Segregation analysis of 389 Icelandic pedigrees with Breast and prostate cancer

Breast cancer and prostate cancer are the most commonly occurring cancers in females and males, respectively. The objective of this project was to test the hypothesis that breast cancer in females and prostate cancer in males represent homologous cancers that may be controlled by one or more common unidentified genes that may explain some of the observed familial aggregation. We modeled the transmission of a breast-prostate cancer phenotype in 389 pedigrees ascertained through a breast cancer proband drawn from the Icelandic Cancer Registry. Assuming that age at diagnosis of this combined phenotype followed a logistic distribution, segregation analyses were performed to evaluate residual parental effects, a sibship covariate, and a dichotomous cohort effect. The most parsimonious model was a Mendelian codominant model, which could partly explain the familial aggregation of both cancers. Inheritance of a putative high-risk allele (A) predicted gender-specific mean ages of onset for females as 53.8 years, 59.7 years, and 65.6 years for the putative AA, AB, and BB genotypes, respectively. Similarly, the predicted means were 73.7 years, 75.6 years, and 78.3 years, respectively, among males. Under this codominant model, the lifetime risk of a woman being affected was 19% by age 80 years. This implies that when prostate cancer among male relatives of breast cancer probands (unselected for family history or early-onset disease) is considered a pleiotrophic effect of the same gene that increases the risk for breast cancer, women are predicted to have a less than 1 in 5 risk of developing breast cancer when they carry the putative high-risk allele. However, this is a higher risk than in the general Icelandic population. Our results suggest that BRCA2 mutations alone are inadequate to explain all of the excess clustering of prostate cancer cases in families of breast cancer probands, and that additional genes conferring excess risk to both breast and prostate cancer may exist in this population.     

BRCA2 mutation carriers,reproductive factors and breast cancer risk

Background

Germline mutations in the BRCA genes dramatically increase the risk of breast cancer. In the general population, breast cancer risk is affected by age at menarche, by age at first birth, by the number of births and by the duration of breast feeding. Whether this is true for mutation carriers is not clear.

Methods

In a case–control study, nested in a population-based cohort of the Icelandic Cancer Detection Clinic, two groups of cases were defined, matched on year of birth, on age at diagnosis and on age when giving information on reproductive factors: 100 carriers of the Icelandic founder BRCA2 mutation 999del5, and 361 BRCA2-negative cases. The mean age at diagnosis was 48 years. There were 1000 women in a matched group of unaffected controls. Conditional logistic regression was used for the analysis.

Results

An increased number of births was associated with a decreased risk of breast cancer in BRCA2-negative cases but not in BRCA2-positive cases. A negative association between risk and duration of breast feeding was observed only in the mutation carriers. These associations were not statistically significant, but the effects of the two variables differed significantly according to mutation status (P = 0.007 and P = 0.045 for interaction with number of births and with duration of breast feeding, respectively). This was maintained when limiting the analysis to women diagnosed older than the age of 40 years.

Conclusion

The association between breast cancer and the number of pregnancies and between breast cancer and the duration of breast feeding was not the same for carriers and noncarriers of a detrimental BRCA2 mutation. In the context of other epidemiological and laboratory studies, this may indicate that the product of the BRCA2 gene has a function relating to the differentiation of epithelial tissue in the breast.     

Vitamin D Intake and Status in 6-Year-Old Icelandic Children Followed up from Infancy

