Familial colorectal adenocarcinoma and hereditary nonpolyposis colorectal cancer: a nationwide epidemiological study from Sweden

Although estimates are available of the proportion of hereditary nonpolyposis colorectal cancer (HNPCC) among all colorectal cancer (CRC), its proportion among familial CRC is unclear. We estimated these proportions epidemiologically from the nationwide Swedish Family-Cancer Database on 9.6 million individuals. Colorectal adenocarcinomas were retrieved from the Cancer Registry covering years 1958-1996. Standardized incidence ratios (SIRs) were calculated for offspring (aged less than 62 years) when their parent had colorectal adenocarcinoma. In 9.82% of all families, an offspring and a parent were affected, giving a population attributable proportion of 4.91% and a familial SIR of 2.00. When offspring and parents shared the anatomic site, the SIR was 2.32 for proximal and 2.00 for distal CRC. When offspring were diagnosed before age 40 years and parents before age 50 years, the SIR was 25.72 for familial proximal CRC. In older age groups familial risks did not differ between proximal and distal CRC. Familial risks were increased also for endometrial, small intestinal and gastric cancers, manifestations in HNPCC. Depending on which assumptions were made, HNPCC was calculated to account for 20 to 50% of familial CRC, corresponding to 1 or 2.5% of all CRC among 0-61-year-old individuals.     

Helicobacter pylori and oesophageal and gastric cancers in a prospective study in China

In a cohort of 29,584 residents of Linxian, China, followed from 1985 to 2001, we conducted a case-cohort study of the magnitude of the association of Helicobacter pylori seropositivity with cancer risk in a random sample of 300 oesophageal squamous cell carcinomas, 600 gastric cardia adenocarcinomas, all 363 diagnosed gastric non-cardia adenocarcinomas, and a random sample of the entire cohort (N=1050). Baseline serum was evaluated for IgG antibodies to whole-cell and CagA H. pylori antigens by enzyme-linked immunosorbent assay. Risks of both gastric cardia and non-cardia cancers were increased in individuals exposed to H. pylori (Hazard ratios (HRs) and 95% confidence intervals=1.64; 1.26-2.14, and 1.60; 1.15-2.21, respectively), whereas risk of oesophageal squamous cell cancer was not affected (1.17; 0.88-1.57). For both cardia and non-cardia cancers, HRs were higher in younger individuals. With longer time between serum collection to cancer diagnosis, associations became stronger for cardia cancers but weaker for non-cardia cancers. CagA positivity did not modify these associations. The associations between H. pylori exposure and gastric cardia and non-cardia adenocarcinoma development were equally strong, in contrast to Western countries, perhaps due to the absence of Barrett's oesophagus and oesophageal adenocarcinomas in Linxian, making all cardia tumours of gastric origin, rather than a mixture of gastric and oesophageal malignancies.     

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.     

Familial colorectal adenocarcinoma from the Swedish Family-Cancer Database.

Familial risks for colorectal (CRC) adenocarcinoma were characterized from the Swedish Family-Cancer Database covering 9.6 million individuals, whose family relationships and cancers were obtained from registered sources, not sensitive to reporting or ascertainment bias. Cancer cases were retrieved from the Swedish Cancer Registry from years 1958-96. Standardized incidence ratios (SIRs) were calculated based on gender-, age-, period- and tumor type specific rates. A total of 4,794 and 67,925 CRCs were recorded in offspring and parents, respectively. For colon and rectal adenocarcinoma, the SIRs in offspring were 2.28 and 1.68 by parental CRC adenocarcinoma, giving attributable proportions of 6.45 and 3.31%, respectively. The SIR of CRC was over 10 when both offspring and parents were diagnosed at a young age. The risk for parental CRC adenocarcinoma was over 100 when 2 or more children were affected. The risk in siblings was also very high when a parent was affected. The familial cancer sites that associated with CRC were those typical of hereditary nonpolyposis colorectal cancer (HNPCC). This is the largest study published on familial CRC and the only one reporting specifically on adenocarcinoma. The data suggest that HNPCC is the largest single disease entity among CRCs, probably accounting for less than 50% of familial CRC. Other familial components appear heterogeneous, characterized by incomplete penetrance, recessive mode of inheritance and few associated tumor sites.     

