Prevalence and Penetrance of BRCA1 and BRCA2 Germline Mutations in Colombian Breast Cancer Patients.

Pathogenic BRCA1/2 germline mutations confer high risks of breast and ovarian cancer to women of European ancestry. Characterization of BRCA1/2 mutations in other ethnic groups is also medically important. We comprehensively screened 68 Colombian breast/ovarian cancer families for small-range mutations, 221 families for large-genomic rearrangements, and 1,022 unselected breast cancer cases for Colombian founder mutations in BRCA1/2. The risk of cancer among relatives of mutation carriers and the mutation penetrance were estimated by survival analysis. Identified BRCA2 mutations included 6310delGA and the recurrent 1991del4 mutations. A novel large BRCA2 deletion was found in 0.9% of the screened families. Among unselected breast cancer cases, 3.3% tested positive for BRCA1/3450del4, 2.2% for BRCA1/A1708E, 1.1% for BRCA2/3034del4, and 0.4% for BRCA2/1991del4. Female relatives of carriers of BRCA1/2 founder mutations showed a 5.90 times higher risk of breast cancer, when the woman herself carried a BRCA1 mutation compared to a non-carrier (95% CI 2.01-17.3). The estimated cumulative risk of breast cancer by age 70 years for BRCA1 mutations carriers was 14% (95% CI 5-38) compared to 3% for the general Colombian population (relative risk of breast cancer 4.05). Together with known founder mutations, reported novel variants may ease a cost-effective BRCA1/2 screening in women with Colombian ancestry.

A meta-analysis of immunogenetic Case-Control Association Studies in irritable bowel syndrome.

BACKGROUND: To date, genetic-association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune-related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk. METHODS: We conducted two independent case-control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta-analysis which included 12 additional, earlier studies. The meta-analysis comprised a total of 2894 patients (839 IBS-C, 1073 IBS-D, 502 IBS-M), and 3138 healthy volunteers with self-reported Caucasian ancestry. KEY RESULTS: The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta-analysis: IBS (OR 1.19, 95% CI 1.08-1.31), and IBS-C (OR 1.24, 95% CI 1.08-1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes. CONCLUSIONS & INFERENCES: Our meta-analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS-C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.

Age of onset in familial breast cancer as background data for medical surveillance.

BACKGROUND: Familial breast cancers are known to be of early onset. This article provides differences in the age of onset of breast cancer and death by breast cancer between women with and without a family history. METHODS: The Swedish Family-Cancer Database was used to estimate the cumulative risk of breast cancer and death by breast cancer according to family history with a stratified Cox model. Family history was defined separately for affected mother or sister considering their diagnostic ages. RESULTS: The age to reach the same cumulative incidence as women without family history decreased with decreasing diagnostic age of the affected relative. Women with a maternal history reached the risk of women lacking a family history at the age of 50 years between 12.3 (mother affected <40 years) and 3.3 years (mother affected >82 years) earlier. The trend for breast cancer mortality was essentially similar. CONCLUSIONS: Women with mother or sister affected by breast cancer are diagnosed and die at earlier ages than do women without family history. The differences depend on the diagnostic age of the affected relative. The present data may provide a rationale to derive recommendations for the starting age of screening in women with affected family members.

Bladder cancer in cancer patients: population-based estimates from a large Swedish study.

BACKGROUND: This study quantified the risk of urinary bladder neoplasms in cancer patients taking into account the age at first diagnosis, the gender of the patients and the lead time between diagnoses. METHODS: We used standardised incidence ratios (SIRs) to compare the incidence of bladder tumours in 967 767 cancer patients with the incidence rate in the general Swedish population. A total of 3324 male and 1560 female patients developed bladder tumours at least 1 year after first cancer diagnosis. RESULTS: After bladder and renal pelvis cancers, the SIRs of bladder neoplasms were higher in female than in male patients. Men affected by lung, stomach and larynx tumours belonged to the population at high risk for bladder cancer. Treatment of breast, ovarian and cervical cancers seems to contribute to the subsequent development of bladder neoplasms. Long latencies (16-25 years) were observed after testicular, cervical and endometrial cancers. Detection bias had an important role after prostate cancer. Chemotherapy with cyclophosphamide and cisplatin, and also radiotherapy, seem to increase the risk of subsequent neoplasms in the bladder. CONCLUSIONS: These population-based results may help urologists to assess the risk of bladder neoplasms in cancer survivors. Our data should guide ongoing studies that investigate the effectiveness of bladder cancer screening in cancer patients.

Familial gastrointestinal carcinoid tumours and associated cancers.

BACKGROUND: Carcinoid tumours are neuroendocrine neoplasms mainly located in the gastrointestinal tract and bronchopulmonary system. Our study's aim was to characterise the familial nature of gastrointestinal carcinoid tumours using the Swedish Family-Cancer Database, which includes >11.5 million individuals. METHODS: Familial relative risks (RRs) of carcinoid tumours were estimated for individuals with family history of invasive cancers. RRs of invasive cancers for the offspring of patients with carcinoid tumours were calculated as well. RRs were based on Poisson regression. RESULTS: The risk of carcinoid tumours was significantly increased among individuals with a parental history of carcinoid tumours (RR 4.33). An association was also found between carcinoid tumours in the offspring and parental invasive cancers of the brain, breast, liver, endocrine glands and urinary organs. In addition, parental invasive cancers of the kidney as well as squamous cell skin cancer associated with small intestinal carcinoids in the offspring. The risk of carcinoid tumours was elevated among those whose siblings were affected by colon and rectal cancers. CONCLUSION: The results describe the familial aggregation of carcinoid tumours with other noncarcinoid malignancies. Carcinoid tumours are rare and translating these results into screening programmes needs more research; however, gene finding studies should be stimulated.

