Pauli Vaittinen

The nation-wide Swedish family-cancer database updated structure and familial rates

The Swedish Family-Cancer Database was expanded to include all Swedes born in 1932 and later (offspring) with their parents, totaling 10.2 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry from the years 1958 to 1998, including over 1 million primary cancers and in situ tumors. Some 10% of offspring diagnosed with cancer lack any parental information. Incidence rates of cancers were similar in the database and in the Cancer Registry to age 70, but at higher ages the rates in the Database were lower, probably because of selection. The familial risk for all types of cancer in offspring was 1.73 when a parent had the same type of cancer. The familial rates were increased for all main cancer sites, except for the upper aerodigestive tract, stomach, liver, pancreas and bone marrow (leukemia). The rates were 7.47 for thyroid, 4.69 for testis, and over 2.00 for melanoma, ovary, prostate, skin, endocrine glands and endometrium.The Swedish Family-Cancer Database was expanded to include all Swedes born in 1932 and later (offspring) with their parents, totaling 10.2 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry from the years 1958 to 1998, including over 1 million primary cancers and in situ tumors. Some 10%, of offspring diagnosed with cancer lack any parental information. Incidence rates of cancers were similar in the database and in the Cancer Registry to age 70, but at higher ages the rates in the Database were lower, probably because of selection. The familial risk for all types of cancer in offspring was 1.73 when a parent had the same type of cancer. The familial rates were increased for all main cancer sites, except for the upper aerodigestive tract, stomach, liver, pancreas and bone marrow (leukemia). The rates were 7.47 for thyroid, 4.69 for testis, and over 2.00 for melanoma, ovary, prostate, skin, endocrine glands and endometrium.

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.

Parental age as a risk factor of childhood leukemia and brain cancer in offspring

We use here the Swedish Family-Cancer Database to analyze the time trends in childhood leukemia and brain cancer between 1960 and 1994 and the effect of parental age on childhood leukemia and brain cancer of some 1500 cases each. The database includes all persons born in Sweden after 1940 with their biological parents, over 6 million individuals, whose cancers were retrieved from the Swedish Cancer Registry from years 1958-1994. Incidence in cancer increased from 1960 to 1994; low grade astrocytoma accounted for most of the increase, whereas high grade astrocytoma has not increased in incidence. There has been a moderate increase in leukemia to about 1980. We found a parental age effect for both leukemia and brain cancer, with the former (of about 50% excess in those over 35 years) being mediated by maternal age and the latter (of about 25% excess) by paternal age. Accumulation of chromosomal aberrations and mutations during the maturation of germ cells is a likely mechanism for these findings. They can help to explain partially the secular trends of these malignancies and the excess risks in offspring of the well educated.

Familial risks in cervical cancer: is there a hereditary component?

The Swedish Family‐Cancer Database was used to analyze familial relationships in mothers and daughters in invasive and in situ cervical cancers from years 1958–1994, including a total of 125,000 in situ and 14,000 invasive cancers. In situ cancers were diagnosed on average 10 years earlier than invasive cancers. Familial relative risks (FRRs) were calculated separately for mothers and daughters, and were between 1.8 and 2.3 for the 2 forms. The risks were only slightly modified by age of onset, except at higher ages where there was no familial risk; in mothers, the risks increased if more than one daughter was affected. Aggregation of in situ cases among sisters was observed in families. Heritability estimates were between 0.11 and 0.15 for in situ and 0.22 and 0.34 for invasive cervical cancer. A comparison of cancers in mothers and daughters showed an association between cervical cancer and many cancer types observed in immunosuppressed patients, suggesting a role for a mild form of immunosuppression, in addition to sexual behavior leading to human‐papilloma‐virus infections, in familial cervical cancer. Int. J. Cancer 82:775–781, 1999.

Risk factors and age-incidence relationships for contralateral breast cancer.