Familial and second gastric carcinomas: a nationwide epidemiologic study from Sweden

BACKGROUND: Familial risks in gastric carcinoma have been assessed mainly through case-control studies based on reported but not medically verified carcinomas in family members. Reliable data on familial risks are needed for prevention and clinical decisions. METHODS: The authors used the nationwide Swedish Family-Cancer Database on 10.2 million individuals and more than 34,000 gastric carcinomas to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for gastric carcinoma in offspring, from birth to 66 years old, by carcinomas in family members. In addition, SIRs for second gastric carcinomas were analyzed. RESULTS: Standardized incidence ratios for gastric carcinoma were 1.31 (95% CI, 0.97-1.70) and 1.47 (95% CI, 1.08-1.92) when a parent presented with gastric carcinoma or gastric adenocarcinoma, respectively. The risk was 1.59 (95% CI, 1.10-2.16) in offspring whose diagnosis was at ages older than 50 years. Offspring risk from parental corpus carcinoma was of borderline significance whereas that from cardia carcinoma was below unity. The sibling risk for gastric carcinoma was 3.16 (95% CI, 1.35-5.72) and 5.75 (95% CI, 2.07-11.26) when diagnosed before age 50. The population attributable proportion of familial gastric carcinoma was 0.45%. Risks for second gastric carcinomas were increased in men and women after esophageal and skin carcinomas, and after non-Hodgkin lymphoma. CONCLUSIONS: The data suggest that environmental factors, perhaps Helicobacter pylori infections are the main reason for familial clustering of gastric carcinoma. The population attributable proportion of familial gastric carcinoma is much lower than that cited in the literature. The patterns of multiple carcinomas suggest that immunologic factors modulate susceptibility to gastric carcinoma.     

Risk of adenocarcinomas of the oesophagus and gastric cardia in patients hospitalized for asthma.

In the first cohort study of the question we followed 92 986 (42 663 men and 50 323 women) adult patients hospitalized for asthma in Sweden from 1965 to 1994 for an average of 8.5 years to evaluate their risk of oesophageal and gastric cardia adenocarcinoma. Standardized incidence ratio (SIR) adjusted for gender, age and calendar year was used to estimate relative risk, using the Swedish nationwide cancer incidence rates as reference. Asthmatic patients overall had a moderately elevated risk for oesophageal adenocarcinoma (SIR = 1.5, 95% confidence interval CI, 0.9-2.5) and gastric cardia cancer (SIR = 1.4, 95% CI, 1.0-1.9). However, the excess risks were largely confined to asthmatic patients who also had a discharge record of gastro-oesophageal reflux (SIR = 7.5, 95% CI, 1.6-22.0 and SIR = 7.1, 95% CI, 3.1-14.0, respectively). No significant excess risk for oesophageal squamous-cell carcinoma or distal stomach cancer was observed. In conclusion, asthma is associated with a moderately elevated risk of developing oesophageal or gastric cardia adenocarcinoma. Special clinical vigilance vis-à-vis gastro-esophageal cancers seems unwarranted in asthmatic patients, but may be appropriate in those with clinically manifest gastro-oesophageal reflux.     

Familial clustering of cancer at human papillomavirus-associated sites according to the Swedish Family-Cancer Database

Familial aggregation of cervical cancer has been demonstrated previously, however aggregation of other human papillomavirus-associated anogenital, upper aerodigestive tract and skin cancers has not been fully characterized. The Swedish Family-Cancer Database, which contains reliable data on cancer incidence and nuclear family linkages for all residents of Sweden between 1958 and 2004, was used to calculate standardized incidence ratios (SIR) and 95% confidence intervals for offspring site-specific cancer risks according to site-specific cancer in sibling and parental probands. Offspring cancer risk was significantly increased when either a sibling or parent was affected at the same site for penile squamous cell carcinoma (SCC, SIR = 7.54), cervical adenocarcinoma (AC, SIR = 2.31), vulvar SCC (SIR = 2.27), skin SCC (SIR = 2.14), rectal AC (SIR = 1.86), in situ cervical SCC (SIR = 1.80), invasive cervical SCC (SIR = 1.77) and upper aerodigestive tract SCC (SIR = 1.57). Significant aggregation on the order of 2-fold between anogenital cancers at different sites or histologies was also observed. In situ cervical SCC risk in offspring was strongly influenced by siblings affected with oropharyngeal SCC (SIR = 3.17) and tonsillar SCC (SIR = 1.84). Familial skin SCC was largely unassociated with anogenital or upper aerodigestive tract cancer risk in offspring. These data suggest that common host factors exist among individuals affected with anogenital and upper aerodigestive tract cancers.     