Modification of second cancer risk after malignant melanoma by parental history of cancer.

The Swedish Family-Cancer Database was used to quantify the incidence of second tumours in melanoma patients with a parental history of cancer. Patients with parents affected by melanoma showed a 32.3-fold risk of second primary melanomas, which was greater than a multiplicative interaction.

Age of onset in familial cancer.

BACKGROUND: Reliable estimates on the age of onset between familial and sporadic cancers are important for etiological understanding and clinical practice. Specific studies on the age of onset of familial cancer compared with sporadic cancer are less common than studies on familial risks and these are almost lacking for rare cancers. MATERIALS AND METHODS: The Swedish Family-Cancer Database was used to estimate cumulative risks of all common cancer types according to family history with a stratified Cox model based on Tsiatis' method. We calculated the age at which the cumulative risk of cancer reached 0.1% and 0.5%. RESULTS: The age to reach a cumulative risk of 0.1% was significantly lower among individuals with a parent or a sibling affected for any of the investigated cancer sites. The age differences ranged from 2.6 years (sons of prostate cancer patients) to 16.3 years (brothers of urinary bladder cancer patients). A cumulative risk of 0.5% was also reached earlier for individuals with a family history, especially for individuals with a parent and a sibling affected. CONCLUSIONS: Cancers in individuals with a family history occur earlier than in sporadic patients. The derived estimates may be useful for clinical counseling and screening recommendations.

Gene-environment interactions and familial relative risks.

OBJECTIVES: Parents share genes and environmental exposures with their offspring. Spouses are often unrelated and their excess of genetic sharing is low, but the similar lifestyles of spouses regarding, for example, tobacco consumption may also result in a familial clustering of disease. This study investigates the influence of gene-environment interactions on the relative risks of disease for the offspring and the spouses of affected individuals. METHODS: Theoretical models were developed to explore the dependence of familial relative risks on environmental parameters (exposure frequency, relative risk of disease for exposed versus unexposed individuals, extent of environmental sharing), on genetic parameters (allele frequency, genotype relative risk and mode of inheritance), on the number of descendants in exposed versus unexposed individuals, and on the model of gene-environment interaction. Lung cancer was used as an example of a complex disease with smoking as a known risk factor. RESULTS: The parent-offspring and the spouse-spouse relative risks of disease varied widely in the strength of the environmental and genetic components and their degree of interaction. The familial relative risk of lung cancer decreased with increasing smoking prevalence. The relationship between exposure frequency and relative risk was markedly different when genes and environment had similar effects on disease susceptibility. CONCLUSIONS: Estimates of the relative risk of disease for varying exposure frequencies may help to assess the relevance of genetic effects in disease etiology. In particular, a positive association between offspring relative risk and exposure frequency may be indicative of genes interacting with environmental factors of similar effect sizes, with the corresponding implications for gene identification studies.

Association of colorectal adenoma with other malignancies in Swedish families.

Using the Swedish Family-Cancer Database covering over 11.5 million individuals, estimated relative risks (RRs) for colorectal adenoma were using Poisson's regression. The RR of colorectal adenoma was found to be increased among first-degree relatives of patients with colorectal cancer (2.72; 95% confidence interval=2.46-3.00) and among the offspring and siblings of patients with endometrial and prostate cancers. We also found an increased risk of colorectal adenoma for the offspring of individuals with stomach cancer and leukaemia, and for siblings of those with pancreatic cancer and multiple myeloma. Our results suggest that colorectal adenoma may share a genetic aetiology with cancer even at extracolorectal sites. Increases of colorectal adenoma in families affected by prostate cancer and acute leukaemia cannot be attributed to known cancer syndromes, although the play of chance cannot be excluded.

Familial risk of cancer shortly after diagnosis of the first familial tumor.

BACKGROUND: The diagnosis of the first cancer in a family may lead to the medical examination of the patient's relatives and the subsequent identification of additional familial cancers. If detection bias is present, familial risks could be overestimated soon after first diagnosis. METHODS: We followed 1,677,722 offspring/siblings of 846,448 probands from the year of diagnosis of the first familial tumor to the diagnosis of first cancer, death, emigration, or December 31, 2002, using the Swedish Family Cancer Database. The risks of cancer among the offspring and siblings of patients with melanoma and cancers of the breast, prostate, colorectum, cervix, and lung were compared with those in the general population. Relative risks (RRs) were determined using Poisson regression, according to the time after first diagnosis. All statistical tests were two-sided. RESULTS: Daughters of women with breast cancer had a statistically significantly higher relative risk of in situ breast cancer during the year of the mother's diagnosis than they did 5 or more years later (RR = 4.78, 95% confidence interval [CI] = 2.16 to 10.6, 26.6 cases per 100,000, versus RR = 1.97, 95% CI = 1.65 to 2.37, 27.2 cases per 100,000; P = .033). Daughters diagnosed the same year as their mothers were younger and were diagnosed earlier in the calendar year than daughters of women diagnosed 5 or more years after their mothers. Similarly, the risk of invasive melanoma among the offspring of individuals with invasive melanoma was higher during the year of the parent's diagnosis than it was 5 or more years afterward (RR = 8.27, 95% CI = 3.82 to 17.9, 57.0 cases per 100,000, versus RR = 3.18, 95% CI = 2.55 to 3.97, 37.6 cases per 100,000; P = .019). Sibling risks of in situ breast cancer, in situ cervical cancer, and invasive prostate cancer also decreased with time after diagnosis of the first familial tumor. CONCLUSIONS: Increased surveillance may result in the earlier detection of asymptomatic familial cancers, i.e., in detection bias. The possibility of overestimated familial risks of cancer shortly after diagnosis of the first familial tumor should be considered before a patient's clinical and genetic counseling is implemented.