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Biomedical subjects

K Hemminki

Publications and source records attributed to K Hemminki.

At least 73 records · Page 4Linked to original sources
PubMed2001

Sibling risks in cancer: clues to recessive or X-linked genes?

A systematic analysis of cancer risks to offspring and to siblings of cancer cases was carried out based on the nation-wide Swedish Family-Cancer Database. For all 13 cancer sites examined, risks to both offspring and siblings of cases of cancer at the same site were significantly elevated. The relative risk to siblings was approximately 2 fold more than the offspring risk for cancers of the prostate, testis, kidney and bladder, suggesting that recessive or X-linked susceptibility genes may be important for these cancers. Risks to siblings of cases where a parent was also affected were increased >20 fold over population rates for colorectal, ovarian, prostate and renal cancer, and for leukaemia, consistent with the effects of rare high-risk susceptibility alleles.

Family Health↗
PubMed2001

Genetic epidemiology of multistage carcinogenesis.

It is commonly believed that cancer is a multistage, polygenic disease. Even though conceptually appealing, the evidence supporting the multistage theory remains limited. Most known tumor suppresser genes are associated with monogenic dominant cancers following a two-hit pathway. We review results from a recent twin study on 90000 individuals that give support to the multistage theory. Statistically significant heritability estimates were shown for cancers of the colorectum (35%), breast (27%), and prostate (42%). These estimates are much higher than those obtained from family studies in which parents and offspring, or sibs are compared. The difference can be accounted for by the involvement of many genes. A polygenic cancer would show small effects in family studies but large effects in twin studies. We present calculations on the decrease in familial risks when the number of genes involved increases or when the penetrance decreases. We test the apparent number of stages involved in the main cancers from the Swedish Family-Cancer Database. The logarithms of the slopes suggest large differences in the apparent numbers of mutations involved in different cancers. The number of mutations required appears to be less in familial breast cancer compared to sporadic breast cancer. Study designs for gene identification should be revised to accommodate polygenic cancers.

Databases, Factual↗
PubMed2001

Estimation of genetic and environmental components in colorectal and lung cancer and melanoma.

Cancer has predominant environmental and somatic causes but the assessment of hereditary (genetic) causes is difficult, except for highly penetrant single-gene causes. Family studies are only partially informative in this regard because family members share diet and life-styles. Twin studies have been classically used to disentangle the effects of heredity and environment on disease etiology. We estimate the genetic and environmental components in colorectal and lung cancer and melanoma by comparing cancer risks in family members. The Swedish Family-Cancer Database, comprising more than 6 million individuals, was used as the source of family and cancer data. Tetrachoric correlations were used to describe similarity in cancer liability among family members. Structural equation modelling was used to derive estimates of the importance of genetic and environmental effects. The estimated genetic component ranged from 10% in colon and colorectal cancer to 18% in melanoma. For lung cancer, the share was 14%. If assortative mating were important for liability to cancer, these heritability estimates may be an underestimation of the true genetic effects. Non-shared environmental effect was 67-68% in colorectal cancer and melanoma, and 71% in lung cancer. Shared and childhood environments were equally important in colorectal cancer and melanoma, whereas no childhood effect was observed for lung cancer.

Adolescent↗
PubMed2001

Cancer risks to spouses and offspring in the Family-Cancer Database.

It is generally accepted that cancer is caused by environmental and inherited factors but these are only partially identified. Family studies can be informative but they do not separate shared lifestyles and genes. We estimate familial risks for concordant cancers between spouses in common cancers of both sexes in order to quantify cancer risks from the shared environment. The risks are compared to those seen between parents and offspring in order to estimate the inherited component. The nation-wide Family-Cancer Database was used as the source of family and cancer data. Standardized incidence ratios (SIRs) were calculated for concordant cancer in offspring by parental cancer and in spouses. Among the 23 cancer sites considered, all but two showed an increased SIR for offspring by father or mother. Only two sites, stomach and lung, showed an increase in SIR of concordant cancer among spouses. Additionally, pancreatic cancer and melanoma were increased in couples where at least one spouse was diagnosed before age 50. If both spouses presented melanoma before age 40, SIR was 3.82 for husbands. SIRs of colon, renal, and skin (squamous cell) cancers were unchanged by spouses' concordant cancer. Shared lifestyle among spouses seems to explain only a small proportion of cancer susceptibility. Because lifestyles are likely to differ more between parents and offspring than between spouses, familial cancer risks between parents and offspring are likely to be more due to heritable rather than environmental effects.

