Population attributable faction (PAF) shows the proportion of the disease that could be prevented if the cause could be removed. PAFs for most types of familial cancer have not been determined. We used the Swedish Family-Cancer Database on 10.2 million individuals and 688,537 parental and 116,741 offspring cancers to calculate familial risks, proportions of affected individuals, and familial PAFs for 28 neoplasms among 0-66-year-old offspring. The data were calculated by an exact proband status in the nuclear families. The familial risks for offspring cancer were increased at 23 of 28 sites from the same cancer in only the parent, at 17 sites from a sibling proband and at 12 sites from a parent and sibling proband. The highest PAFs by parent were for prostate (9.01%), breast (3.67%), and colorectal (5.15%) cancer. However, considering that in gender-specific cancers, the familial effect may originate from grandparents, the PAFs for prostate and breast cancer could be multiplied by 2. The PAFs for the sibling history of prostate, breast, and colorectal cancers were 1.55, 2.85, and 1.23% and for the parent and sibling history 0.99, 0.42, and 0.48%, respectively. Because of mutually exclusive proband definition, the PAFs were additive, giving a total PAF of 20.55% for prostate, 10.61% for breast, and 6.87% for colorectal cancer. The present PAF values give an estimate of the heritable single locus or additive effects for cancer in nuclear families. The data show that the familial PAF of prostate cancer was 20.55%, and breast cancer 10.61%, but for most other sites, it was between 1 and 3%.
Increased knowledge about inherited susceptibility for cancer and the identification of genes associated with cancer risk has increased the need for individuals with training in genetics to work closely with oncology professionals in the familial cancer arena. Genetic counselors can provide a variety of useful services: They may function as clinical coordinators of a family cancer risk counseling (FCRC) program and serve as study coordinatiors on research teams. In the oncology practice setting, genetic counselors who are trained to do cancer risk counseling can help ascertain and evaluate familial clusters of cancers. In the context of FCRC, the genetic counselor can educate family members about risk factors for cancer and the significance of a positive family history, assess psychosocial functioning and provide psychosocial support and referrals. Genetic susceptibility testing should be offered only with appropriate genetic counseling.
The early events in the G2 checkpoint response to ionizing radiation (IR) were analyzed in diploid normal human fibroblasts (NHFs) and fibroblasts from patients with two heritable cancer syndromes. Exposure to gamma-radiation of asynchronously growing NHFs resulted in a rapid reduction in the number of cells in mitosis (G2 delay) and was accompanied by a quantitatively similar reduction in the p34CDC2/cyclin B in vitro histone H1 kinase activity as compared with sham-treated controls. This G2 delay was strong by 1 h following exposure to IR, maximal by 2 h, and was accompanied by an accumulation of tyrosine-phosphorylated p34CDC2 molecules. In contrast, fibroblasts from individuals with ataxia telangiectasia displayed significantly less reduction of the mitotic index or histone H1 kinase activity after IR. Low passage fibroblasts from individuals with Li-Fraumeni syndrome having one wild-type and one mutated p53 allele were similar to NHFs in their immediate G2 checkpoint response to IR, as were NHFs expressing the human papilloma virus type 16 E6 gene product (functionally inactivating p53) and low passage cells from p53-deficient mouse embryos. However, the p53-deficient fibroblasts were genomically unstable and became defective in their early G2 checkpoint response to IR. Furthermore, immortal Li-Fraumeni syndrome fibroblasts lacking wild-type p53 displayed an attenuated G2 checkpoint response. These results link the early events in G2 checkpoint response to IR in NHFs with a rapid inhibition of p34CDC2/cyclin B protein kinase activity and demonstrate that while not required for this immediate G2 delay, lack of p53 can lead to subsequent genetic alterations that result in defective G2 checkpoint function.
Relatives of cancer patients are at an increased risk of the same (concordant) cancer but whether they are at a risk for different (discordant) cancers is largely unknown - beyond well characterized hereditary cancer syndromes - but would be of major scientific and clinical interest. We therefore decided to resolve the issue by analyzing familial risks when family members were diagnosed with any discordant cancers. We compared the population impact of concordant to discordant familial cancer. The Swedish Family-Cancer Database (FCD) was used to calculate familial relative risks (RRs) for family members of cancer patients, for the 27 most common cancers. Population attributable fractions (PAFs) were estimated for concordant and discordant family histories. Discordant cancers in the family were detected as significant risk factors for the majority of cancers, although the corresponding RRs were modest compared to RRs for concordant cancers. Risks increased with the number of affected family members with the highest RRs for pancreatic (2.31), lung (1.69), kidney (1.98), nervous system (1.79) and thyroid cancers (3.28), when 5 or more family members were diagnosed with discordant cancers. For most cancers, the PAF for discordant family history exceeded that for concordant family history. Our findings suggest that there is an unspecific genetic predisposition to cancer with clinical consequences. We consider it unlikely that shared environmental risk factors could essentially contribute to the risks for diverse discordant cancers, which are likely driven by genetic predisposition. The identification of genes that moderately increase the risk for many cancers will be a challenge.
