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M Swift

Publications and source records attributed to M Swift.

At least 19 recordsLinked to original sources
PubMed2001

Parotid and thyroid gland cancers in patients with ataxia-telangiectasia.

This study describes the clinicopathologic features of parotid and thyroid gland cancers in patients with ataxia-telangiectasia (AT). The medical records of 412 AT patients were reviewed to identify those patients who developed parotid or thyroid gland cancers. Presenting features, diagnoses, types of therapy, risk factors, and other primary cancers were analyzed. Five patients with parotid or thyroid gland cancers were identified. Three had parotid (2 mucoepidermoid and 1 acinic cell) and 2 had thyroid gland (1 papillary and 1 follicular) cancers. Four patients presented with head and neck masses and 1 had an occult papillary thyroid carcinoma. Four patients had more than one primary cancer. The only mode of therapy was surgery. The 2 patients with mucoepidermoid carcinoma had complete parotidectomies. One is alive without any evidence of disease 12 months after diagnosis and 1 died of refractory lymphoma without any evidence of mucoepidermoid carcinoma at autopsy. The patient with acinic cell carcinoma had a parotid biopsy only. The 2 patients with thyroid cancer were diagnosed at autopsy. The results indicate that patients with AT are at risk for developing multiple primary cancers including those of the parotid and thyroid gland, and should be evaluated for such primaries.

Adolescent↗
PubMed2000

Mortality rates among carriers of ataxia-telangiectasia mutant alleles.

BACKGROUND: Mutations at the ataxia-telangiectasia locus cause a distinctive autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer and ischemic heart disease. OBJECTIVE: To examine mortality rates among persons carrying a mutated ataxia-telangiectasia gene. DESIGN: Retrospective cohort study. SETTING: The United States and Canada. PARTICIPANTS: 405 grandparents of patients with ataxia-telangiectasia. MEASUREMENTS: Ages at death and risk for death (from all causes, cancer, ischemic heart disease, and other causes) among carriers and noncarriers of ataxia-telangiectasia mutations. RESULTS: Compared with noncarriers, carriers of a mutated ataxia-telangiectasia allele had a significantly increased risk for death at 20 through 79 years of age (relative risk, 1.9 [95% CI, 1.3 to 2.8]) (P < 0.001). On average, carriers died 7 to 8 years earlier than noncarriers. Cancer caused most of the excess deaths, and ischemic heart disease caused the remainder. Among carriers, relative risk for death from cancer and ischemic heart disease before 80 years of age was 2.6 (CI, 1.4 to 4.7; P = 0.002) and 2.0 (CI, 1.0 to 4.0; P = 0.062), respectively. Compared with noncarriers, carriers who died of cancer were a mean of 4 years younger (P > 0.2) and carriers who died of ischemic heart disease were a mean of 11 years younger (P = 0.006). CONCLUSION: Carriers of mutations at the ataxia-telangiectasia locus, who make up 1.4% to 2% of the general population, have a higher mortality rate and an earlier age at death from cancer and ischemic heart disease than noncarriers.

Adult↗
PubMed2000

Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.

Mutations at the ataxia-telangiectasia (A-T) locus on chromosome band 11q22 cause a distinctive autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer, ischemic heart disease, and early mortality. PCR amplification from genomic DNA and automated sequencing of the entire coding region (66 exons) and splice junctions detected 77 mutations (85%) in 90 A-T chromosomes. Heteroduplex analysis detected another 42 mutations at the A-T locus. Out of a total of 71 unique mutations, 50 were found only in a single family, and 51 had not been reported previously. Most (58/71, 82%) mutations were frameshift and nonsense mutations that are predicted to cause truncation of the A-T protein; the less common mutation types were missense (9/71, 13%), splicing (3/71, 4%) and one in-frame deletion, 2546 3 (1/71, 1%). The mean survival and height distribution of 134 A-T patients correlated significantly with the specific mutations present in the patients. Patients homozygous for a single truncating mutation, typically near the N-terminal end of the gene, or heterozygous for the in-frame deletion 2546 3, were shorter and had significantly shorter survival than those heterozygous for a splice site or missense mutation, or heterozygous for two truncating mutations. Alterations of the length or amino acid composition of the A-T gene product affect the A-T clinical phenotype in different ways. Mutation analysis at the A-T locus may help estimate the prognosis of A-T patients.