High serum 25-hydroxyvitamin D (25(OH)D) levels have been observed in infants in Nordic countries, likely due to vitamin D supplement use. Internationally, little is known about tracking vitamin D status from infancy to childhood. Following up 1-year-old infants in our national longitudinal cohort, our aims were to study vitamin D intake and status in healthy 6-year-old Icelandic children (n = 139) and to track vitamin D status from one year of age. At six years, the mean 25(OH)D level was 56.5 nmol/L (SD 17.9) and 64% of children were vitamin D sufficient (25(OH)D ≥ 50 nmol/L). A logistic regression model adjusted for gender and breastfeeding showed that higher total vitamin D intake (Odds ratio (OR) = 1.27, 95% confidence interval (CI) = 1.08–1.49), blood samples collected in summer (OR = 8.88, 95% CI = 1.83–43.23) or autumn (OR = 5.64, 95% CI = 1.16–27.32) compared to winter/spring, and 25(OH)D at age one (OR = 1.02, 95% CI = 1.002–1.04) were independently associated with vitamin D sufficiency at age six. The correlation between 25(OH)D at age one and six was 0.34 (p = 0.003). Our findings suggest that vitamin D status in infancy, current vitamin D intake and season are predictors of vitamin D status in early school age children. Our finding of vitamin D status tracking from infancy to childhood provides motivation for further studies on tracking and its clinical significance.     

Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines.

One of the most important components of G1 checkpoint is the retinoblastoma protein (pRB110). The activity of pRB is regulated by its phosphorylation, which is mediated by genes such as cyclin D1 and p16/MTS1. All three genes have been shown to be commonly altered in human malignancies. We have screened a panel of 26 oral squamous cell carcinomas (OSCC), nine premalignant and three normal oral tissue samples as well as eight established OSCC cell lines for mutations in the p16/MTS1 gene. The expression of p16/MTS1, cyclin D1 and pRB110 was also studied in the same panel. We have found p16/MTS1 gene alterations in 5/26 (19%) primary tumours and 6/8 (75%) cell lines. Two primary tumours and five OSCC cell lines had p16/MTS1 point mutations and another three primary and one OSCC cell line contained partial gene deletions. Six of seven p16/MTS1 point mutations resulted in termination codons and the remaining mutation caused a frameshift. Western blot analysis showed absence of p16/MTS1 expression in 18/26 (69%) OSCC, 7/9 (78%) premalignant lesions and 8/8 cell lines. One cell line, H314, contained a frameshift mutation possibly resulting in a truncated p16/MTS1 protein. pRB was detected in 14/25 (56%) of OSCC but only 11/14 (78%) of these contained all or some hypophosphorylated (active) pRB. In premalignant samples, 6/8 (75%) displayed pRB, and all three normal samples and eight cell lines analysed contained RB protein. p16/MTS1 protein was undetectable in 10/11 (91%) OSCCs with positive pRB. Overexpression of cyclin D1 was observed in 9/22 (41%) OSCC, 3/9 (33%) premalignant and 8/8 (100%) of OSCC cell lines. Our data suggest p16/MTS1 mutations and loss of expression to be very common in oral cancer cell lines and less frequent in primary OSCC tumours. A different pattern of p16/MTS1 mutations was observed in OSCC compared to other cancers with all the detected p16/MTS1 mutations resulting in premature termination codons or a frameshift. The RB protein was expressed in about half (44%) of OSCCs and its expression inversely correlated with p16/MTS1 expression. In conclusion, we show that abnormalities of the RB pathway are a common mechanism of oral carcinogenesis.     

BRCA2 mutation in Icelandic prostate cancer patients

 Molecular genetic analysis of prostate cancer has gained considerable attention in recent years. The hope is to find genetic markers that can help to determine which patients are likely to develop a progressive or lethal disease and would therefore benefit from early treatment. The BRCA2 gene on chromosome 13 has been associated with familial male and female breast cancer. A founder mutation in this gene has been detected in the Icelandic population. This is a 5-bp deletion that leads to an early termination and truncated protein. Clustering of prostate cancers in some of the Icelandic BRCA2 families implies that mutation carriers are at increased risk of developing cancer of the prostate. The aim of the study was to investigate this mutation in Icelandic prostate cancer patients related to BRCA2 positive breast cancer probands and to estimate the prevalence of this mutation in unselected prostate cancer patients. To examine the potential role of this mutation in prostate cancer we analyzed prostate cancer cases from 16 BRCA2 families and all available samples from individuals diagnosed with prostate cancer in Iceland over a period of 1 year. The risk ratio of prostate cancer was 4.6 (1.9–8.8) in first-degree relatives and 2.5 (1.2–4.6) in second-degree relatives of the 16 BRCA2 positive breast cancer probands. Of 26 prostate cancer cases found in these families 12 were analyzed, and 8 of these (66.7%) had the BRCA2 mutation. All of these patients developed an advanced disease, and all have died of prostate cancer (median survival 22.5 months). Among unselected cases 3.1% (2/65) had the mutation and developed an advanced disease as well. This specific mutation in the BRCA2 gene is found in a subset of Icelandic prostate cancer cases and appears to be a marker for poor prognosis. Received: 31 January 1997 / Accepted: 23 May 1997     