Role of Helicobacter pylori CagA+ strains and risk of adenocarcinoma of the stomach and esophagus

Infection with Helicobacter pylori (H. pylori), especially CagA+ strains, has been associated with an increased risk of noncardia gastric adenocarcinoma. The relationship with junctional cancer (adenocarcinomas of the esophagus and gastric cardia combined) has not been adequately investigated, although some studies have reported a reduced risk associated with H. pylori and CagA seroseropositivity. We investigated this question in a subset of cases and controls from a recently completed, large population-based case-control study of gastric and esophageal adenocarcinomas in Los Angeles County. Using established antigen-specific ELISAs, serum IgG antibodies to H. pylori whole-cell antigens (Helico-G) and CagA were measured in population controls (n = 356) and patients with incident esophageal adenocarcinoma (n = 80), gastric cardia cancer (n = 87) or distal gastric cancers (noncardia gastric adenocarcinoma) (n = 127). After controlling for demographic characteristics (age, gender, race, birthplace, education), smoking and body mass index, seropositivity for H. pylori was associated with a statistically significant increased risk of distal gastric cancer (adjusted odds ratio [OR] = 1.85, 95% confidence interval [CI] = 1.03, 3.32) but the risk of junctional cancer was not increased (adjusted OR = 1.26, 95% CI = 0.82, 1.94). The risk of junctional cancer was not changed when CagA and H. pylori were both considered, but the risk of distal gastric cancer was further increased. Subjects who were seropositive for both CagA and H. pylori compared to those who were seronegative for H. pylori showed a risk of 2.20 (95% CI = 1.13, 4.26) for distal gastric cancer and 0.86 (95% CI = 0.47, 1.59) for junctional cancer. Although tests for interaction between smoking and H. pylori were not statistically significant for junctional or distal gastric cancers, risk for both tumor types tended to be higher among current smokers who were also H. pylori seropositive. In conclusion, we find no evidence that infection with CagA+ strains of H. pylori reduces risk of esophageal and gastric cardia adenocarcinoma in this population. Our findings confirm the positive association between risk of distal gastric cancer and infection with H. pylori infection, especially CagA+ strains.     

Tamoxifen exposure and risk of oesophageal and gastric adenocarcinoma: a population-based cohort study of breast cancer patients in Sweden

In a population-based cohort study of all women aged over 50 years with breast cancer in the Swedish Cancer Register in 1961-2003, those diagnosed before 31 December 1987 were regarded as unexposed to tamoxifen, whereas those diagnosed after that date were considered potentially exposed. Crosslinkages within the Cancer Register and the Registers of Death and Emigration enabled follow-up. Standardised incidence ratios (SIRs) of oesophageal and gastric cancer represented relative risks. Among 138 885 cohort members contributing with 1 075 724 person-years of follow-up, we found a nonsignificantly increased risk of oesophageal adenocarcinoma during the potential tamoxifen exposure period (SIR 1.60, 95% confidence interval (CI) 0.83-3.08), but the risk estimates decreased with increasing latency interval. No association was observed during the unexposed period. No increased risk of cardia adenocarcinoma was identified in either period. The risk of non-cardia gastric adenocarcinoma was increased in the potential tamoxifen period (SIR 1.27, 1.03-1.57), and almost doubled (SIR 1.86, 95% CI 1.10-3.14) in the period of longest latency (10-14 years). The corresponding overall SIR was increased in the unexposed group also, but here SIR did not increase with longer latency intervals. An increased risk of tobacco-related tumours, that is, oesophageal squamous-cell carcinoma and lung cancer, was limited to the unexposed cohort, indicating that confounding by smoking might explain the increased SIR during the unexposed period. We concluded that there might be a link between tamoxifen and risk of non-cardia gastric adenocarcinoma.     

