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S Neuhausen

Publications and source records attributed to S Neuhausen.

At least 19 recordsLinked to original sources
PubMed2004

CYP1A1, cigarette smoking, and colon and rectal cancer.

Cytochrome P-450 (CYP) is involved in the activation and metabolism of polycyclic aromatic hydrocarbons in tobacco products. The authors evaluated the association of two polymorphisms in the CYP1A1 gene--the noncoding Msp I polymorphism in the 3'-untranslated region and the Ile462Val polymorphism in exon 7--with colon and rectal cancer. The authors used data from two incident case-control studies of colon cancer (1,026 cases and 1,185 controls) and rectal cancer (820 cases and 1,036 controls) conducted in California and Utah (1991-2002). CYP1A1 genotype was not associated with colon or rectal cancer. Having GSTM1 present, a CYP1A1 variant allele, and the rapid-acetylator NAT2 imputed phenotype was associated with increased risk of colon cancer (odds ratio = 1.7, 95% confidence interval: 1.2, 2.3). Among men, the greatest colon cancer risk was observed for having any CYP1A1 variant allele and currently smoking (odds ratio = 2.5, 95% confidence interval: 1.3, 4.8; Wald chi(2)test: p < 0.01). Assessment of GSTM1 and CYP1A1 and rectal cancer in men showed a twofold elevation in risk for more than 20 pack-years of smoking, except among those with GSTM1 present who had a variant CYP1A1 allele. These data support the association between smoking and colon and rectal cancer. Smoking may have a greater impact on colorectal cancer risk based on CYP1A1 genotype; this might further be modified by GSTM1 for rectal cancer risk.

3' Untranslated Regions↗
PubMed2004

Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Several studies have reported that the risk of breast cancer decreases with increasing duration of breast-feeding. Whether breast-feeding is associated with a reduced risk of hereditary breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations is currently unknown. METHODS: We conducted a case-control study of women with deleterious mutations in either the BRCA1 or the BRCA2 gene. Study participants, drawn from an international cohort, were matched on the basis of BRCA mutation (BRCA1 [n = 685] or BRCA2 [n = 280]), year of birth (+/-2 years), and country of residence. The study involved 965 case subjects diagnosed with breast cancer and 965 control subjects who had no history of breast or ovarian cancer. Information on pregnancies and breast-feeding practices was derived from a questionnaire administered to the women during the course of genetic counseling. Conditional logistic regression analyses were used to estimate odds ratios (ORs) for the risk of breast cancer. All statistical tests were two-sided. RESULTS: Among women with BRCA1 mutations, the mean total duration of breast-feeding was statistically significantly shorter for case subjects than for control subjects (6.0 versus 8.7 months, respectively; mean difference = 2.7 months, 95% confidence interval [CI] = 1.4 to 4.0; P<.001). The total duration of breast-feeding was associated with a reduced risk of breast cancer (for each month of breast-feeding, OR = 0.98, 95% CI = 0.97 to 0.99; P(trend)<.001). Women with BRCA1 mutations who breast-fed for more than 1 year were less likely to have breast cancer than those who never breast-fed (OR = 0.55, 95% CI = 0.38 to 0.80; P =.001), although no such association was seen for BRCA2 (OR = 0.95, 95% CI = 0.56 to 1.59; P =.83). CONCLUSIONS: Women with deleterious BRCA1 mutations who breast-fed for a cumulative total of more than 1 year had a statistically significantly reduced risk of breast cancer.

Adult↗
PubMed2001

Variants of the VDR gene and risk of colon cancer (United States).

OBJECTIVES: Genetic factors involved in regulating cell growth, such as the vitamin D receptor (VDR) gene, may contribute to the etiology of colon cancer. METHODS: Using data from a population-based case-control study of colon cancer and from a family-based study of cases with colon cancer and population-based controls, we evaluated the association between four variants of the VDR gene and risk of colon cancer. RESULTS: The polyA (short), BsmI (BB), and TaqI (tt) variants of the VDR gene were in linkage disequilibrium in this mostly Caucasian population. These variants were associated with reduced risk of colon cancer (OR 0.5, 95% CI 0.3-0.9). The FokI variant was not associated with colon cancer risk. Although estimates of association were imprecise, there were suggestions that associations were slightly stronger for women than men, for people diagnosed at a younger age, and for those with proximal tumors. Consistent associations were observed from sporadic cases of colon cancer from a population-based study as well as from colon cancer cases from a family-based study. There were no interactions observed by family history. CONCLUSIONS: These data suggest that molecular variants of the VDR gene may be related to the development of colon cancer. To further define the impact of the VDR gene on cancer etiology, studies to evaluate the association of these variants with diet and lifestyle factors are needed.

Adult↗
PubMed2001

A candidate prostate cancer susceptibility gene at chromosome 17p.

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).

Amino Acid Sequence↗
PubMed2000

Celiac disease and human leukocyte antigen genotype: accuracy of diagnosis in self-diagnosed individuals, dosage effect, and sibling risk.

