Familial risk for colon and rectal cancers.
Explore the source record for details and available documents.
Adenocarcinoma↗
Biomedical subjects
Kari Hemminki
Publications and source records attributed to Kari Hemminki.
The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer.
The insulin-like growth factor 1 (IGF-1) pathway plays an important role in regulating cell proliferation, differentiation and apoptosis. IRS1, IRS2 and SHC1 are the key mediators for the downstream pathway processes. Genetic variation within these genes may lead to altered signalling. We screened IRS1, IRS2 and SHC1 for published coding region polymorphisms and choose five of them, IRS1 Ala804Ala and Gly972Arg, IRS2 Cys816Cys and Gly1057Asp and SHC1 Met300Val, for further analysis. We studied the association of the polymorphisms with breast cancer risk using a case-control design with Polish familial breast cancer cases and respective controls. For the polymorphisms in IRS1 and IRS2 no differences in the allele, genotype or haplotype distributions could be detected between the case and control subjects. Carriers of the variant allele of the SHC1 polymorphism were at decreased risk of breast cancer (OR 0.54, 95% CI 0.32-0.90, P = 0.016). A non-significant trend for a protective effect of the SHC1 Val300 allele was also seen in an independent population consisting of German familial breast cancer cases and matched controls. The joint analysis after Mantel-Haenzsel adjustment of the two populations gave an OR of 0.62 (95% CI 0.41-0.93, P = 0.02) for the SHC1 Val300 carriers. A stronger effect was detected in women diagnosed below the age of 50 (OR 0.54, 95% CI 0.32-0.89, P = 0.01). A genotype combination analysis of the non-synonymous polymorphisms in the IRS1, IRS2 and SHC1 genes did not show any effect on breast cancer risk.
Adaptor Proteins, Signal Transducing↗
Familial risks of cancer as a guide to gene identification and mode of inheritance.
Occurrence of cancer in parents and offspring may be due to dominant causes, whereas cancer affecting only siblings may indicate a recessive causation. Systematic comparisons of mode of inheritance have not been available for most types of cancer. Using the Swedish Family-Cancer Database, standardized incidence ratios (SIR) were calculated for offspring whose parents or siblings were diagnosed with the same cancer. The degree of environmental causation was assessed by spouse correlation and by comparing risks among siblings of different ages. We identified reliable familial risks for all common neoplasms, SIRs ranging from 1.6 to 4.3 when only a parent was affected and up to 8.5 when only a sibling was effected. Risks between siblings were particularly high for renal cancer. Spouse correlation was found only for lung and stomach cancer, but the analysis of sibling risks by their age difference suggested that even for some other cancers environmental effects in childhood may contribute to familial aggregation. The results from these analysis suggest that familial cluster of cancer at most sites is heritable, caused by dominant effects; for renal cancer recessive effects may be most important.
Family↗
Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database.
The importance of genetic factors in etiology of chronic lymphocytic leukemia (CLL) is suggested by family and population studies. However, the spectrum of malignancies sharing common genetic factors with CLL and the effects of sex and age on familial risk are unknown. We used the Swedish Family-Cancer Database to test for increased familial risks of CLL and other lymphoproliferative tumors. Cancer diagnoses from 1958 to 1998 were assessed in 14 336 first-degree relatives of 5918 CLL cases and in 28 876 first-degree relatives of 11 778 controls. Cancer risks in relatives of cases were compared with those in relatives of controls using marginal survival models. Relatives of cases were at significantly increased risk for CLL (relative risk [RR] = 7.52; 95% confidence interval [CI], 3.63-15.56), for non-Hodgkin lymphoma (RR = 1.45; 95% CI, 0.98-2.16), and for Hodgkin lymphoma (RR = 2.35; 95% CI, 1.08-5.08). CLL risks were similar in parents, siblings, and offspring of cases, in male and female relatives, and were not affected by the case's age at diagnosis. Anticipation was not significant when analyzed using life table methods. We conclude that the familial component of CLL is shared with other lymphoproliferative malignances, suggesting common genetic pathways. However, because clinically diagnosed CLL is uncommon, absolute excess risk to relatives is small.
