Chuanhui Dong

Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families

Comparisons of cancer risks in persons by sibling cancers and those by parental cancers are informative of elucidating the potential genetic modes in the etiology of the cancers. The Swedish Family‐Cancer Database was used to systematically estimate the effects of parental and sibling cancers on the cancer risks in the individuals born after 1934 (offspring). The study population included 5,520,756 offspring and their parents from 2,112,616 nuclear families. Standardized incidence ratios (SIRs) were calculated to analyze the risks for cancers in offspring by parental cancers (offspring risk) and by sibling cancers (sibling risk). For 20 concordant sites, all offspring and sibling risks were significantly increased except for sibling risks for squamous cell carcinoma of the skin and myeloma. Apart from breast cancer, the SIRs were more than 10 when offspring had both an affected parent and an affected sib at the concordant site. The ratio for the sibling to offspring risk was around 2.0 or more for gastric, renal, non‐thyroid endocrine, urinary bladder, colon, testicular and prostate cancers and leukemia. For discordant sites, many reported across‐site associations were confirmed and several consistent novel associations (rectum‐skin, breast‐endocrine and lung‐endocrine) were found only among sibs. Our findings suggested that low‐penetrance polygenic dominant effects or dominant genes of high penetrance but low mutant allele frequency in the population may be involved in the observed familial cancers at many sites. Recessive or X‐linked effects may contribute particularly to gastric, renal, non‐thyroid endocrine, bladder, colon, testicular and prostate cancers and leukemia. The search for pleiotropic recessive/X‐linked susceptibility genes should be well motivated based on our results.

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.

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.

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 relationships in thyroid cancer by histo-pathological type

Thyroid cancer was studied in the Swedish Family‐Cancer Database, which was updated in 1999 to cover individuals born after 1934 with their biological parents, for a total of 9.6 million persons. Cancer data were obtained from the Swedish Cancer Registry from 1958 to 1996 and included 2,435 thyroid cancers among offspring. Seventy‐eight families were identified in which a parent and an offspring had a thyroid cancer. The familial standardized incidence ratios (SIRs) were 7.8 and 2.5 for male and female adenocarcinomas (papillary and follicular cancer combined), giving a sex ratio of 2.8. The familial SIRs for medullary and anaplastic carcinomas were about 4,000 and 300, respectively, without large sex difference. Medullary thyroid cancer has been coded as a separate entity since 1985, and the high familial SIR for anaplastic cancer was probably due to medullary cancer. The familial risks for all subgroups of thyroid cancer were highest in young age groups. The familial risk of medullary thyroid cancer may be the highest ever reported in population‐based studies. Multiple endocrine neoplasia type 2 (MEN2) families were probably included but unambiguous diagnosis was not possible because of the coding practice. There was a strong association of medullary thyroid cancer in offspring and endocrine gland tumors in parents, which may be related to MEN2. Adenocarcinoma in offspring was not associated with discordant parental cancer. Int. J. Cancer 85:201–205, 2000. ©2000 Wiley‐Liss, Inc.

A genetic study of Hodgkin's lymphoma: an estimate of heritability and anticipation based on the familial cancer database in Sweden

Abstract. Hodgkins lymphoma (HL) is a heterogeneous hemopoietic malignancy. Previous studies have implicated a genetic etiology responsible for familial HL. We have estimated the heritability of HL and tested the hypothesis of genetic anticipation by using a high quality cancer database of the Swedish population. Heritability was estimated by employing a threshold-liability model. To test the hypothesis of anticipation, the usual T-test procedure was used to test whether there was a difference in cancer age-of-onset between parents and children who were affected with HL. A randomization test was carried out to test the validity of the P-values. Additional analyses were performed after stratifying the data based on birth cohorts. This data set revealed that there was a difference between the age-of-onset of parents and of offspring who were affected with HL. We also estimated the heritability of HL in the Swedish population to be approximately 28.4%. Both findings provide further evidence for a genetic basis for HL.

Second primary cancer after in situ and invasive cervical cancer.