BACKGROUND: Celiac disease is an autoimmune disorder of the small intestine characterized by intolerance to gluten. Traditionally, diagnosis is made by intestinal biopsy. Testing for immunoglobulin (Ig) A endomysial antibodies in the serum also is used for diagnosis. Biopsy and serology revert to normal with adherence to a gluten-free diet. Often, after an index case is diagnosed, siblings with symptoms adhere to a gluten-free diet without biopsy or serologic confirmation. More than 90% of patients with celiac disease have the human leukocyte antigen (HLA) DQA1*0501-DQB1*0201 genotype. Non-HLA genes also have been implicated. METHODS: One hundred ninety-five individuals with confirmed or suspected celiac disease were identified in 73 families affected by the disease. IgA endomysial antibody testing was performed for all symptomatic family members who did not have biopsy-confirmed diagnoses. DNA samples were genotyped at D6S276 and the HLA class II loci DQA and DQB. RESULTS: At the time sampling was begun in families, 88 of 177 (49.7%) individuals were self-diagnosed and adhering to a gluten-free diet. Ninety percent (91/101) of confirmed cases (biopsy or serology) had at least 1 copy of the DQA1*0501-DQB1*0201 genotype, whereas only 67% (46/69) of cases self-diagnosed (adherence to gluten-free diet without confirmation) had at least 1 copy. Of confirmed cases, 61% carried two copies of DQB*0201. It is estimated that the HLA association and other unlinked genes contribute approximately equally to the sibling risk of celiac disease. CONCLUSIONS: A dosage effect of DQB1*0201 may be associated with an increased risk of celiac disease. Self-diagnosis of celiac disease is as common as confirmed diagnosis in families in the United States. Diagnosis of celiac disease on the basis of clinical response to gluten restriction is inaccurate. With long-term adherence to a gluten-free diet, serologic test results are likely to be negative. Based on HLA genotype, approximately one third of self-diagnosed individuals are unlikely to have celiac disease. However, it is not possible to determine which individuals consuming a gluten-free diet have the disease. Therefore, before starting a gluten-free diet, serologic screening and biopsy confirmation are necessary.

Biopsy↗
PubMed2000

The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2.

Breast cancers arising in carriers of mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, differ histologically from each other and from breast cancers unselected for a family history. However, a substantial proportion of families with multiple cases of breast cancer is not attributable to these two genes (non-BRCA1/2 families). We have now characterized the pathology of 82 breast cancers from non-BRCA1/2 families. Breast cancers in non-BRCA1/2 families were of lower grade (P = 0.0018), showed fewer mitoses (P < 0.0001), less nuclear pleomorphism (P = 0.0014), less lymphocytic infiltrate (P < 0.0001), a lesser extent of the tumor with a continuous pushing margin (P = 0.004), a lesser extent of the tumor composed of solid sheets of cells (P = 0.0047), less necrosis (P = 0.002), and wereparison with BRCA2 tumors, non-BRCA1/2 tumors were lower grade (P = 0.017) and exhibited less pleomorphism (P = 0.01) and more tubule formation (P = 0.05). In comparison with control breast cancers unselected for a family history of the disease, non-BRCA1/2 tumors were of significantly lower grade (P = 0.001), showed less pleomorphism (P = 0.0002), and had a lower mitotic count (P = 0.003). The results indicate that non-BRCA1/2 breast cancers differ histologically from both BRCA1 and BRCA2 breast cancers and are overall of lower grade. They also suggest that non-BRCA1/2 breast cancers differ from nonfamilial breast cancers, but these differences may be attributable to various types of bias.

BRCA2 Protein↗
PubMed1999

Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat.

Compared with the general population, women who have inherited a germline mutation in the BRCA1 gene have a greatly increased risk of developing breast cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothesize that other genes, particularly those involved in endocrine signaling, may modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the androgen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without breast cancer. We found that women were at significantly increased risk of breast cancer if they carried at least one AR allele with >/=28 CAG repeats. Women who carried an AR-CAG allele of >/=28, >/=29, or >/=30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women who did not carry at least one such allele. All 11 women in our sample who carried at least one AR-CAG allele with >/=29 repeats had breast cancer. Our results support the hypothesis that age at breast cancer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer.

Adult↗
PubMed1998

Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group.

BACKGROUND: Women with mutations in either the BRCA1 or the BRCA2 gene have a high lifetime risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they also protect against hereditary forms of ovarian cancer. METHODS: We enrolled 207 women with hereditary ovarian cancer and 161 of their sisters as controls in a case-control study. All the patients carried a pathogenic mutation in either BRCA1 (179 women) or BRCA2 (28 women). The control women were enrolled regardless of whether or not they had either mutation. Lifetime histories of oral-contraceptive use were obtained by interview or by written questionnaire and were compared between patients and control women, after adjustment for year of birth and parity. RESULTS: The adjusted odds ratio for ovarian cancer associated with any past use of oral contraceptives was 0.5 (95 percent confidence interval, 0.3 to 0.8). The risk decreased with increasing duration of use (P for trend, <0.001); use for six or more years was associated with a 60 percent reduction in risk. Oral-contraceptive use protected against ovarian cancer both for carriers of the BRCA1 mutation (odds ratio, 0.5; 95 percent confidence interval, 0.3 to 0.9) and for carriers of the BRCA2 mutation (odds ratio, 0.4; 95 percent confidence interval, 0.2 to 1.1). CONCLUSIONS: Oral-contraceptive use may reduce the risk of ovarian cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene.

