Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic.

BACKGROUND: A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear. PATIENTS AND METHODS: Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden. RESULTS: Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years). CONCLUSIONS: In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.

Familial aggregation of stroke amongst young patients in Lund Stroke Register.

BACKGROUND AND PURPOSE: The known monogenic forms of stroke are rare. The aim of this study was to analyze pedigrees of young stroke patients regarding possible monogenic cerebrovascular disease and to evaluate the possibility of genetic stroke in these families. This may contribute to a better understanding of disease mechanism in stroke. METHODS: Lund Stroke Register includes consecutive patients with first-ever stroke from a defined geographical area in southern Sweden. Early-onset (≤55 years) stroke patients were systematically screened with regard to family history (FHx), and families with stroke aggregation were compiled. Participants provided information in a questionnaire on occurrence of stroke or transient ischaemic attack (TIA) in their families. Information on cardiovascular risk factors (VRFs) and clinical stroke subtype was collected. FHx for stroke was considered positive when the patient reported either ≥1 first-degree relative with stroke/TIA, or no first-degree relative but ≥3 second- or third-degree relatives with stroke/TIA in a distribution compatible with monogenic inheritance. RESULTS: Of 4103 stroke patients registered, 426 (10%) had first-ever stroke at ≤55 years and 338 (79%) of these answered the questionnaire. Of them, 159 (47%) reported a positive FHx. Twenty-eight (18%) of the probands with positive FHx had no known VRFs. Thirty-two families with ≥4 members with stroke were identified. In all these larger families the affected individuals with stroke were present in more than one generation. CONCLUSION: Aggregation of stroke in families of early-onset stroke patients is not uncommon. Genetic factors with impact on stroke risk, including monogenic causes, need to be evaluated in future stroke studies.

Are 25 SNPs from the CARDIoGRAM study associated with ischaemic stroke?

BACKGROUND AND PURPOSE: The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Study (CARDIoGRAM) reported 25 single-nucleotide polymorphisms (SNPs) on 15 chromosomes to be associated with coronary artery disease (CAD) risk. Because common vascular risk factors are shared between CAD and ischaemic stroke (IS), these SNPs may also be related to IS overall or one or more of its pathogenetic subtypes. METHODS: We performed a candidate gene study comprising 3986 patients with IS and 2459 control subjects. The 25 CAD-associated SNPs reported by CARDIoGRAM were examined by allelic association analysis including logistic regression. Weighted and unweighted genetic risk scores (GRSs) were also compiled and likewise analysed against IS. We furthermore considered the IS main subtypes large-vessel disease (LVD), small-vessel disease and cardioembolic stroke [according to Trial of Org 10172 in Acute Stroke Treatment (TOAST)] separately. RESULTS: SNP rs4977574 on chromosome 9p21.3 was associated with overall IS [odds ratio (OR) = 1.12; 95% confidence interval (CI): 1.04-1.20; P = 0.002] as well as LVD (OR = 1.36; 95% CI: 1.13-1.64; P = 0.001). No other SNP was significantly associated with IS or any of its main subtypes. Analogously, the GRSs did not show any noticeable effect. CONCLUSIONS: Besides the previously reported association with SNPs on chromosome 9p21, this study did not detect any significant association between IS and CAD-susceptible genetic variants. Also, GRSs compiled from these variants did not predict IS or any pathogenetic IS subtype, despite a total sample size of 6445 participants.

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer.