Adolescent↗
PubMed2000

Psychiatric disorders and mutations at the Wolfram syndrome locus.

Identifying genetic loci at which mutations predispose individuals to common psychiatric illnesses will have major impact on the diagnosis and treatment of mental illness. The available evidence indicates that mutations at the Wolfram syndrome locus contribute substantially to the prevalence of psychiatric illness in the general population. Patients with mutations at this locus on both parental chromosomes, called Wolfram syndrome homozygotes, have a distinctive and rare autosomal recessive syndrome characterized by juvenile onset diabetes mellitus and bilateral progressive optic atrophy. Diverse and serious psychiatric manifestations frequently have been observed in Wolfram syndrome patients; however, the population burden of mental illness attributable to mutations at this locus is almost entirely from individuals who carry a single mutation, called Wolfram syndrome heterozygotes, who have no distinguishing physical characteristics but constitute approximately 1% of the population. Molecular genotyping of blood relatives of Wolfram syndrome patients has shown that Wolfram syndrome heterozygotes are 26-fold more likely than noncarriers to have a psychiatric hospitalization. Severe depression was the predominant finding in the test group studied. The prediction that approximately 25% of all patients hospitalized for depression are Wolfram syndrome heterozygotes now can be tested by mutation screening of hospitalized patients from the general population. Many other behavioral and cognitive difficulties also have been observed in Wolfram syndrome families. For each specific psychiatric abnormality, a "test group" of blood relatives within Wolfram syndrome families with that abnormality can be formed. By comparing the number of Wolfram syndrome heterozygotes found in each test group by molecular genotyping with the number expected under the null hypothesis, the index-test method can determine which clinical phenotypes result from mutations at the Wolfram syndrome locus. This method can be utilized to identify other loci at which mutations predispose individuals to psychiatric illnesses.

Depressive Disorder↗
PubMed1999

Neutral sequence variants and haplotypes at the 150 Kb ataxia-telangiectasia locus.

Sequence variants occur every few hundred bases in the human genome. We evaluated the relationship between disease-causing mutations and neutral sequence variants at the 150 Kb ataxia-telangiectasia (A-T) locus. Mutations at this locus cause a distinct autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer and coronary heart disease. Nine common neutral sequence variants were observed in the coding and splice junction regions of 132 chromosomes from Caucasian individuals of European origin. Each of these variants appeared frequently in both A-T and non-A-T chromosomes. However, there was remarkable linkage disequilibrium between the polymorphic loci, resulting in only 7 haplotypes in analyzed chromosomes. These 7 haplotypes fell into 3 major ancestral groups. No individual polymorphic variant or haplotype correlated reliably with the presence of an A-T mutation. Thus, comparing the frequency of neutral variants at the A-T locus in diseased and non-diseased populations is unlikely to uncover the relationship of mutations at this locus to common diseases. These data reflect general limitations on using single nucleotide polymorphisms (SNPs) to identify loci for many common diseases.

Alleles↗
PubMed1998

Radiosensitivity of normal tissues in ataxia-telangiectasia heterozygotes.

PURPOSE: Approximately 5% of cancer patients given radiation therapy exhibit severe injuries to the noncancerous tissue in the radiation field. Striking clinical sensitivity to ionizing radiation has been observed frequently in ataxia-telangiectasia (A-T) homozygotes. This study was undertaken to test the hypothesis that heterozygous carriers of a mutated gene for A-T may represent a substantial proportion of all patients who suffer severe radiation toxicity. METHODS: The medical records of all A-T heterozygotes treated with radiation therapy for breast or prostate cancer were compiled from an ongoing study of mortality and cancer incidence in A-T families. Diagnostic, treatment, and follow-up records were reviewed. Acute and long-term radiation complications were scored according to Radiation Therapy and Oncology Group criteria. RESULTS: There were no instances of soft tissue necrosis or other apparent serious injuries to normal tissues of two A-T heterozygotes with prostate carcinoma and 11 with breast carcinoma who received moderate-to-high doses of conventionally fractionated radiation therapy by megavoltage techniques. CONCLUSION: There is no evidence that abnormal clinical radiosensitivity occurs in A-T heterozygotes receiving conventionally fractionated radiation therapy for breast or prostate cancer.

Adult↗
PubMed1998

Treatment of lymphoid malignancies in patients with ataxia-telangiectasia.