Familial risks for eye melanoma and retinoblastoma: results from the Swedish Family-Cancer Database

No systematic population-based studies have been conducted on familial eye cancers. Reliable data on familial risks are important for clinical counselling and cancer genetics. The current analysis was based on the nation-wide Swedish Family-Cancer Database on 10.5 million individuals, containing families with parents and offspring. Cancer data were retrieved from the Swedish Cancer Registry from the years 1958 to 2002, including 3636 patients with any type of eye cancer. Familial risk for offspring was defined using the standardized incidence ratio (SIR), adjusted for many variables. Ocular melanoma was detected in two parent-offspring pairs, but the SIR of 3.90 was not significant. Parental upper aerodigestive tract (2.05), left-sided colon (1.83) and male non-medullary thyroid (6.98) cancers showed an association with ocular melanoma, albeit some with a borderline significance. The SIR for leukaemia was increased when parents were diagnosed with eye melanoma. There was no evidence for the association of ocular melanoma with cutaneous melanoma. The SIR for ocular melanoma was 1.76 when a sister was diagnosed with breast cancer, but there was no increase when a mother was diagnosed with breast cancer. When both a child and the parent presented with retinoblastoma, the SIR was 900. The parents of children with retinoblastoma had an excess of small intestinal and rectal cancers and Hodgkin's disease. The present findings were based on a limited number of cases, but they display a complex and heterogeneous pattern of familial associations in ocular melanoma, including an association with breast cancer through a putative recessive mechanism.     

Gastric adenocarcinoma and Helicobacter pylori infection.

Helicobacter pylori infection, thought to be causally related to chronic gastritis, may also be associated with an increased risk of gastric cancer. To determine whether an association with gastric cancer does exist, we retrospectively evaluated serum samples from 69 patients with histologically confirmed gastric adenocarcinoma (32 with cancer at the cardia and 37 with cancer at other sites) and from 218 patients with one of three categories of nongastric cancers, with other gastric cancers, or with benign gastric neoplasms. These samples were compared with samples from 252 cancer-free control subjects, a group comprising 76 asymptomatic volunteers and 176 persons with nonmalignant disorders. Serum samples collected from cancer patients prior to surgery and from cancer-free controls were tested for antibodies to H. pylori by using a highly sensitive and specific IgG enzyme-linked immunosorbent assay. The risk of H. pylori infection in the case patients relative to the control subjects was estimated with the use of multivariate logistic regression analysis to adjust for potential confounding variables. Antibodies to H. pylori were detected in 65% of the patients with noncardia gastric cancer but in only 38% of the patients with gastric cancer located at the cardia. A significant association was found between H. pylori infection and noncardia gastric cancer (odds ratio = 2.67; 99% confidence interval = 1.01-7.06). Within the subset of patients with noncardia gastric cancer, a statistically nonsignificant tendency existed for those with the intestinal versus the diffuse histologic type of noncardia gastric cancer to have a higher risk of H. pylori infection. Our results support the hypothesis of a relationship between H. pylori infection and the development of noncardia gastric adenocarcinoma.     

Risk of Gastric Cancer in Children with Helicobacter pylori Infection

Background: Helicobacter pylori (H. pylori) is the most common chronic infectious agent in the stomach.Most importantly, it may lead to atrophy, metaplasia and cancer. The aim of this study was to investigate theincidence of H. pylori infection and to detect early mucosal changes that may lead to malignant degenerationin children. Materials and Methods: Children who underwent upper gastrointestinal endoscopy were included.Familial history of gastric cancer was noted. Endoscopic examinations were performed by a single pediatricgastroenterologist. A minimum of three biopsy samples were collected during endoscopy. The patients wereaccepted as H. pylori infected if results of biopsies and rapid urease test were both positive. Biopsies wereevaluated for the presence and degree of chronic inflammation, the activity and severity of gastritis, glandularatrophy and intestinal metaplasia. Results: A total of 750 children (388 boys, 362 girls) were evaluated in ourstudy, with a mean age of 10.1 years. A total of 390 patients (52%) were found to be infected with H. pylori.Among the H. pylori infected patients, 289 (74%) were diagnosed to have chronic superficial gastritis, 24 (6.2%)had gastric atrophy. Most strikingly, intestinal metaplasia was observed in 11 children, all were in the H. pyloripositive group. There was no difference in the mean of age, gender and socioeconomic class between H. pyloriinfected and non-infected groups. The frequency of gastric cancer in family members (4 in number) was higherin patients with H. pylori infection. No gastric cancer case was reported from the parents of non-infected children.The worst biopsy parameters (atropy and metaplasia) were improved after H. pylori eradication on controlendoscopy. Conclusions: The current study shows a higher prevalence of familial history of gastric cancer in H.pylori infected children. Intestinal metaplasia was also higher in the infected children. Eradication of H. pyloriinfection for this risk group may prevent subsequent development of gastric cancer.     