BACKGROUND: BRCA1 and BRCA2 are the two major susceptibility genes involved in hereditary breast cancer. This study was undertaken to provide reliable population-based estimates of genetic influence and to characterize the nature and prevalence of BRCA1 and BRCA2 germline mutations in early-onset breast cancer. METHODS: In a series comprising all women diagnosed with breast cancer under the age of 41 years in southern Sweden during 1990 through 1995 (n = 262), family history of cancer was evaluated in 95% (n = 250) of the case subjects and germline mutations in BRCA1 and BRCA2 were analyzed in 89% (n = 234). All statistical tests were two-sided. RESULTS: A total of 97 case subjects had at least one first- or second-degree relative with breast or ovarian cancer; 34 (14%; 95% confidence interval [CI] = 9.6% to 18%) cases had at least two first- or second-degree relatives, 22 (8.8%; 95%CI = 5.3% to 12%) had one first-degree relative, and 41 (16%; 95% CI = 12% to 21%) had one second-degree relative with either cancer. If two females affected with breast or ovarian cancer who were related through an unaffected male were also defined as first-degree relatives, then a higher number of case subjects, 120 (48%; 95% CI = 42% to 54%), had at least one first-degree or second-degree relative with breast or ovarian cancer. Sixteen (6.8%; 95% CI = 4.0% to 11%) BRCA1 mutation carriers and five (2.1%; 95% CI = 0.70% to 4.9%) BRCA2 mutation carriers were identified. Among case subjects with one first- or more than one first- or second-degree relative with breast or ovarian cancer, BRCA mutations were more frequent (P<.001) than among the case subjects without this degree of family history. BRCA mutations were also statistically significantly more common among women with bilateral breast cancer than among women with unilateral breast cancer (P =.002). BRCA mutations were more common among younger case subjects than among older ones (P =.0027). CONCLUSIONS: Almost half (48%) of women in southern Sweden with early-onset breast cancer have some family history of breast or ovarian cancer, and 9.0% of early-onset breast cancer cases are associated with a germline mutation in BRCA1 or BRCA2. Mutation carriers were more prevalent among young women, women with at least one first- or second-degree relative with breast or ovarian cancer, and women with bilateral breast cancer.

The FHIT and PTPRG genes are deleted in benign proliferative breast disease associated with familial breast cancer and cytogenetic rearrangements of chromosome band 3p14.

We have used nested reverse transcription-PCR (RT-PCR) and PCR on genomic DNA to search for aberrations in the FHIT and PTPRG genes, both located in chromosomal band 3p14.2, in specimens from cytogenetically analyzed benign breast lesions (three samples with atypical hyperplasia and one with fibroadenosis) from two women belonging to breast cancer families. The transcription analysis showed that the FHIT gene was either not expressed or that its expression was dramatically reduced to a level not detectable by nested RT-PCR in the samples with atypical hyperplasia. Genomic analysis of exons 3 and 5 of FHIT and exon 12 of PTPRG provided evidence that these DNA segments were homozygously deleted in the majority of the cells. These data are in line with the histopathological features and cytogenetic findings in the three samples; none contained normal parenchyma, and all had chromosomal aberrations involving band 3p14. RT-PCR analysis of the fibroadenosis specimen, which had a normal karyotype, detected the expected 856-bp fragment as well as an additional alternative transcript variant of FHIT with 1014 bp. The additional 158-bp sequence, which may add 38 amino acids to the NH2-terminal part of the previously described FHIT protein, was inserted between exons 4 and 5 and seems to be a new exon located in intron 4 of FHIT.

Karyotypic patterns in chronic myeloproliferative disorders: report on 74 cases and review of the literature.

During the 15 year period 1975-1989, 74 cases of chronic myeloproliferative disorder (CMPD) were cytogenetically analyzed in our department. Thirty patients had polycythemia vera (PV), 23 had idiopathic myelofibrosis (MFS), 15 had idiopathic thrombocythemia (IT), and six had unclassifiable CMPD (UCMPD). The overall frequency of clonal chromosome aberrations was 36% (50% in PV, 30% in MFS, 27% in IT, and 17% in UCMPD). The frequency was markedly higher (53%) in the subset of patients who had received myelosuppressive therapy and/or had developed acute leukemia prior to the initial cytogenetic analysis. The pattern of the chromosome rearrangements in our series is in agreement with the karyotypic findings in the 411 previously reported cases of CMPD. Trisomy 8 and 9 and del(20q) dominate in PV. The picture in MFS is more heterogenous with several aberrations, dup(1q), -5, del(5q), -7, del(7q), +8, +9, del(13q), del(20q), and +21, found equally frequently. No pathognomonic chromosome aberration has been detected in IT, but t(9;22) occurs more often than other changes. Thus, although a non-random cytogenetic pattern is discernible in CMPD, there is considerable overlap both with other myeloid malignancies and among the different CMPD subtypes.

Variant translocation t(3;15)(q21;q22) in a patient with acute promyelocytic leukemia.

Bone marrow cells from most patients with acute promyelocytic leukemia contain a highly specific cytogenetic rearrangement, a reciprocal translocation between the long arms of chromosomes 15 and 17. Several cases of variant translocations involving 17q but not 15q have been reported, leading to the suggestion that the break in 17q rather than the one in 15q is the crucial change in the regular t(15;17). We describe a hematologically typical case of acute promyelocytic leukemia with a t(3;15)(q21;q22). This is the first report in this leukemia subset of a variant translocation affecting 15q without involvement of 17q.