Adverse life experiences and common mental health problems in pregnancy: a causal pathway analysis

Risk factors for antenatal common mental problems include a history of depression, lack of social support and a history of both childhood and adulthood sexual and physical abuse. However, it is less clear whether pregnancy is a time of particular susceptibility to mental disorders due to prior childhood experiences. The aim of the paper was to investigate the potential pathways to antenatal mental health problems. A total of 521 women attending prenatal care attended a clinical interview and answered psychological questionnaires. Univariate analysis, sequential binary logistic regression and structural equation modelling (SEM) were used to analyse the relationships between variables. Having experienced parental maladjustment, maltreatment and serious physical illness in childhood and domestic violence, financial difficulties and serious spousal substance abuse in adulthood significantly predicted antenatal common mental health symptoms. SEM showed that history of depression and adverse experiences in adulthood had mediating effects on the relationship between adverse childhood events and symptoms of antenatal common mental disorders. Adverse childhood experiences are distal risk factors for antenatal common mental health problems, being significant indicators of history of depression and adverse experiences in adulthood. We therefore conclude that pregnancy is not a time of particular susceptibility to common mental health problems as a result of childhood abuse, but rather, these childhood experiences have increased the risk of adulthood trauma and prior mental disorders. Women at risk for antenatal common mental disorders include those with a history of depression, domestic violence, financial difficulties, spousal substance abuse and lack of social support.

     

Patients' experiences of abuse in health care: a Nordic study on prevalence and associated factors in gynecological patients

BACKGROUND: In an earlier Swedish study conducted with The NorVold Abuse Questionnaire, we found that one-third of female patients who had experienced adult abuse in health care (AAHC) had a background of childhood emotional, physical and/or sexual abuse (EPSA) ('revictimised'). But since the majority of women with AAHC were 'new victims' without such a background, there might be other factors associated with AAHC. The present study aimed to map prevalence of abuse in health care (AHC), and associated variables among new victims and revictimised patients. METHODS: We carried out a cross-sectional questionnaire study at 5 Nordic gynecological clinics. Associations between AAHC and other variables were tested in a multivariate model in 4 groups of women with adult EPSA, childhood EPSA, childhood and adult EPSA, and no EPSA. RESULTS: The response rate was 77% (n=3,641). The overall prevalence of any lifetime experience of AHC was 13-28%. High educational level, physical complaints, post-traumatic stress symptoms, and sleeping problems were associated with AAHC in women without EPSA (new victims). Poor self-rated health was strongly associated with AAHC in the 3 groups of women with EPSA. CONCLUSION: AHC is commonly reported by gynecological patients in the Nordic countries, but not yet properly explored or understood. The most important factors associated with AAHC were high educational level and poor self-rated health.     

Tumour diploidy and survival in breast cancer patients with BRCA2 mutations

It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24–2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91–4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41–1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours.     

Dietary patterns in adolescence and risk of colorectal cancer: a population-based study

Cancer Causes & Control - To study whether dietary patterns in adolescence are associated with risk of colorectal cancer (CRC). Food frequency data were obtained from the AGES-Reykjavik study,...