Heredity and risk of cancer of the esophagus and gastric cardia.

The importance of genetic factors in the etiology of esophageal cancer is uncertain. We addressed the question of heredity in a population-based, nationwide case-control study conducted in Sweden during 1995 through 1997. The study involved 189 patients with esophageal adenocarcinoma, 262 with cardia adenocarcinoma, 167 with esophageal squamous cell carcinoma, and, for comparison, 820 control subjects. Familial occurrence of cancer was explored at face-to-face interviews. Logistic regression, with multivariate adjustment for potential confounders, was used to calculate odds ratios (ORs), which estimated relative risk. Occurrence of esophageal cancer among first-degree relatives did not increase the risk of adenocarcinoma or squamous cell carcinoma of the esophagus. Neither were there any significant associations with familial occurrence of gastric cancer or other gastrointestinal tumors. The risk of cardia adenocarcinoma was moderately increased among persons with first-degree relatives with gastric cancer (OR, 1.6; 95% confidence interval, 1.0-2.6). Familial occurrence of any cancer was not associated with increased risks of any of the three studied tumors. In conclusion, heredity does not seem to contribute importantly to the occurrence of esophageal cancer of any histological type. A weak association between familial gastric cancer and the risk of cardia cancer may represent a genetic link.     

Role of Helicobacter pylori infection among offspring or siblings of gastric cancer patients

A positive family history is an increased risk factor for gastric cancer within family members, and one of the possible causes of this is the intrafamilial clustering of Helicobacter pylori infection. Our study examined the prevalence of H. pylori infection, serum antibodies to CagA and VacA and atrophic gastritis and/or intestinal metaplasia in the offspring or siblings of gastric cancer patients. A total of 726 subjects included 300 relatives of 300 separate gastric cancer patients and 426 controls. All subjects underwent upper gastrointestinal endoscopic examination with a rapid urease test. Blood samples were obtained to test for the presence of serum antibodies to the CagA and VacA proteins of H. pylori. The prevalence of H. pylori infection was higher in relatives of cancer patients (75.3%) than in controls (60.1%), and the adjusted odds ratio was 2.1 (95% CI 1.5-2.9). When either siblings or 2 or more family members were gastric cancer patients, the prevalence of H. pylori infection was much higher compared to the prevalence in controls. There was no specific relationship between CagA and VacA, and H. pylori infection. Atrophic gastritis and/or intestinal metaplasia were more frequently found in H. pylori-infected relatives of cancer patients (26.1%) than in H. pylori-infected controls (12.9%). These results strongly support a role for H. pylori infection in familial aggregation of gastric cancer. The prophylactic eradication of H. pylori infection in the offspring or siblings of gastric cancer patients may be clinically beneficial.     

The Swedish Family-Cancer Database: Update,Application to Colorectal Cancer and Clinical Relevance