Deletion of chromosome arm 3p in hematologic malignancies.

Cytogenetic aberrations resulting in deletion of 3p are common in solid tumors, indicating the presence of tumor suppressor genes (TSG) on this chromosome arm. The present study was undertaken to investigate 3p loss in hematologic disorders. Ten acute myeloid leukemias (AML), two myelodysplastic syndromes (MDS), one Philadelphia chromosome-positive chronic myeloid leukemia (CML), three acute lymphoblastic leukemias (ALL), one chronic lymphoproliferative disorder (CLD), and three non-Hodgkin's lymphomas (NHL) with abnormalities leading to 3p deletions were identified, constituting 2.9% of AML, 0.7% of MDS, 1.0% of CML with changes in addition to t(9;22), 1.5% of ALL, 4.2% of CLD, and 1.1% of NHL with cytogenetic abnormalities analyzed at our Department. Among 19042 karyotypically aberrant published cases, 1.2% of 6260 AML, 1.3% of 2285 MDS, 0.8% of 840 chronic myeloproliferative disorders (CMD), 0.7% of 1894 CML with additional aberrations to t(9;22), 0.6% of 3589 ALL 2.4% of 1602 CLD, 4.5% of 178 Hodgkin disease (HD), and 3.1% of 2394 NHL displayed partial loss of 3p (0.6-4.5%; P < 0.001); the majority occurring together with other abnormalities. The frequencies of 3p loss did not differ significantly among the MDS, ALL, and CLD morphologic subgroups, between B and T cell ALL, CLD, and NHL, among low-, intermediate-, and high-grade NHL, or between therapy-related MDS and de novo MDS, whereas the incidence of 3p deletions was higher in treatment-associated AML (P < 0.001) than in de novo AML and varied among the AML FAB groups (P < 0.001). The most frequently deleted chromosome bands were 3p25 in AML, 3p26 in MDS, 3p14 in CMD, 3p25, 3p23, and 3p21 in CML, 3p26 and 3p25 in ALL, 3p26 and 3p25 in CLD, 3p26 in HD, and 3p26 in NHL. These deletion hot spots are more distal than those reported in most solid tumor types, suggesting that different TSG are involved in hematologic malignancies and solid neoplasms.

Clinical impact of breakpoint position within M-bcr in chronic myeloid leukemia.

We have analyzed the M-bcr breakpoint position in 133 Philadelphia-positive chronic myeloid leukemia patients and correlated the findings with clinical, hematologic, and cytogenetic data. We also investigated the splicing pattern of the BCR-ABL mRNA in 30 patients, using reverse transcriptase PCR. No statistically significant differences were found between breakpoint position within M-bcr and clinical parameters at diagnosis, the karyotypic evolution pattern, or the leukemic phenotype during blast crisis. Furthermore, the breakpoint position within M-bcr did not correlate with the duration of chronic phase or survival time. When the splicing pattern of the BCR-ABL mRNA was compared with the results of the genomic breakpoint mapping, it was found that approximately 60% (8/14) of the patients with a 5' break expressed b2a2 fusion mRNA, whereas all patients (10/10) with a 3' break expressed b3a2 BCR-ABL mRNA.

A new specific chromosomal rearrangement, t(11;20)(p15;q11), in myeloblastic leukemia with maturation.

The translocation t(11;20)(p15;q11) was found as the sole acquired clonal chromosome abnormality in two patients with acute myeloid leukemia. The bone marrow morphology in both cases corresponded to the M2 subtype of the French-American-British (FAB) classification. None of the patients achieved complete remission, and both died less than 6 months after diagnosis. This particular translocation has not previously been reported in acute nonlymphocytic leukemia.

New structural chromosomal rearrangements in congenital leukemia.