Age of Onset↗
Familial aggregation of Hodgkin lymphoma and related tumors.
BACKGROUND: The importance of genetic factors in the etiology of Hodgkin lymphoma (HL) has been suggested by family and population studies. However, the spectrum of malignancies associated with common genetic etiology and the effects of gender and age on familial risk have not been established. METHODS: Diagnoses of lymphoproliferative malignancies were compared in 15,799 first-degree relatives of 5047 patients with HL versus 32,117 first-degree relatives of 10,078 control probands from Sweden and in 7185 first-degree relatives of 2429 patients with HL versus 27,434 first-degree relatives of 8,495 control probands from Denmark using marginal survival models. RESULTS: The risk of HL in relatives of patients with HL was increased significantly in both populations, with relative risks of 3.47 (95% confidence interval [95% CI], 1.77-6.80) in Sweden and 2.55 (95% CI, 1.01-6.45) in Denmark and a pooled estimate of 3.11 (95%CI, 1.82-5.29). In Sweden, risks for relatives of patients also were increased significantly for chronic lymphocytic leukemia and non-Hodgkin lymphoma (in males). Relative risks were higher in males compared with females and in siblings of patients compared with parents and offspring of patients. Relatives of patients with earlier-onset disease were at higher risk for HL. CONCLUSIONS: HL has an important familial component, which is stronger in families of affected individuals age < 40 years, in males, and in siblings, and it is shared with some (but not other) lymphoproliferative malignancies. The cumulative lifetime risks are very small, however, for the development of HL de novo or in first-degree relatives of affected patients.
Adolescent↗
Familial sarcoma: challenging pedigrees.
Explore the source record for details and available documents.
Adolescent↗
Familial association of histology specific breast cancers with cancers at other sites.
Breast cancer histologies show important differences in their incidence pattern, method of detection and management. Aggregation of breast cancer occurs also in families diagnosed for cancer at sites different from the breast. Therefore, the familial association of histology specific breast cancers with cancers at other sites is of great interest. The nationwide Swedish Family-Cancer Database was used to calculate standardised incidence ratios (SIRs) for breast cancer when parents or sibling were diagnosed with cancer at the most common sites. Significant SIRs were found when parents had breast, ovarian, laryngeal, endometrial, prostate, lung and colon cancers. If women were diagnosed before the age of 50 years, the SIRs were significant when parents were diagnosed with breast, ovarian, and prostate cancers, and leukaemia, and when siblings were diagnosed with squamous cell skin, pancreatic, breast and endometrial cancers. If mothers were diagnosed with breast cancer, histology-specific SIRs were ranked as comedo > tubular > ductal > lobular; SIR for medullary carcinoma was not significant but it was high when mothers presented with ovarian cancer. Other associations were between the upper aerodigestive tract and lobular, colon and comedo, larynx and ductal cancer. Moreover, cervical cancer was associated with comedo and endometrial cancer with the medullary histology. In conclusion, histology-specific breast cancers were associated with specific cancer sites and the strength of the association varied among histologies.
Aged↗
Familial association of specific histologic types of ovarian malignancy with other malignancies.
BACKGROUND: Population-based data on the familial association of specific histologic types of ovarian malignancy with other malignancies are limited. Such data may help to elucidate etiologic differences among histologic types of ovarian malignancy. METHODS: The nationwide Swedish Family-Cancer Database, which includes 10.3 million individuals and 20,974 ovarian carcinomas, was used to calculate standardized incidence ratios and 95% confidence intervals for age- and histology-specific ovarian malignancies in women whose parents or siblings were affected with malignancies at the most common disease sites. RESULTS: Ovarian malignancy was found to be associated with ovarian, laryngeal, breast, endometrial, liver, and colon carcinoma, as well as myeloma; epithelial ovarian malignancy was found to be associated with ovarian, endometrial, and skin malignancies and with melanoma and myeloma; papillary serous cystadenocarcinoma was found to be associated with ovarian and skin malignancies and with myeloma; and endometrioid carcinoma was found to be associated with endometrial, ovarian, and prostate malignancies and with melanoma. For younger women (ages 40-45 years) whose mothers were affected with endometrial malignancies, the risk of developing endometrioid carcinoma was slightly greater than the risk of developing papillary serous cystadenocarcinoma. CONCLUSIONS: Specific types of ovarian malignancy may be associated with specific familial disease sites, with such associations depending on age at diagnosis; the strength of the observed associations varied according to histology. Associations were found between endometrioid carcinoma and endometrial malignancy and between serous carcinoma and Hodgkin disease.