BACKGROUND: Patients with ataxia-telangiectasia (A-T) are at an increased risk for developing lymphoid malignancies, yet the appropriate therapy remains unknown. Radiation therapy at conventional doses results in destruction of normal tissue, which has suggested that full-dose chemotherapy might result in unacceptable toxicity in A-T patients with cancer. PROCEDURE: The medical records of 412 A-T patients were reviewed to identify those patients who developed lymphoid malignancies and to analyze the type and duration of therapy, events during therapy, and off-therapy follow-up. RESULTS: Of 74 A-T patients with lymphoid malignancies, 32 patients received chemotherapy. The 21 patients treated with standard chemotherapy had a significantly better median survival (9 months, range, 1-162+ months vs. 5 months, range, 0.5-28 months) (P = 0.03) and complete remission rate (76% vs. 9%) (P = 0.001) than the 11 treated with reduced dose chemotherapy. Three of the 21 full-dose chemotherapy patients required dose reductions because of neutropenia. Seven of the 14 patients exposed to 1,200 mg/m2 or greater of cyclophosphamide developed hemorrhagic cystitis. All three patients exposed to bleomycin developed pulmonary disease which was fatal in two. Of the 16 standard-dose chemotherapy patients who achieved a complete remission, two remain disease-free, five have died of recurrent disease, and five died of pulmonary disorders and four of other causes while in remission. CONCLUSIONS: Standard-dose chemotherapy should be given to each A-T patient with a lymphoid malignancy unless additional physical or emotional problems make it unlikely that the patient will benefit. Morbidity and mortality may be reduced by prophylaxis against hemorrhagic cystitis and early detection and treatment of pulmonary disorders.

Adolescent↗
PubMed1998

Predisposition of Wolfram syndrome heterozygotes to psychiatric illness.

Identification of specific genes that predispose to psychiatric illness will lead to more precise psychiatric diagnosis and more effective treatment. Heterozygous carriers of genes for many autosomal recessive syndromes may be 1% or more of the general population. Thus, if mutations at a specific locus produce psychiatric manifestations in homozygous affected individuals, it is important to determine whether mutations at such a locus also predispose heterozygous carriers to psychiatric disorders. The hypothesis that heterozygous carriers of the gene for the Wolfram syndrome (WS) are predisposed to psychiatric illness was supported previously by the finding of an excess of psychiatric hospitalizations and suicides in WS blood relatives compared to spouse controls. This hypothesis has now been tested further by comparing the number of psychiatrically hospitalized blood relatives with the specific marker haplotype associated with the Wolfram syndrome gene in their families to the number expected under the null hypothesis, calculated from Mendelian inheritance principles and the estimated haplotype frequency. The proportion of psychiatrically hospitalized relatives who were WS carriers (10/11) was much higher than expected (3.1/11), leading to the provisional estimate that WS gene carriers are 26-fold more likely to require psychiatric hospitalization than non-carriers.

Adult↗
PubMed1997

Breast cancer genetics.

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Ataxia Telangiectasia Mutated Proteins↗
PubMed1996

Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer.

About 1.4% of the general population are heterozygous carriers of the gene for ataxiatelangiectasia (A-T), an autosomal recessive progressive neurologic syndrome in which cancer incidence of homozygotes is approximately 100-fold greater than the general population's rates. The hypothesis that A-T heterozygotes are predisposed to breast cancer was tested by the unbiased statistically powerful index-test method based on molecular genotyping. The A-T gene carrier status of 775 blood relatives in 99 A-T families was determined by tracing the A-T gene in each family through tightly linked flanking DNA markers. There were 33 women with breast cancer who could be genotyped; 25 of these were A-T heterozygotes, compared to an expected 14.9 (odds ratio 3.8, 95% confidence limits 1.7-8.4, one-sided p = .0001). This demonstrates that the A-T gene predisposes heterozygotes to breast cancer. For the 21 breast cancers with onset before age 60, the odds ratio was 2.9 (1.1-7.6, p = .009) and for the 12 cases with onset at age 60 or older, the odds ratio was 6.4 (1.4-28.8, p = .002). Thus the breast cancer risk for A-T heterozygous women is not limited to young women but appears even higher at older ages. Of all breast cancers in the United States, 6.6% may occur in women who are A-T heterozygotes. This proportion is several fold greater than the estimated proportion of carriers of BRCA1 mutations in breast cancer cases with onset at any age.

Adult↗