Adolescent↗
PubMed2001

DNA adducts of 1,3-butadiene in humans: relationships to exposure, GST genotypes, single-strand breaks, and cytogenetic end points.

The modulation of 1,3-butadiene (BD)-induced DNA adducts by occupational exposure, glutathione S-transferase (GST) genotypes, single-strand breaks, and cytogenetic end points was studied in 15 workers and 11 controls. The exposed group consisted of 8 smokers and 7 nonsmokers, whereas the control group consisted of 7 nonsmokers and 4 smokers. Among all subjects, the adduct levels in workers lacking GSTM1 were significantly higher than in those who were GSTM1 positive (P = 0.026), and individuals with combined GSTM1(-) and GSTT1(+) genotype had elevated level of adducts compared to that of persons with GSTM1(+) and GSTT1(+) (P = 0.049). The increase in BD-DNA adduct levels in all subjects was significantly related to BD exposure and GSTM1 genotype (linear multiple regression analysis, P = 0.001; P = 0.035). The results suggest that DNA adducts serve as a sensitive and specific biomarker, integrating exposure and host metabolic capacity, although the data are limited to a small number of subjects.

Adult↗
PubMed2001

A population-based study of familial soft tissue tumors.

We used the nationwide Swedish Family-Cancer Database to analyze the risk for soft tissue tumors in offspring by parental cancers and in siblings of soft tissue tumor probands. Additionally, risk for second cancer following soft tissue tumor was investigated. In offspring, 1488 soft tissue tumors were diagnosed between years 1958 and 1996. Groups of offspring were compared by calculating standardized incidence ratios (SIRs) for soft tissue tumors. Parental breast, prostate and connective tissue cancers were associated with offspring soft tissue tumors in sex- and age-specific groups. The SIRs were of borderline significance, suggesting a small etiological contribution by Li-Fraumeni syndrome. Soft tissue tumors conveyed a high risk of second soft tissue tumor, probably partially due to recurrences. However, the observed risk for second nervous system cancer was consistent with Li-Fraumeni syndrome. Other associations were unlikely to be due to Li-Fraumeni or other known syndromes, but they could be spurious findings arising from multiple comparisons. Among these, parental stomach cancer (SIR 3.19, 95% CI 1.69-5.17) and endocrine gland tumors (SIR 3.66, 95% CI 1.32-7.17), particularly parathyroid tumors (SIR 4.46, 95% CI 1.41-9.23), were associated with offspring fibrosarcoma, and parental breast cancers with offspring leiomyosarcoma (SIR 2.04, 95% CI 1.08-3.30).

Adolescent↗
PubMed2001

Loss of heterozygosity in tumour-adjacent normal tissue of breast and bladder cancer.

Normal tumour-adjacent breast tissue samples from 12 breast cancer patients forming six monozygotic twin pairs were analysed for loss of heterozygosity (LOH) on chromosomes 1, 13 and 17. 7 patients showed LOH at one or more markers. Each of them had a different LOH pattern. Only one twin pair showed LOH at the same locus, but the twins had lost a different allele. Multiple (n=1-13), histologically normal samples were collected from 6 bladder cancer patients and analysed for LOH on chromosomes 3 and 9. On chromosome 9, all 6 patients analysed showed LOH in at least one sample and one marker. Four of them also showed LOH on chromosome 3. Samples surrounding different tumours of a given patient resembled each other. More heterogeneity was seen between the patients, even though they shared some similarities in LOH clustering. The results demonstrate that tumour-adjacent normal tissues already harbour genetic changes typical for tumours. These alterations can reveal the earliest changes leading to tumorigenesis.