Adult↗
Re: Integrin beta3 Leu33Pro homozygosity and risk of cancer.
Explore the source record for details and available documents.
Alleles↗
Genetic polymorphisms in DNA repair genes and possible links with DNA repair rates, chromosomal aberrations and single-strand breaks in DNA.
We analysed the associations between genetic polymorphisms in genes coding for DNA repair enzymes XPD (exon 23 A --> C, K751Q), XPG (exon 15 G --> C, D1104H), XPC (exon 15 A --> C, K939Q), XRCC1 (exon 10 G --> A, R399Q) and XRCC3 (exon 7 C --> T, T241 M) and the levels of chromosomal aberrations (CAs) and single-strand breaks (SSBs) in peripheral lymphocytes in a central European population. We also measured the irradiation-specific DNA repair rates and the repair rates of 8-oxoguanines in these individuals. An elevated frequency of CAs was observed in individuals with the XPD exon 23 A allele (AA and AC) genotypes (F = 3.6, P = 0.028, ANOVA). In multifactorial analysis of variance, the XPD exon 23 polymorphism appeared as a major factor influencing CAs (F = 4.2, P = 0.017). SSBs in DNA, on the other hand, were modulated by XPD (F = 4.3, P = 0.023), XPG (F = 4.3, P = 0.024) and XRCC1 genotypes (F = 3.0, P = 0.064). Irradiation-specific DNA repair rates (reflecting mainly base excision repair activity) were affected by XRCC1 (F = 5.9, P = 0.010) and XPC polymorphisms (F = 4.2, P = 0.046, MANOVA). Our results from this study suggest that markers of genotoxicity are associated with polymorphisms in genes encoding DNA repair enzymes.
Adult↗
Familial risk of cancer: data for clinical counseling and cancer genetics.
Familial risks for cancer are important for clinical counseling and understanding cancer etiology. Medically verified data on familial risks have not been available for all types of cancer. The nationwide Swedish Family-Cancer Database includes all Swedes born in 1932 and later (0-to 68-year-old offspring) with their parents, totaling over 10.2 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry up to year 2000. Standardized incidence ratios (SIR) and 95% confidence limits (CI) were calculated for age-specific familial risk in offspring by an exact proband status. The familial risks for offspring cancer were increased at 24/25 sites from concordant cancer in only the parent, at 20/21 sites from a sibling proband and at 12/12 sites from a parent and sibling proband. The highest SIRs by parent were for Hodgkin's disease (4.88) and testicular (4.26), non-medullary thyroid (3.26), ovarian (3.15) and esophageal (3.14) cancer and for multiple myeloma (3.33). When a sibling was affected, even prostate, renal, squamous cell skin, endocrine, gastric and lung cancer and leukemia showed SIRs in excess of 3.00. The highest cumulative risks were found for familial breast (5.5%) and prostate (4.2%) cancers. We identified reliable familial risks for 24 common neoplasms, most of which lack guidelines for clinical counseling or action level. If, for example, a familial SIR of 2.2 would be use as an action level, counseling would be needed for most cancers at some diagnostic age groups. The present data provide the basis for clinical counseling.
Adolescent↗
Markers of individual susceptibility and DNA repair rate in workers exposed to xenobiotics in a tire plant.
