Increased cancer risk in offspring of women with colorectal carcinoma: a Swedish register-based cohort study.

BACKGROUND: Colorectal carcinoma is one of the most common malignancies in the Western population, and a considerable proportion of colorectal carcinomas are estimated to have a familial background. METHODS: Individuals whose mothers were diagnosed with colon carcinoma or rectal carcinoma from 1958 to 1993, a total of 1. 48 million person-years, constituted the cohort of this Swedish population-based register study. The children were born during the period 1941-1993, and the cancer incidence was observed during the period 1961-1993, with the expected national Swedish incidence used as a reference. RESULTS: A significantly increased risk of colon carcinoma, rectal carcinoma, and non-Hodgkin lymphoma was observed in the cohort. The cancer risk was more pronounced in children whose mothers were age < 50 years at the time of diagnosis or had developed metachronous colorectal carcinoma. Whereas colon carcinoma in the proband implied an increased risk for both colon tumors and rectal tumors, the offspring of women who were diagnosed with rectal carcinoma were at increased risk of developing rectal carcinoma, but no significantly altered risk of colon carcinoma was observed. In the cohort, the cumulative risk for colorectal carcinoma before age 50 years was increased about 3.0 times compared with the general population. CONCLUSIONS: This report shows a significant familial aggregation of colorectal carcinoma, demonstrates possible differences in hereditary pattern between colon carcinoma and rectal carcinoma, and confirms that younger age at the time of diagnosis or the occurrence of metachronous tumors indicate familial carcinoma.

Somatic frameshift alterations in mononucleotide repeat-containing genes in different tumor types from an HNPCC family with germline MSH2 mutation.

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of several DNA repair genes, which in the tumors is reflected as microsatellite instability (MSI). MSI+ tumors have been found to carry somatic frameshift mutations in mononucleotide repeats within the coding regions of several genes involved in growth control, apoptosis, and DNA repair, e.g., TGFBRII, BAX, IGFIIR, TCF4, MSH3, and MSH6. We have studied the occurrence of somatic frameshift alterations in these mononucleotide repeat-containing genes in 24 tumors (15 colorectal cancers, 1 colon adenoma, 4 endometrial cancers, 1 ovarian cancer, 1 gastric cancer, 1 urothelial cancer, and 1 duodenal cancer) from 14 individuals in an HNPCC family with germline hMSH2 mutation. Such somatic frameshift mutations occurred at a variable frequency; the long mononucleotide repeats that characterize intronic MSI markers were mutated in the majority of tumors, 13 of the tumors displayed alterations in the (A)(10) tract of TGFBII, eight tumors (all of gastrointestinal origin) had alterations in the (A)(9) repeat of TCF4, and one to five tumors had somatic frameshift alterations in the shorter mononucleotide repeats of IGFIIR, BAX, MSH3, and MSH6. Thus, longer mononucleotide repeats were more frequently affected by somatic frameshift mutations. The pattern of alterations varied between the tumors from different family members as well as between different tumors from the same individual. To what extent this variable pattern depends on the widespread mismatch repair deficiency induced by the underlying MSH2 mutation, or represents alternative ways whereby the tumors can achieve a tumorigenic phenotype, is unknown. We suggest, however, that the accumulation of somatic frameshifts, rather than the specific loci in which these occur, drives the development of the tumorigenic phenotype in HNPCC.

hMLH1, hMSH2 and hMSH6 mutations in hereditary non-polyposis colorectal cancer families from southern Sweden.

We have screened 17 Southern Sweden individuals/families with suspected hereditary non-polyposis colorectal cancer (HNPCC) for mutations in the DNA-mismatch repair genes hMLH1, hMSH2 and hMSH6 using denaturing gradient gel electrophoresis, protein truncation test and direct DNA sequencing. The families were selected on the basis of a family history of HNPCC-related tumors or the occurrence of metachronous colorectal cancer/endometrial cancer at young age in an individual with a weak family history of cancer. Furthermore, we required that tumor tissue from at least one individual in the family had to display microsatellite instability. We identified germ-line mutations in 9 individuals from 8 families. Five families had mutations in hMLH1, 4 of which were splice site mutations, 2 had frameshift mutations in hMSH2 and 1 patient with metachronous endometrial and rectal cancer but with a weak family history of cancer had a nonsense mutation in hMSH6. Our results present novel germ-line DNA-repair gene mutations, one of these in hMSH6, and demonstrate the diversified mutation spectrum in Sweden, where no founder mutation has so far been identified.