The population attributable fraction (PAF) defines the proportion of a disease that would be prevented if the exposure to a particular risk factor was avoided. Familial risk is a known risk factor for many cancers, but an unbiased estimation of the PAF for familial risk requires a large study population to include rare cancers. PAFs and their corresponding standardized incidence ratios (SIRs) were calculated for familial relative risk among first-degree relatives (FDRs) and second-degree relatives (SDRs) diagnosed with the same (concordant) invasive or in situ cancers. Calculations were based on the Swedish Family-Cancer Database considering 8,148,737 individuals. To assess environmental effects, PAFs were also calculated for concordant cancers among spouses. Almost all cancers showed a significant familial risk. The highest PAFs were found for the common cancers of the prostate (13.94%), breast (7.46%) and colorectum (6.78%) among the FDRs. In the FDRs, the overall PAF for any concordant cancer was 4.20%, but in the SDRs, it was only 0.34%. The overall PAFs for in situ cancers were 0.86% and 0.56% for the FDRs and SDRs, respectively. The overall independent familial PAF was 5.96% for the invasive and in situ cancers in the FDRs and SDRs. The cancers between spouses yielded an overall PAF of 0.14%. For esophageal cancer, the risk among spouses was higher than the familial risk. Our study shows that the overall familial PAF of 5.96%, although underestimated for sex-specific cancers, ranks as the third most common population burden after tobacco smoking and unhealthy diet.
BACKGROUND: Familial cancer can be defined through the occurrence of the same cancer in two or more family members. We describe a nationwide landscape of familial cancer, including its frequency and the risk that it conveys, by using the largest family database in the world with complete family structures and medically confirmed cancers. PATIENTS/METHODS: We employed standardized incidence ratios (SIRs) to estimate familial risks for concordant cancer among first-degree relatives using the Swedish Cancer Registry from years 1958 through 2016. RESULTS: Cancer risks in a 20-84 year old population conferred by affected parents or siblings were about two-fold compared to the risk for individuals with unaffected relatives. For small intestinal, testicular, thyroid and bone cancers and Hodgkin disease, risks were higher, five-to-eight-fold. Novel familial associations included adult bone, lip, pharyngeal, and connective tissue cancers. Familial cancers were found in 13.2% of families with cancer; for prostate cancer, the proportion was 26.4%. High-risk families accounted for 6.6% of all cancer families. DISCUSSION/CONCLUSION: High-risk family history should be exceedingly considered for management, including targeted genetic testing. For the major proportion of familial clustering, where genetic testing may not be feasible, medical and behavioral intervention should be indicated for the patient and their family members, including screening recommendations and avoidance of carcinogenic exposure.
The objective was to evaluate the effect of an assessment strategy using the computer decision support system (the GRAIDS software), on the management of familial cancer risk in British general practice in comparison with best current practice. The design included cluster randomised controlled trial, and involved forty-five general practice teams in East Anglia, UK. Randomised to GRAIDS (Genetic Risk Assessment on the Internet with Decision Support) support (intervention n=23) or comparison (n=22). Training in the new assessment strategy and access to the GRAIDS software (GRAIDS arm) was conducted, compared with an educational session and guidelines about managing familial breast and colorectal cancer risk (comparison) were mailed. Outcomes were measured at practice, practitioner and patient levels. The primary outcome measure, at practice level, was the proportion of referrals made to the Regional Genetics Clinic for familial breast or colorectal cancer that were consistent with referral guidelines. Other measures included practitioner confidence in managing familial cancer (GRAIDS arm only) and, in patients: cancer worry, risk perception and knowledge about familial cancer. There were more referrals to the Regional Genetics Clinic from GRAIDS than comparison practices (mean 6.2 and 3.2 referrals per 10 000 registered patients per year; mean difference 3.0 referrals; 95% confidence interval (CI) 1.2-4.8; P=0.001); referrals from GRAIDS practices were more likely to be consistent with referral guidelines (odds ratio (OR)=5.2; 95% CI 1.7-15.8, P=0.006). Patients referred from GRAIDS practices had lower cancer worry scores at the point of referral (mean difference -1.44 95% CI -2.64 to -0.23, P=0.02). There were no differences in patient knowledge about familial cancer. The intervention increased GPs' confidence in managing familial cancer. Compared with education and mailed guidelines, assessment including computer decision support increased the number and quality of referrals to the Regional Genetics Clinic for familial cancer risk, improved practitioner confidence and had no adverse psychological effects in patients. Trials are registered under N0181144343 in the UK National Research Register.