The Swedish Family-Cancer Database was used to analyze 9,426 second primary cancers in 117,830 subjects diagnosed with in situ and 17,556 subjects with invasive cervical cancer from the years 1958-1996. We calculated standardized incidence ratios (SIRs) from age- and period-specific rates for all women. SIRs were elevated after both in situ and invasive cervical cancer for cancers of the upper aerodigestive tract, anus, pancreas, lung, other female genitals, and urinary bladder. Anus and other female genitals, known targets of human papilloma virus, showed SIRs exceeding 3.0 and 10 or more within the year of diagnosis of cervical cancer, probably implying the effects of diagnostic intensity or transient faltering of host immunosurveillance. Among the remaining sites, smoking appeared to be the major cause, but for urinary bladder cancer it only explained one-half of the excess; human papilloma virus infection, possibly through immunosuppression, could account for the remaining excess. Although urinary bladder cancer showed a relatively small SIR compared with anal cancer, because it is more common, the number of attributable cases was about equal for the two sites. Invasive cervical cancer showed an SIR of 2.3 after in situ cancer. On follow-up, we also observed increased SIRs at many radiosensitive sites 10 or more years after diagnosis of invasive cervical cancer.

Multiple primary cancers of the colon, breast and skin (melanoma) as models for polygenic cancers

To assess the role of family history in the development of multiple primary cancer, the Swedish Family‐Cancer Database was used to analyze second primary cancer in patients born in 1935 to 1996 with an initial primary cancer of the colon, breast and skin (melanoma) by familial cancer in first‐degree relatives. Standardized incidence ratios (SIRs) were calculated from site‐, sex‐ and age‐specific rates for all persons (offspring) born in 1935 to 1996. Familial risk (SIR) was calculated for the first and second primary cancers in offspring. A Poisson regression analysis was also performed to assess the risk factors for occurrence of second primary cancer. The familial proportion of multiple primary cancers was 29.0% (9/31) for colon, 16.3% (122/747) for female breast and 14.5% (17/117) for melanoma. Compared with all offspring, patients with family history were at a much higher and significantly increased risk for subsequent primary cancer at colon (SIR = 59.1), skin (SIR = 48.2) and female breast (SIR = 7.9). The corresponding SIRs in patients without family history were 13.8, 10.5 and 5.2 at the three sites. The ratios for incidence of second primary to first primary were highest when diagnosis age was less than 40 years. A Poisson regression analysis showed that family history was one of the major risk factors for occurrence of multiple primary cancers at colon, breast and skin. The high risk of second cancer, even in the absence of family history, would be consistent with a polygenic model of carcinogenesis.

Cancers in the first-degree relatives of children with brain tumours

We used the nationwide Swedish Family-Cancer Database with 2060 childhood brain tumours diagnosed in the period 1958–1996 to analyse the risk of this tumour by parental cancers and in siblings of childhood brain tumour probands. Groups of patients were compared by calculating standardized incidence ratios (SIRs) for brain tumours in offspring. 1.3% of brain tumour patients had a parent with nervous system cancer; SIRs were 2.4 and 1.88 for diagnostic ages < 5 and < 15 years, respectively. The data showed distinct patterns of familial risks for childhood brain tumours, the SIR was 10.26 for brain astrocytoma given a parent with meningioma. Parental colon cancer was associated with offspring ependymoma (SIR 3.70), and parental salivary gland cancers with offspring medulloblastoma (SIR 13.33, but two cases only). SIR for sibling nervous system cancer from childhood brain tumour probands was 3.55 up to age 61.

Cancer in husbands of cervical cancer patients

We used the Swedish Family-Cancer Database to analyze the spectrum of cancers diagnosed in husbands of women with in situ or invasive cervical cancer, and we compared these to second carcinogenic events in women presenting with these cancers. Our hypothesis was increased cancer susceptibility from human papilloma virus (HPV). When the wives had in situ or invasive cervical cancer, the standard incidence ratios (SIRs) for anal cancer in husbands were 1.75 (95% CI = 1.05-2.62) and 1.92 (95% CI = 0.69-3.76). Anal cancer was also increased as a second primary cancer in women. Other common cancers were related to tobacco smoking. The results indicate that HPV infection is associated with anal cancer in both men and women.