Workers employed in tire plants are exposed to a variety of xenobiotics, such as 1,3-butadiene (BD), soots containing polycyclic aromatic hydrocarbons, and other organic chemicals (e.g., styrene). In the present study, we investigated markers of genotoxicity [chromosomal aberrations (CAs) and single-strand breaks (SSBs)] in a cohort of 110 tire plant workers engaged in jobs with different levels of xenobiotic exposure in relation to various polymorphisms in genes coding for biotransformation enzymes (CYP1A1, CYP2E1, EPHX1, GSTM1, GSTP1, and GSTT1) and in genes involved in DNA repair (XPD exon 23, XPG exon 15, XPC exon 15, XRCC1 exon 10, and XRCC3 exon 7). In addition, the expression of CYP2E1, a gene playing a key role in BD metabolism, was determined by real-time PCR in peripheral blood lymphocytes, and the capacity of lymphocytes to repair gamma-ray-induced SSBs and to convert 8-oxoguanine in HeLa cell DNA into SSBs was assessed using in vitro assays. No positive associations were detected between the CA frequency or SSB induction and levels of workplace exposure; however, a nonsignificant twofold higher irradiation-specific DNA repair rate was found among highly exposed workers. In evaluations conducted with the markers of individual susceptibility, workers with low-EPHX1-activity genotypes exhibited a significantly higher CA frequency as compared to those with medium and high-EPHX1-activity genotypes (P = 0.050). CA frequencies were significantly lower in individuals homozygous for the XPD exon 23 variant allele in comparison to those with the wild-type CC genotype (P = 0.003). Interestingly, CAs were higher in individuals with higher CYP2E1 expression levels, but the association was nonsignificant (P = 0.097). The results from this study suggest the importance of evaluating markers of individual susceptibility, since they may modulate genotoxic effects induced by occupational exposure to xenobiotics.
Adult↗
Use of pyrosequencing to detect clinically relevant polymorphisms of genes in basal cell carcinoma.
BACKGROUND: Pyrosequencing is a new method to detect single nucleotide polymorphisms (SNPs). Basal cell carcinoma (BCC) is one of the most common neoplasms in the world, and its incidence has been increasing worldwide in recent years. BCC is caused by an interplay between genetic and environment factors. METHODS: Pyrosequencing and restrict fragment length polymorphism (RFLP) were used in the study. We conducted a case-control association study in BCC cases and controls from Sweden. For SNPs in IL-6, IL-10 and IL-1beta, 241 cases were at the age of 27-70 years (mean 50 years) and 260 healthy controls were 26-71 years (mean 48 years), 241 cases were 27-70 years (mean 50 years) and 574 healthy controls were 22-74 years (mean 52 years) for cyclin D1 G870A, 197 cases were 29-69 years (mean 47 years) and 574 healthy controls were 22-74 years (mean 52 years) for MTHFR C677T and A1298C. Nine SNPs for IL-6-174G/C, -634G/C and -597G/A; IL-10-1082G/A and -592C/A; IL-1beta-511C/T; cyclin D1 G870A; MTHFR C677T and A1298C were analyzed. RESULTS: Most genotype distributions were in accordance with Hardy-Weinberg equilibrium (HWE), except IL-10-1082G/A, which had a significantly deviation from HWE in BCC cases (P<0.05). Linkage disequilibrium was observed between the -174 and -597 alleles in the IL-6 gene in the studied populations. The differences for cyclin D1 G870A and methylenetetrahydrofolate reductase (MTHFR) C677T were found between BCC cases group and control group (P<0.05, OR=1.34, 95% CI, 1.00-1.74; P<0.05, OR=1.67, 95% CI, 1.13-2.47, respectively). CONCLUSIONS: Cyclin D1 G870A and MTHFR C677T were associated with BC cases from Sweden, the other SNPs studied here were not associated with BCC, but chance cannot be excluded.
Adult↗
Familial association of colorectal adenocarcinoma with cancers at other sites.
Data on the familial associations of colorectal cancer (CRC) of adenocarcinoma histology are limited, but they are of interest because they may give us clues about as yet unknown family clusters. We calculated standardised incidence ratios (SIRs) for right- and left-sided colon cancer and rectal cancer in offspring using data from the Swedish Family-Cancer Database covering familial tumours from 1991 to 2000. The offspring were at an increased risk of developing colon adenocarcinoma when parents presented with CRC (SIR 1.81), endometrial (SIR 1.52) and kidney (SIR 1.42) cancers. The SIRs in siblings were increased when a co-sibling was diagnosed with CRC (SIR 3.26), myeloma (SIR 2.65) and leukaemia (SIR 2.53). Right-sided colon cancer was associated with familial pancreatic, squamous cell skin cancers, thyroid gland cancer and Hodgkin's disease. Left-sided colon cancer was associated with testicular cancers. Rectal cancer was associated with cervical and genital cancers in mothers. Most of the findings were consistent with data on known cancer syndromes. A new association was noted where rectal cancer in offspring was related to cervical and female genital cancers in mothers through an unknown mechanism. Hodgkin's disease and myeloma were also associated with right-sided colon cancer in offspring. The association with carcinoma of the testis, renal parenchyma, skin and leukaemia need to be confirmed in an independent series.