Breast Neoplasms↗
PubMed2001

Familial testicular cancer and second primary cancers in testicular cancer patients by histological type.

The Swedish Family-Cancer Database was used to assess familial cancer risks in first-degree relatives and the risks of second primary cancers in testicular cancer patients by the histological type of their testicular cancers. Standardised incidence ratios (SIRs) were employed to estimate cancer risks. Among 4650 patients, 1.3% were familial testicular cancer. Seminomas showed a 10 years later median age of onset than teratomas (30 versus 40 years). The familial risks of testicular cancer were 3.8 for fathers, 8.3 for brothers and 3.9 for sons; they were similar for the two histologies. The fraternal risks were elevated 2- to 2.8-fold for pure histologies compared with the mixed histologies. Significantly increased risks for subsequent cancers were observed in the stomach, pancreas, testis, kidney, bladder, thyroid and connective and lymphatic tissues in the patients. Our data support the contention that genetic predisposition is one of the major contributors to familial and multiple testicular cancers.

Adult↗
PubMed2001

Second primary neoplasms after 19281 endocrine gland tumours: aetiological links?

The nationwide Swedish Family-Cancer Database of 9.6 million individuals was used to analyse the development of second neoplasia after 6909 thyroid and 12697 other endocrine tumours. Tumour cases were retrieved from the Swedish Cancer Registry from 1958 to 1996. The risk of a second endocrine tumour was markedly increased compared with first endocrine tumour; e.g. the standardised incidence ratios (SIRs) were well over 10 for adrenal tumours after thyroid cancer, and vice versa. Familial risks were higher for the development of second compared with first neoplasms, and the SIRs for men were usually higher than those for women. Many increases between different endocrine glands can probably be ascribed to known cancer syndromes. Even cancers at some other sites were increased after the development of primary endocrine tumours. Notably, small intestinal carcinoids were increased after thyroid and other endocrine tumours, and brain menigiomas were increased after parathyroid and pituitary adenomas. These novel associations suggest shared risk factors for these sites. However, many endocrine tumours are benign and the diagnosis of the first tumour may increase the likelihood of a second diagnosis.

Endocrine Gland Neoplasms↗
PubMed2001

Parental cancer as a risk factor for brain tumors (Sweden).

OBJECTIVE: We used the nationwide Swedish Family-Cancer Database to analyze the risk for adult (15-61 years) brain tumors in offspring through parental cancer probands. Additionally, cancer risks were assessed among siblings of brain tumor probands. METHODS: In offspring and parents, respectively, 5,425 and 20,938 cases of brain tumors were diagnosed between the years 1958 and 1996. Groups of offspring were compared by calculating standardized incidence ratios (SIRs) for brain tumors. RESULTS: Of brain tumor patients, 2.1% had a parent with nervous system cancer; SIRs were 1.7, 2.4, and 2.5 for all brain tumors, astrocytomas, and meningiomas, respectively. Parental endometrial cancer and melanoma were associated with offspring astrocytoma, and parental breast and thyroid cancers with offspring ependymoma and neurinoma, respectively. SIR for sibling nervous system tumors from brain tumor probands was not increased overall but was 2.5 in those diagnosed at ages 15-34 years. CONCLUSION: These data show a familial risk for brain tumors among adults.

Adolescent↗
PubMed2001

Population-based study of familial medullary thyroid cancer.