The nation‐wide Swedish Family‐Cancer Database was used to analyze the risk of contralateral breast cancer among 72,092 women with unilateral breast cancer. Contralateral breast cancer, defined as being diagnosed 6 months or more after the first breast cancer, affected 2,529 women (3.5%). In a young age group the incidence of contralateral breast cancer was 50 times higher than the incidence of first breast cancer; for all contralateral breast cancer the difference was 5‐fold. Because only 1 breast was at risk for contralateral breast cancer, the true differences to unilateral cancer were 2 times higher. The age‐incidence relationship was unusual, exhibiting a high incidence (800/105 person‐years) component at an early age (25 to 49 years) and a lower incidence (460/105 person‐years) component at a later age (50–80 years). The discrete components suggest population heterogeneity. Age at diagnosis of the first breast cancer and family history of breast cancer associated with the risk of contralateral breast cancer. Other, weaker risk factors were birth cohort, age at first childbirth, parity and interval between first and second breast cancer. The incidence of familial contralateral breast cancer was 1.5 times higher than that of sporadic disease, and its age‐incidence curve also exhibited 2 separate components. The age‐incidence relationships of contralateral breast cancer suggest that the disease affects a small and heterogeneous susceptible population. Int. J. Cancer 88:998–1002, 2000.

National database of familial cancer in Sweden

A family cancer database was constructed from the nationwide Swedish registries and includes ˜6 million persons and >30,000 cancers in offspring diagnosed at ages 15–51 years and their parents. A particular advantage of the database is that the contribution of both parental lineages on cancer risk can be examined. Cancer risk in the offspring was increased ˜1.1 times when the father had cancer, and no increase was noted when the mother had cancer. If both parents had cancer, the risk for sons was 1.4 and for daughters 1.3. The sites of increased cancer risk in the offspring were colorectum, breast, cervix, corpus uteri, ovary, testis, melanoma, eye, other endocrine glands, and multiple myeloma. The results among young and middle‐age adults suggest that cancer in both parents increases the cancer risk in the offspring at many sites. The molecular genetic explanation may be that rare dominant single genes increase susceptibility at many sites, or that overlapping sets of genes control susceptibility at multiple sites. Genet. Epidemiol. 15:225–236, 1998.

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. Genet. Epidemiol. 20:107–116, 2001.

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. Genet. Epidemiol. 20:247–257, 2001.

Familial breast cancer in the family-cancer database

We use the population‐based Family‐Cancer Database from Sweden to study familial breast cancer. The size of the population and the nation‐wide registration of cancer offer unique possibilities for epidemiological studies of familial cancer, including complete and unbiased identification of cases in the probands and in their relatives, and complete and unbiased identification of the family relationships. Using the Database, we wanted to answer the following questions: (i) proportion of familial breast cancer among all breast cancers; (ii) familial relative risks in breast cancer alone or in combination with another cancer, defined either through the mother or the daughter; (iii) modification of familial risk by age; and (iv) effects of paternal breast cancer alone or in combination with maternal breast cancer. The proportion of familial female breast cancer among all breast cancers before 54 years of age in Sweden was 8.7%. The familial relative risk was about 1.8, but is likely to decrease to about 1.5 in the ageing population. The higher familial relative risks were evident in young women, being 4.0 when both the mothers and their daughters were diagnosed at ages <40 years. Paternal breast cancer, in combination with maternal breast cancer, caused a large (but not statistically significant) risk in the daughters. In mothers and daughters, ovarian but not colon cancer was increased in combination with breast cancer. Int. J. Cancer 77:386–391, 1998.

Time trends in the incidence of cervical and other genital squamous cell carcinomas and adenocarcinomas in Sweden, 1958–1996

OBJECTIVES We wanted to examine reasons for the different incidence trends for cervical squamous cell carcinoma (SCC, declining) and adenocarcinoma (increasing). METHODS The Swedish Family-Cancer Database on 9.6 million individuals was used to derive incidence trends between 1958 and 1996. Cervical cancers were compared to vaginal and vulvar cancers. RESULTS A total of 15405 invasive cervical SCCs and 1920 adenocarcinomas were identified. The incidence of SCCs decreased and that of adenocarcinoma increased during the study period, with similar trends among the in situ forms. The incidence of in situ vaginal and vulvar SCC increase 22-fold, whereas, invasive SCC and adenocarcinoma remained unchanged. The age-incidence curves for adenocarcinoma resembled those for SCC before screening, suggesting similar clinical course. CONCLUSIONS The data suggest that the increase in the incidence of adenocarcinoma is related to an increasing prevalence of human papilloma virus (HPV) infection in female genitals, perhaps in addition to other factors. The increase is not seen in SCC because of effective screening.