Adenocarcinoma↗
Familial association of leukemia with colorectal cancer.
Explore the source record for details and available documents.
Adolescent↗
BRAF mutations are common somatic events in melanocytic nevi.
We determined mutations in the BRAF, N-ras, and CDKN2A genes in 27 histologically diverse melanocytic nevi and corresponding surrounding tissues from 17 individuals. Mutations in the BRAF and N-ras gene were found in 22 nevi (81%) from 16 individuals (94%). The predominant BRAF mutation T1799A (V600E) was detected in 18 nevi; 1 nevus had a novel A1781G (D594V) mutation in the same gene and 3 nevi had mutations in codon 61 of the N-ras gene. In 4 individuals both nevi carried a BRAF mutation, whereas in 2 other individuals 1 nevus showed a BRAF mutation and the second nevus had an N-ras mutation. In 2 individuals normal skin distant from nevi showed a BRAF mutation. No mutations were detected in the CDKN2A gene. The mutations in the BRAF and N-ras genes, in this study, were not associated with histologic type, location, skin type, size, or numbers of nevi. Our results suggest that mutations in the BRAF gene and to some extent in the N-ras gene represent early somatic events that occur in melanocytic nevi. We hypothesize the dual effect of solar ultraviolet irradiation on melanoma, through mutagenesis and by increasing the number of melanocytic nevi, many of which carry a BRAF or N-ras mutation.
Adult↗
Occupational risks for nasal cancer in Sweden.
An elevated risk of nasal cancer (NC) has been associated with numerous occupations but with contradicting results. We sought to address recent and current risks of NC in a nationwide study. The nationwide Swedish Family-Cancer Database was used to calculate standardized incidence ratios (SIRs) for 52 occupational groups. SIRs were adjusted for age and socioeconomic status. Among 739 male cases, significantly elevated SIRs for nasal adenocarcinoma were observed in woodworkers, teachers, and fishermen. In woodworkers, the risk increased with a longer occupational history in exposure to softwood in combination with hardwood. Electrical workers had a significant elevated risk for squamous cell carcinoma. Among 182 female cases, significantly elevated SIRs were observed in glass, ceramic, and tile workers. The study identified some known risk occupations and suggested some new ones.
Adenocarcinoma↗
Age-specific familial risks for renal cell carcinoma with evidence on recessive heritable effects.
BACKGROUND: Systematic comparisons of mode of inheritance for renal cell carcinoma (RCC) have not been carried out. The occurrence of cancer in parents and offspring may be due to dominant causes, whereas cancer affecting only siblings may indicate a recessive causation. Environmental effects need to be excluded. METHODS: The Swedish Family-Cancer Database includes all Swedes born after 1931 with their biologic parents, totaling 10.2 million persons. Cancer data were retrieved from the Swedish Cancer Registry from years 1961 to 2000, included 2415 cases of RCC in offspring and 18531 in parents. Standardized incidence ratios (SIRs) and 95% CI limits were calculated for offspring whose parents or sibling were diagnosed with RCC. RESULTS: The SIRs for siblings for RCC depended on their age difference. SIR was 7.63 (95% CI 3.63-14.08) when the age difference was less than 3 years and compared to 3.43 (95% CI 1.77-6.02) for large age difference. SIRs for familial risk of RCC were 1.73 (95% CI 1.31-2.26) when a parent and 4.58 (95% CI 2.87-6.94) when a sibling had RCC. Age-specific analysis of familial RCC among siblings revealed maxima at ages 40 to 49 and 60 to 68 years. CONCLUSION: The findings in the present study offer evidence on recessive effects in early onset RCC.
Adolescent↗