BACKGROUND: We wanted to carry out a population-based study on medullary thyroid cancer (MTC) in order to quantify familial risks. METHODS: MTC was studied in the Swedish Family-Cancer Database, updated in 1999 to cover individuals and offspring, born after 1934 with their biological parents, totaling 9.6 million persons. Cancer data were obtained from the Swedish Cancer Registry from year 1958 to 1996 and included 2,435 thyroid cancers among offspring. RESULTS: 65 offspring were identified with MTC, which was coded as a separate entity since 1985. 62% had neither affected parent nor sib. Most familial cases were diagnosed at ages 15 to 24 and sporadic cases 25 years later. The familial SIRs of MTC were 3,080 and 3,650 when either a parent or a sib had MTC; when both had MTC the SIR was 35,800. All the familial risks were highest in young age groups, 0-9 years. MEN 2 or MEN 2-like families were considered when one family member had a TC and an adrenal pheochromocytoma. SIR of MTC in offspring was 61,000 when a parent had a MEN 2-like cancer and a sib had MTC. CONCLUSIONS: We described familial and sporadic MTC in a population-based database. The familial risks of MTC may be the highest ever reported in population based studies.

Adolescent↗
PubMed2001

Age-incidence relationships and time trends in cervical cancer in Sweden.

Age-incidence relationships are informative of carcinogenic mechanisms. These have been previously assessed for cervical squamous cell carcinoma (SCC) but not for adenocarcinoma. The aim was to assess by means of age-, period- and cohort-specific analyses and Poisson regression modelling whether the two types of cervical cancer show an age-incidence maximum at a relatively young age, as shown in cross-sectional analyses. The Swedish Family-Cancer Database was used to analyse age-incidence relationships in cervical SCC and adenocarcinoma diagnosed in years 1958-1996, including a total of 15,118 and 1866 cases, respectively. Area of residence and socio-economic status were included in analyses because they were risk factors of cervical cancer. The analysis of cervical SCC confirmed an incidence maximum at ages 35-39 years. The data for adenocarcinoma also suggested a similar early age maximum but the curves differed extensively by birth cohort. The incidence of adenocarcinoma increased substantially at young age groups towards the end of follow-up. Endometrial adenocarcinoma and vaginal and vulvar SCC, which share some risk factors with cervical cancer, did not show an early age incidence maximum. The results also showed that there was a decrease in the incidence of cervical SCC around year 1960, almost 10 years before the organized population screening, probably due to introduced opportunistic pap testing. The benefits of the organized screening were observed as a further decline in the incidence rates. The unique age-incidence relationships in cervical cancer call for biological explanations.

Adenocarcinoma↗
PubMed2001

The prevalence of loss of heterozygosity in chromosome 3, including FHIT, in bladder cancer, using the fluorescent multiplex polymerase chain reaction.

OBJECTIVE: To determine some of the genetic alterations involved in the pathogenesis and progression of transitional cell carcinoma of the bladder. Materials and methods In a population-based study, freshly frozen tissue was collected from all patients newly diagnosed with urinary bladder cancer in the Stockholm region during 1995-1996. The prevalence of loss of heterozygosity (LOH) was assessed at seven sites on chromosome 3, analysed in 151 patients, using a fluorescent multiplex polymerase chain reaction based on DNA from the tumour and peripheral blood. RESULTS: LOH was detected in 12.1% (at 3q25-26.2) to 22.1% (at 3p11-12) of the informative cases. Relatively frequent LOH was detected at 3p22-24.2 (21.6%), at 3p14.2 within FHIT (21.5%), and at 3p11-12 (22.1%). Of 151 tumours, 72 (47.7%) showed LOH at one or more loci on chromosome 3. LOH on chromosome 3 was weakly associated with tumour grade (P = 0.095), but not with tumour stage (P = 0.701). However, when the frequency of LOH was analysed individually at each site, the prevalence of LOH at 3p11-12 was closely correlated with higher tumour stage (P = 0.011). Replication errors were detected in only four of 151 (2.6%) tumours. Conclusion These findings suggest that the 3p11-12 locus may involve a putative candidate tumour-suppressor gene which might be associated with bladder tumour invasiveness. The FHIT gene locus showed a relatively high frequency of LOH even in Ta tumours.

Acid Anhydride Hydrolases↗