Familial cancer clustering, without obvious heritability, poses a major challenge for current cancer risk assessment and management. Reliable determination of familial risks for cancer is important for clinical genetic counselling, but medically verified data on familial risks for many malignancies have been limited. However, the nationwide Swedish Family-Cancer Database allows a reliable characterisation of familial risk for all major neoplasms. Even though alert genetic counsellors and certainly clinical cancer geneticists will consider familial cancer clustering in their purview, the standard medical referral systems, which have already been shown to be poor in capturing and referring families at high risk for heritable cancers, are unlikely to ascertain familial aggregations of other cancers that are not known to belong to an inherited cancer syndrome. The data will be helpful in implementing evidence based guidelines for helping the general medical system to ascertain and refer even familial cancer clusters to cancer genetics professionals.
Public perception and anxiety of familial cancer have increased demands for clinical counseling, which may be well equipped for gene testing but less prepared for counseling of the large domain of familial cancer with unknown genetic background. The aim of the present study was to highlight the full scope of familial cancer and the variable levels of risk that need to be considered. Data on the 25 most common cancers were obtained from the Swedish Family Cancer Database and a Poisson regression model was applied to estimate relative risks (RR) distinguishing between family histories of single or multiple affected first-degree relatives and their diagnostic ages. For all cancers, individual risks were significantly increased if a parent or a sibling had a concordant cancer. While the RRs were around 2.00 for most cancers, risks were up to 10-fold increased for some cancers. Familial risks were even higher when multiple relatives were affected. Although familial risks were highest at ages below 60 years, most familial cases were diagnosed at older ages. The results emphasized the value of a detailed family history as a readily available tool for individualized counseling and its preventive potential for a large domain of non-syndromatic familial cancers.
Several pre-malignant diseases are known to have a genetic etiology. This study focuses attention upon precancerous disorders wherein the mode of inheritance is either well established or wherein it remains unclear even though familial aggregation of the particular diseases have been amply documented. These conditions will be discussed as useful models for systematic investigations of the host etiologic component in carcinogenesis. Our survey of hereditary precancerous syndromes includes multiple polyposis of the coli, the multiple mucosal neuroma syndrome, the Cancer Family Syndrome, Sipple's syndrome, Von Recklinghausen's neurofibromatosus, the multiple nevoid basal cell carcinoma syndrome, tuberous sclerosis, familial cutaneous malignant melanoma, and carcinoma of the breast. We have emphasized the heterogeneous character of many forms of familial cancer. Familial breast cancer associations clearly show such heterogeneity, as do colon cancer syndromes. Certain of these precancerous states are characterized by phenotypes which are clinically apparent, polyposis coli being the classic example. Others, such as Sipple's syndrome are amenable to routine screening for biochemical markers. The bulk of putative genetic cancer-predisposing problems require further basic investigation of modes of inheritance. Cancer control may be enhanced through communication of useful genetic and diagnostic information to primary care physicians. Referral of cancer clusters of possible genetic etiology from clinicians to human geneticists facilitates the necessary basic research.
We used the nationwide Swedish Family-Cancer Database to analyze the effect of parental age on cancer in offspring at ages 15-53 years. We studied 13 cancer sites, including 37,877 people. Data on familial and sporadic cancers were analyzed separately. We adjusted for age of spouse, year of diagnosis, and birth order. Rate ratios (RRs) were calculated by Poisson regression. Maternal age was associated with sporadic melanoma and leukemia, causing a 30% excess if mothers were more than 40 years vs. less than 20 years of age. A marginal effect of about 10% of both maternal and paternal age was observed for sporadic breast cancer. Paternal age increased the RR of sporadic nervous system cancer by about 15%. Accumulation of chromosomal aberrations and mutations during the maturation of germ cells may be a mechanism for these findings. In familial cancers of colon, melanoma, and thyroid, higher age showed an apparent protective effect, which was also noted for sporadic cervical cancer and melanoma. The results argue against major age-induced mutagenic/carcinogenic effects on germ cells as well as against age-induced adverse cancer-related hormonal effects during pregnancy. Because two or more mutations are required for adult cancers, however, these cancers may be an insensitive indicator of germ cell mutagenesis.