Population-based cohort investigations of the risk for malignant tumors in first-degree relatives and wives of men with breast cancer.

BACKGROUND: Retrospective studies of familial cancer risks could be subjected to bias and should be supplemented with prospective studies if possible. Few such studies exist, and no prospective population-based study has addressed the risk for malignant tumors among relatives or wives of men with breast cancer. METHODS: All first-degree relatives and wives of 153 men whose conditions were diagnosed as male breast cancer from 1965 to 1989 in the southern health-care region of Sweden were identified through parish data. Relatives and wives alive January 1, 1958, were included in two cohorts. Their vital status and cancer morbidity were studied in the Swedish Cancer Registry, Cause of Death Registry, and Census Registry. RESULTS: The incidence for malignant tumors was significantly increased among female first-degree relatives (standardized morbidity ratio [SMR], 1.36). Significantly elevated SMR were seen for breast carcinoma (SMR, 1.80), ovarian carcinoma (SMR, 2.27), and cancer of the parotid gland (SMR, 5.58). Elevated nonsignificant SMR were seen for cancer of the cervix uteri and for bone and soft tissue sarcoma. An almost significant decreased overall cancer incidence was seen for male first-degree relatives (SMR, 0.75). The most pronounced decrease was seen for cancer of the prostate. The increased breast cancer incidence in female relatives were present in mothers, sisters, and daughters. The overall tumor incidence was not increased (SMR, 0.98) in wives of men with breast cancer. There was no significant increase in breast cancer incidence (SMR, 0.97). CONCLUSIONS: Female first-degree relatives of men with breast cancer have an elevated incidence of breast cancer and other female genital tumors, whereas male first-degree relatives have a reduced cancer incidence. Wives of men with breast cancer have a similar cancer incidence as the general population.

Chromosome 1 alterations in breast cancer: allelic loss on 1p and 1q is related to lymphogenic metastases and poor prognosis.

The development of human breast cancer is characterized by a variety of genetic alterations, and cytogenetic analyses have documented the consistent involvement of both arms of chromosome 1. In the present study, molecular markers detecting restriction fragment length polymorphisms were used in pairwise screening of normal and tumor DNA to determine the frequency of allelic imbalance in breast tumors. Loss of heterozygosity (LOH) in the polymorphic epithelial mucin (PEM or MUCI) gene at 1q21 was found in 16% of 89 informative (constitutionally heterozygous) cases, whereas gain in intensity of one allelic band was more frequent (37%), a total of 47% of cases manifesting either allelic loss or gain. Three additional tumors manifested a structural alteration. Allelic loss or gain in the PEM gene was not associated with other prognostic factors, e.g., tumor size, lymph node status, steroid receptors. DNA ploidy, S phase fraction, protooncogene amplification, histological type, or patient age. However, LOH in the PEM gene was significantly correlated with early disease recurrence (P = 0.006). LOH on 1p was found in 27% of 117 informative cases, using probes for either D1S57 or D1Z2 located at 1p33-p35 and 1p36, respectively. Somatic allelic imbalance on 1p and 1q seemed to be independent events and not the effect of loss of a whole chromosome 1. LOH on 1p was significantly correlated to the presence of lymph node metastasis, to larger tumor size, and to DNA nondiploidy, but not correlation was found to disease outcome at this limited duration of follow-up (median 29 months).

Septic shock in the rat: activation of plasma proteolytic systems and effects of a kallikrein inhibitor/bradykinin antagonist (S-2441).

Septic shock was induced in rats by intraperitoneal injection of live Escherichia coli. Plasma prekallikrein, antithrombin III and plasminogen levels were studied with chromogenic peptide substrate assays. Decrease of all the studied plasma components occurred in all rats, but not until late in shock. S-2441, a kallikrein inhibitor/kinin antagonist, slightly delayed the fall in plasma prekallikrein, but no other effects were found. Rat survival was neither enhanced nor prolonged.