The Swedish Family-Cancer Database has been used for almost 10 years in the study of familial risks at all common sites. In the present paper we describe some main features of version VI of this Database, assembled in 2004. This update included all Swedes born in 1932 and later (offspring) with their biological parents, a total of 10.5 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry from 1958-2002, including over 1.2 million first and multiple primary cancers and in situ tumours. Compared to previous versions, only 6.0% of deceased offspring with a cancer diagnosis lack any parental information. We show one application of the Database in the study of familial risks in colorectal adenocarcinoma, with defined age-group and anatomic site specific analyses. Familial standardized incidence ratios (SIRs) were determined for offspring when parents or sibling were diagnosed with colon or rectal cancer. As a novel finding it was shown that risks for siblings were higher than those for offspring of affected parents. The excess risk was limited to colon cancer and particularly to right-sided colon cancer. The SIRs for colon cancer in age matched populations were 2.58 when parents were probands and 3.81 when siblings were probands; for right-sided colon cancer the SIRs were 3.66 and 7.53, respectively. Thus the familial excess (SIR-1.00) was more than two fold higher for right-sided colon cancer. Colon and rectal cancers appeared to be distinguished between high-penetrant and recessive conditions that only affect the colon, whereas low-penetrant familial effects are shared by the two sites. Epidemiological studies can be used to generate clinical estimates for familial risk, conditioned on numbers of affected family members and their ages of onset. Useful risk estimates have been developed for familial breast and prostate cancers. Reliable risk estimates for other cancers should also be seriously considered for routine clinical recommendations, because practically all cancers show a familial effect and the risks are high for some of the rare neoplasms. The implementation of a unified management plan for familial cancers at large will be a major challenge to the clinical genetic counselling community.     

Familial and second primary pancreatic cancers: a nationwide epidemiologic study from Sweden

Familial risk of pancreatic cancer has been mainly assessed through case-control studies based on reported but not medically verified cancers in family members. We used the nationwide Swedish Family-Cancer Database on 10.2 million individuals and 21,000 pancreatic cancers to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for pancreatic cancer in 0- to 66-year-old offspring of parents with pancreatic or other specified tumors. Additionally, SIRs for second primary pancreatic cancers were analyzed after any first neoplasm. SIRs for pancreatic cancer (1.68, 95% CI 1.16-2.35) and pancreatic adenocarcinoma (1.73, 95% CI 1.13-2.54) were increased when a parent presented with pancreatic cancer. The risk was not dependent on diagnostic age of offspring or parents. Pancreatic cancer was associated with parental lung, rectal or endometrial cancer and with melanoma. SIRs for pancreatic cancer were 10.01 and 7.96 among offspring who were diagnosed before age 50 years when parents were diagnosed with squamous cell and adenocarcinoma of the lung, respectively, before age 60 years. The population-attributable proportion of familial pancreatic cancer was 1.1%. Risks for second pancreatic cancers were increased in men and women after small intestinal, colon and bladder cancer. The degree of familial clustering for pancreatic cancer and its population-attributable proportion were lower than the data cited in the literature. Clustering of pancreatic cancer with sites presenting in hereditary nonpolyposis colorectal cancer was noted. The strong association of pancreatic and lung cancers is puzzling, and it remains unclear to what extent this represents familial sharing of smoking habits.     

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.     

Familial aggregation of early-onset cancers

This registry-linkage study evaluates familial aggregation of cancer among relatives of a population-based series of early-onset (≤40 years) cancer patients in Finland. A cohort of 376,762 relatives of early-onset cancer patients diagnosed between 1970 and 2012 in 40,538 families was identified. Familial aggregation of early-onset breast, colorectal, brain and other central nervous system (CNS) cancer and melanoma was explored by standardized incidence ratios (SIR), stratified by relatedness. Gender-, age- and period-specific population cancer incidences were used as reference. Cumulative risks for siblings and offspring of the proband up to age ≤40 years were also estimated. Almost all early-onset cancers were sporadic (98% or more). Among first-degree relatives, SIR was largest in colorectal cancer (14, 95% confidence interval 9.72–18), and lowest in melanoma (1.93, 1.05–3.23). Highest relative-specific SIRs were observed for siblings in families, where also parent had concordant cancer, 90 (43–165) for colorectal cancer and 29 (11–64) for CNS cancer. In spouses, all SIRs were at population level. Cumulative risk of colorectal cancer by age 41 was 0.98% in siblings and 0.10% in population, while in breast cancer the corresponding risks were 2.05% and 0.56%. In conclusion, early-onset cancers are mainly sporadic. Findings support high familial aggregation in early-onset colorectal and CNS cancers. Familial aggregation in multiplex families with CNS cancers was mainly attributed to neurofibromatosis and in colorectal cancer to FAP- and HNPCC-syndromes. The pattern of familial aggregation of early-onset breast cancer could be seen to support very early exposure to environmental factors and/or rare genetic factors.     

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.