Families with autosomal dominant inherited predisposition to gastric cancer have been described. More recently, germline E-cadherin/CDH1 mutations have been identified in hereditary diffuse gastric cancer kindred. The need to have protocols to manage and counsel these families in the clinic led a group of geneticists, gastroenterologists, surgeons, oncologists, pathologists, and molecular biologists to convene a workshop to produce consensus statements and guidelines for familial gastric cancer. Review of the available cancer pathology from people belonging to families with documented germline E-cadherin/CDH1 mutations confirmed that the gastric cancers were all of the diffuse type. Criteria to define the different types of familial gastric cancer syndromes were agreed. Foremost among these criteria was that review of histopathology should be part of the evaluation of any family with aggregation of gastric cancer cases. Guidelines for genetic testing and counselling in hereditary diffuse gastric cancer were produced. Finally, a proposed strategy for clinical management in families with high penetrance autosomal dominant predisposition to gastric cancer was defined.
Breast cancer is known to have an inherited component, consistent in some families with autosomal dominant inheritance; in such families the disease often occurs in association with ovarian cancer. Previous genetic linkage studies have established that in some such families disease occurrence is linked to markers on chromosome 17q. This paper reports the results of a collaborative linkage study involving 214 breast cancer families, including 57 breast-ovarian cancer families; this represents almost all the known families with 17q linkage data. Six markers on 17q, spanning approximately 30 cM, were typed in the families. The aims of the study were to define more precisely the localization of the disease gene, the extent of genetic heterogeneity and the characteristics of linked families and to estimate the penetrance of the 17q gene. Under the assumption of no genetic heterogeneity, the strongest linkage evidence was obtained with D17S588 (maximum LOD score [Zmax] = 21.68 at female recombination fraction [theta f] = .13) and D17S579 (Zmax = 13.02 at theta f = .16). Multipoint linkage analysis allowing for genetic heterogeneity provided evidence that the predisposing gene lies between the markers D17S588 and D17S250, an interval whose genetic length is estimated to be 8.3 cM in males and 18.0 cM in females. This position was supported over other intervals by odds of 66:1. The location of the gene with respect to D17S579 could not be determined unequivocally. Under the genetic model used in the analysis, the best estimate of the proportion of linked breast-ovarian cancer families was 1.0 (lower LOD-1 limit 0.79). In contrast, there was significant evidence of genetic heterogeneity among the families without ovarian cancer, with an estimated 45% being linked. These results suggest that a gene(s) on chromosome 17q accounts for the majority of families in which both early-onset breast cancer and ovarian cancer occur but that other genes predisposing to breast cancer exist. By examining the fit of the linkage data to different penetrance functions, the cumulative risk associated with the 17q gene was estimated to be 59% by age 50 years and 82% by age 70 years. The corresponding estimates for the breast-ovary families were 67% and 76%, and those for the families without ovarian cancer were 49% and 90%; these penetrance functions did not differ significantly from one another.
In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise approximately 15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.
IMPORTANCE: Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction. OBJECTIVE: To estimate familial risk and heritability of cancer types in a large twin cohort. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (N = 203,691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up. EXPOSURES: Shared environmental and heritable risk factors among pairs of twins. MAIN OUTCOMES AND MEASURES: The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twin's development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death. RESULTS: A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%). CONCLUSIONS AND RELEVANCE: In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.