The karyotypic abnormalities and clinical data on three patients in whom acute leukemia was diagnosed within the first 6 months of life are presented. The four structural chromosomal rearrangements detected in the bone marrow from these patients, i.e., t(7;12)(q36;p13) and t(1;19)(q11;q11) in case 1, t(2;10;11;12)(q21q31;p13;q13;q24) in case 2, and t(11;19)(q23;p13) in case 3, have not previously been associated with congenital leukemia. Acquired chromosomal changes have until now been reported in only 31 leukemic infants in this age group. Of the total material, 18 patients had acute lymphoblastic leukemia and 16 had acute nonlymphocytic leukemia. The by far most frequently recorded cytogenetic aberration has been t(4q;11q), seen in 14 cases of lymphoblastic leukemia. Although t(4q;11q) has not been found in a single patient with acute nonlymphocytic leukemia, these leukemias have often had other rearrangements involving the same region of 11q. Hence, genetic material around 4q21 may be active in lymphocytic differentiation, whereas gene(s) in 11q23 may be important in the neoplastic process in a less cell-type specific manner and perhaps particularly vulnerable to neoplastic rearrangement in fetal life. The finding of four cases out of 34 with translocations between 11q23 and chromosome 19 indicates that this rearrangement might characterize a specific cytogenetic subgroup of leukemia in the very young.

Remarkably long survival of a patient with Ph1-positive chronic myeloid leukemia and 5' bcr rearrangement.

Chronic myeloid leukemia (CML) was diagnosed in a 19-year-old man in 1961, and the disease remained in chronic phase, with occasional exacerbations, for 27 years. In 1976, when the first cytogenetic analysis was performed, t(9;22)(q34;q11) was found as the sole abnormality in all mitoses. During accelerated phase in 1988, a second cytogenetic investigation showed the karyotype 45,XY,t(9;22)(q34;q11),-15,-17,+der(15) t(15;17)(p13;q11). Molecular analysis revealed a rearrangement in the 5' end of the major breakpoint cluster region (M-bcr). With the case presented here, sublocalization of the bcr breakpoint has now been undertaken in altogether five CML patients with extremely long survival. It is noteworthy that in all these cases the chromosome 22 breakpoint was located in the 5' region of the M-bcr.

Trisomy 14 in atypical chronic myeloid leukemia.

Trisomy 14 was the sole karyotypic anomaly in three patients with Ph1-negative chronic myeloid leukemia, and the only abnormality in one of three clones in a fourth case. The hematologic features were partly myeloproliferative, partly myelodysplastic, and included myeloid hyperplasia, neutrophilia without basophilia, a relatively high number of immature granulocyte precursors in the peripheral blood, and monocytosis in three and dysgranulopoiesis in two of the patients. These data, in combination with the patients' high age at diagnosis, their short survival, and the lack of rearrangements of the major breakpoint cluster region (M-bcr) in the two cases where cells were available for molecular analysis, indicate that all four patients suffered from atypical chronic myeloid leukemia (aCML). We suggest that trisomy 14 may be a characteristic karyotypic abnormality in this hematologic disorder.

Disease associated balanced chromosome rearrangements: a resource for large scale genotype-phenotype delineation in man.

Disease associated balanced chromosomal rearrangements (DBCRs), which truncate, delete, or otherwise inactivate specific genes, have been instrumental for positional cloning of many disease genes. A network of cytogenetic laboratories, Mendelian Cytogenetics Network (MCN), has been established to facilitate the identification and mapping of DBCRs. To get an estimate of the potential of this approach, we surveyed all cytogenetic archives in Denmark and southern Sweden, with a population of approximately 6.6 million. The nine laboratories have performed 71 739 postnatal cytogenetic tests. Excluding Robertsonian translocations and chromosome 9 inversions, we identified 216 DBCRs ( approximately 0.3%), including a minimum estimate of 114 de novo reciprocal translocations (0.16%) and eight de novo inversions (0.01%). Altogether, this is six times more frequent than in the general population, suggesting a causal relationship with the traits involved in most of these cases. Of the identified cases, only 25 (12%) have been published, including 12 cases with known syndromes and 13 cases with unspecified mental retardation/congenital malformations. The remaining DBCRs were associated with a plethora of traits including mental retardation, dysmorphic features, major congenital malformations, autism, and male and female infertility. Several of the unpublished DBCRs defined candidate breakpoints for nail-patella, Prader-Willi, and Schmidt syndromes, ataxia, and ulna aplasia. The implication of the survey is apparent when compared with MCN; altogether, the 292 participating laboratories have performed >2.5 million postnatal analyses, with an estimated approximately 7500 DBCRs stored in their archives, of which more than half might be causative mutations. In addition, an estimated 450-500 novel cases should be detected each year. Our data illustrate that DBCRs and MCN are resources for large scale establishment of phenotype-genotype relationships in man.

Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas.

