin CK19, basal cytokeratin CK5/6, CD10, and ERM protein moesin) encoded by luminal vs basal discriminator genes confirmed the subtype classification and the validity of the identified markers. Our BCL basal/luminal signature correctly re-classified the published series of tumour samples that originally served to identify the molecular subtypes, suggesting that the identified markers should be useful for tumour classification and might represent promising targets for disease management.

Family change during an unwed teenage pregnancy.

PIP: To determine the qualitative impact of unwed adolescents' pregnancies on family processes and stability, 16 white intact families completed Olson, Portner, and Bell's Family Adaptability and Cohesion Scales III and Cervera's Family Alliance Questionnaire for 4 time periods: 6 months before conception (retrospectively measured), during the 6th and 8th months of pregnancy, and 1 month after delivery. The mean age of family members was 46 years for fathers, 42 years for mothers, and 17 years for the unmarried teen. The families identified themselves as working class. All parents indicated that their daughters had behavioral, emotional, and educational problems prior to the pregnancy, while daughters characterized their families' emotional climate as tense and disengaged. At all 4 points, the family functioning score was well above the midrange for family dysfunction, but a significant increase in cohesiveness and communication with parents and siblings occurred over time, generally after the birth. On the other hand, the pregnancy exerted little effect on family roles, rules, or power distributions and the infant was assimilated into the pre-existing structure. Most striking was an improvement in the intensity of mother-teen communication, from weekly conversations early in the pregnancy to daily communication immediately before delivery; there was no mechanism, however, for evaluating the quality of this communication. For chronically dysfunctional families with poor communication skills, an adolescent pregnancy can represent an opening for clinicians to intervene to restructure family relationships and teach more effective negotiation skills.^ieng

Decision making for pregnant adolescents: applying reasoned action theory to research and treatment.

PIP: Unmarried adolescent mothers face greater risk of less schooling, more emotional problems, higher poverty, and less income than those who relinquish their infants for adoption. Currently, around 5% of unmarried mothers give up their children for adoption (52,000 children annually, of which 24,500 are infants). Reasoned-action theory according to Ajzen and Fishbein (1980) was utilized in order to examine the potent family and personal variables that underlie this decision. In addition, a literature review of research studies applying reasoned-action theory to pregnant teenagers is provided, along with suggestions for clinical application of the theory. Family support has been found an important variable in the teenagers' decision. Family members may encourage or discourage the teenagers to keep the baby. Families may come closer together to cope with an unplanned pregnancy; however, some families experience deterioration of adaptability over time. The theory focuses 1) on the relationship of the individual and the decision or behavioral intention (BI), and 2) on immediate sociopsychological determinants of a BI. In some instances behavior (B) and BI are unrelated. The theory characterizes BIs in terms of the subjective probability concerning behavioral performance. The person's intention to perform a behavior is the result of a choice between behavioral alternatives: 1) adoption, 2) keeping the child as single mother, 3) keeping the child and raising it with the father in a formal relationship, 4) keeping the child and raising it with the help of parents. According to the Fishbein and Ajzen model, differences between minority and White relinquishment rates occur because these groups 1) differ in their beliefs and attitudes toward behavioral alternatives, 2) differ in normative beliefs, and/or 3) differ in relative weights they accord to attitudes versus cultural norms. This model with many variables is useful in measuring behavior, choice, and BI; attitudes and subjective norms; normative beliefs; and beliefs about consequences in clinical application by practitioners and agencies.^ieng

Incarceration, coping, and support.

Data are presented from a study of the effects of incarceration on family life involving 63 inmates and 38 inmate wives. Inmates and wives who participated in the Family Reunion (conjugal visit) Program were contrasted with matched, nonparticipating inmates and wives. Interview data and standardized measures were used to assess inmate and wife coping and support to the wife. Coping was in the normal range for both groups of inmates and wives and, except for measures of wives' passive appraisal, did not differ according to Family Reunion Program participation. Wives used a variety of coping strategies, most commonly family support and religion, and had substantial contact with extended families, with most receiving practical help and emotional support from extended families and neighbors. Implications for clinical intervention are discussed.