Individuals with a family history of pancreatic cancer have an increased risk of developing pancreatic cancer. Quantification of this risk provides a rational basis for cancer risk counseling and for screening for early pancreatic cancer. In a prospective registry-based study, we estimated the risk of pancreatic cancer in individuals with a family history of pancreatic cancer. Standardized incidence ratios were calculated by comparing the number of incident pancreatic cancers observed with those expected using Surveillance, Epidemiology and End Results (SEER) rates. Familial pancreatic cancer (FPC) kindreds were defined as kindreds having at least one pair of first-degree relatives with pancreatic cancer, and sporadic pancreatic cancer (SPC) kindreds as families without such an affected pair. Nineteen incident pancreatic cancers developed among 5,179 individuals from 838 kindreds (at baseline, 370 FPC kindreds and 468 SPC kindreds). Of these 5,179 individuals, 3,957 had at least one first-degree relative with pancreatic cancer and contributed 10,538 person-years of follow-up. In this group, the observed-to-expected rate of pancreatic cancer was significantly elevated in members of FPC kindreds [9.0; 95% confidence interval (CI), 4.5-16.1], but not in the SPC kindreds (1.8; 95% CI., 0.22-6.4). This risk in FPC kindreds was elevated in individuals with three (32.0; 95% CI, 10.2-74.7), two (6.4; CI, 1.8-16.4), or one (4.6; CI, 0.5-16.4) first-degree relative(s) with pancreatic cancer. Risk was not increased among 369 spouses and other genetically unrelated relatives. Risk was higher in smokers than in nonsmokers. Individuals with a strong family history of pancreatic cancer have a significantly increased risk of developing pancreatic cancer.
Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
Previous studies have demonstrated familial clustering of prostate cancer. To define the nature of this familial aggregation and to assess whether Mendelian inheritance can explain prostate cancer clustering, proportional hazards and segregation analyses were performed on 691 families ascertained through a single prostate cancer proband. The proportional hazards analyses revealed that two factors, early age at onset of disease in the proband and multiple affected family members, were important determinants of risk of prostate cancer in these families. Furthermore, segregation analyses revealed that this clustering can be best explained by autosomal dominant inheritance of a rare (q = 0.0030) high-risk allele leading to an early onset of prostate cancer. The estimated cumulative risk of prostate cancer for carriers revealed that the allele was highly penetrant: by age 85, 88% of carriers compared to only 5% of noncarriers are projected to be affected with prostate cancer. The best fitting autosomal dominant model further suggested that this inherited form of prostate cancer accounts for a significant proportion of early onset disease but overall is responsible for a small proportion of prostate cancer occurrence (9% by age 85). These data provide evidence that prostate cancer is inherited in Mendelian fashion in a subset of families and provide a foundation for gene mapping studies of heritable prostate cancer. Characterization of genes involved in inherited prostate cancer could provide important insight into the development of this disease in general.
A predisposition to colorectal cancer is shown to be linked to markers on chromosome 2 in some families. Molecular features of "familial" cancers were compared with those of sporadic colon cancers. Neither the familial nor sporadic cancers showed loss of heterozygosity for chromosome 2 markers, and the incidence of mutations in KRAS, P53, and APC was similar in the two groups of tumors. Most of the familial cancers, however, had widespread alterations in short repeated DNA sequences, suggesting that numerous replication errors had occurred during tumor development. Thirteen percent of sporadic cancers had identical abnormalities and these cancers shared biologic properties with the familial cases. These data suggest a mechanism for familial tumorigenesis different from that mediated by classic tumor suppressor genes.
PURPOSE: To compare the effectiveness of mammography, breast ultrasound, and magnetic resonance imaging (MRI) for surveillance of women at increased familial risk for breast cancer (lifetime risk of 20% or more). PATIENTS AND METHODS: We conducted a surveillance cohort study of 529 asymptomatic women who, based on their family history and/or mutational analysis, were suspected or proven to carry a breast cancer susceptibility gene (BRCA). A total of 1,542 annual surveillance rounds were completed with a mean follow-up of 5.3 years. Diagnostic accuracies of the three imaging modalities used alone or in different combinations were compared. RESULTS: Forty-three breast cancers were identified in the total cohort (34 invasive, nine ductal carcinoma-in-situ). Overall sensitivity of diagnostic imaging was 93% (40 of 43 breast cancers); overall node-positive rate was 16%, and one interval cancer occurred (one of 43 cancers, or 2%). In the analysis by modality, sensitivity was low for mammography (33%) and ultrasound (40%) or the combination of both (49%). MRI offered a significantly higher sensitivity (91%). The sensitivity of mammography in the higher risk groups was 25%, compared with 100% for MRI. Specificity of MRI (97.2%) was equivalent to that of mammography (96.8%). CONCLUSION: Mammography alone, and also mammography combined with breast ultrasound, seems insufficient for early diagnosis of breast cancer in women who are at increased familial risk with or without documented BRCA mutation. If MRI is used for surveillance, diagnosis of intraductal and invasive familial or hereditary cancer is achieved with a significantly higher sensitivity and at a more favorable stage.