Hereditary hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polycystic kidney disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endocrine neoplasia (MEN) types 1 and 2 regions at 11q13 and 10q11. The disease in these two kindreds was linked to five markers in the 1q21-q32 region (logarithm-of-odds scores: 3.2-4.2), whereas linkage to the MEN1 and MEN2 regions was excluded. Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from > 60 to approximately 34 centimorgans. Loss of heterozygosity was studied in seven renal hamartomas from two affected individuals in the first family, as well as in a jaw tumor and a parathyroid tumor from the second family. All renal hamartomas showed loss of heterozygosity at the 1q21-q32 region. The losses invariably involved the wild type allele derived from the unaffected parent, suggesting the inactivation of a tumor suppressor gene in this region.

Prenatal diagnosis in Sweden: organisation and current issues.

Invasive prenatal diagnosis was introduced in Sweden in the early 1970s and is an integral part of the public health care system. Funding is provided by taxation; the patient only pays a consultation fee. Genetic analyses on a broad range of cytogenetic and molecular disorders are performed at the 6 university-affiliated hospitals and in 1 county hospital. About 6% of all newborns have been cytogenetically screened during pregnancy, and about 90% of the analyses are performed after amniocentesis. The main indication is chromosome analysis because of advanced maternal age.

The risk of malignant tumours in first-degree relatives of men with early onset prostate cancer: a population-based cohort study.

Previous studies have indicated that hereditary prostate cancer is common among men with early onset prostate cancer. The aim of this study was to investigate the incidence of malignant tumours in first-degree relatives of men with early onset prostate cancer. All prostate cancer cases diagnosed before the age of 51 years from 1958 to 1994 were identified in the population-based Swedish Cancer Register. The first-degree relatives of clinical cases were identified through parish data. Their vital status and cancer incidence were studied in the Swedish Cancer Register, the Cause of Death Register and the Census Register. The expected incidence of malignant tumours for the first-degree relatives were calculated using regional cancer register data. Cause-specific standardised incidence ratios (SIR) and 95% confidence intervals (CI) were calculated. The study included 423 first-degree relatives of 89 men with clinical prostate cancer. The first-degree relatives' SIR for malignant tumours was 0.99 (95% CI 0.78-1.23). The SIR for prostate cancer diagnosed at any age was 1.43 (95% CI 0.82-2.33), and 3.37 for first-degree relatives diagnosed before the age of 70 years (95% CI 1.36-6.94). There was no significantly increased risk of any non-prostatic malignant tumour. Only in five of the families did the pedigree show a pattern of hereditary prostate cancer. The first-degree relatives of men with early onset prostate cancer had more than a 3-fold increase in the risk of developing prostate cancer before the age of 70 years, but their total cancer risk was not increased. This study does not support the assumption that dominantly inherited susceptibility is a major cause of early onset prostate cancer.

Familial and hereditary prostate cancer in southern Sweden. A population-based case-control study.

The objectives of this study were to investigate the effect of family history on prostate cancer risk, to estimate the incidence of hereditary prostate cancer in southern Sweden and to assess the reliability of self-reported family history of prostate cancer. The study included consecutive prostate cancer patients and age-matched control subjects from a geographically defined population. The controls consisted of 1 male patient with malignant melanoma or non-Hodgkin's lymphoma and 1 male from the community per prostate cancer case. Family history was assessed with questionnaires, and diagnoses of fathers and brothers of cases were validated by the Southern Swedish Regional Tumour Registry. Among fathers and brothers whose names and birth dates were available, 56 (92%) of the 61 reported prostate cancer diagnoses were verified. Fifteen per cent of 356 cases and 5.0% of 712 controls reported at least 1 case of prostate cancer among their brothers or fathers, giving a relative risk of 3.2 (95% confidence interval 2.1-5.1). The relative risk increased with decreasing age at diagnosis of the patient. Based on the pedigree, 3.1% of the 356 patients were classified as having hereditary prostate cancer. This proportion was significantly higher among patients diagnosed before the age of 60 years (7.1%) than among older patients (2.2%). We conclude that there is a substantially increased risk of prostate cancer for sons and brothers of prostate cancer patients. The risk increases with decreasing age at diagnosis of the patient as an effect of a higher prevalence of hereditary prostate among early onset cases. Furthermore, we found self-reported family history of prostate cancer to be a valid estimate of the true incidence of prostate cancer in fathers and brothers of men with prostate cancer.