Adult↗
PubMed1998

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.

BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

Adult↗
PubMed1998

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

Adult↗
PubMed1996

BRCA1 germline mutational spectrum in Italian families from Tuscany: a high frequency of novel mutations.

BRCA1 germline mutations confer susceptibility to familial breast and ovarian cancer. Mutational hot spots have never been detected in BRCA1 cDNA. Some mutations have been reported several times whereas some others appear to be population-related. In this study a group of 36 Italian families were analysed for BRCA1 germline mutations. All of them were screened by allele-specific oligonucleotide hybridization (ASO) for three recurrent mutations (185delAG, 5382insC, nt332-T>G). Twenty families, selected because of their high risk of carrying BRCA1 mutations, were subjected to analysis of the entire coding sequence of the gene. A total of eight mutations were found. ASO screening demonstrated only one known mutation in one patient, whereas cycle sequencing revealed five new mutations. Three of these new mutations were frameshifts: one occurred in exon 11 (1499insA), one in exon 16 (4873delCA) and one in the splice site of exon 3 (252delAAgt). Two were missense mutations (Cys64Arg; Asn158Tyr). The same frameshift mutation, 1499insA, was detected in three unrelated families. Haplotype analysis supported the hypothesis that two of these families may have had common ancestors, whereas in the third family the analysis was uninformative. BRCA1 germline mutations were found in one out of two families with ovarian cancer, in five out of eight families with breast-ovarian cancer, and in two out of 11 families with breast cancer. All three families with 1499insA mutations included at least one case of ovarian cancer. The majority of the ovarian cancers (4/5) associated with detectable BRCA1 germline mutations were of serous histotype.

Adult↗
PubMed1996

Germline BRCA1 185delAG mutations in Jewish women with breast cancer.

BACKGROUND: We aimed to find out the proportion of breast cancers in Ashkenazi Jewish women attributable to the frameshift mutation at position 185 involving the deletion of adenine and guanine (185delAG) in the breast cancer gene BRCA1. METHODS: We studied 107 Ashkenazi Jewish women with breast cancer seen at medical oncology and genetic counseling clinics in New York over a three and a half year period beginning in 1992. 80 of the women were diagnosed before age 42 years; the other 27 were diagnosed between 42 and 50 years and had a positive family history. Genomic DNA testing by PCR amplification was done to identify any 185delAG mutations of the BRCA1 gene. FINDINGS: Of the 80 women diagnosed before the age of 42 years, 16 (20%, 95% CI 11.2-28.8) were heterozygous for the mutation. All 16 women had at least one first-degree or second-degree relative with breast or ovarian cancer. Of 27 probands diagnosed with breast cancer between the ages of 42 and 50 years who had at least one first-degree relative affected with breast or ovarian cancer, 8 (30%, 95% CI 12-47) had 185delAG mutations. INTERPRETATION: These data suggest that screening for the 185delAG mutation may be useful in genetic counselling of these women where options for detection and prevention of possible cancers can be discussed.

Adult↗
PubMed1996

The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.

Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.

BRCA2 Protein↗
PubMed1996

A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes.

The BRCA2 gene on chromosome 13 has been shown to be associated with familial male and female breast cancer. Here we describe a study on BRCA2 in 21 Icelandic families, including 9 with male breast cancer. We have previously reported linkage to the BRCA2 region in an Icelandic male breast cancer family and subsequently found a strong indication of linkage to BRCA2 and the same BRCA2 haplotype in breast cancer cases from 15 additional families, indicating a common origin. We describe a five base-pair deletion in exon 9 of BRCA2 in an affected male from the male breast cancer family. The same mutation occurs in all the families with the shared BRCA2 haplotype indicating a founder effect. Among mutation carriers there are 12 males with breast cancer, which accounts for 40% of all males diagnosed with breast cancer in Iceland over the past 40 years. Three of them have no family history of breast cancer indicating that this mutation may have variable penetrance. The same BRCA2 mutation appears to be associated with different cancer phenotypes in this population including male and female breast cancer, prostate cancer, pancreas cancer and ovarian cancer.

BRCA2 Protein↗
PubMed1996

BRCA2 germline mutations in male breast cancer cases and breast cancer families.

The breast cancer susceptibility gene, BRCA2 on chromosome 13q12-13, was recently isolated. Mutations in BRCA2 are thought to account for as much as 35% of all inherited breast cancer as wall as a proportion of inherited ovarian cancer. Many BRCA2-linked families also contain cases of male breast cancer. We have analysed germline DNA from 50 males with breast cancer (unselected for family history) and 26 individuals from site-specific female breast and breast-ovarian cancer families for mutations in BRCA2. All 17 breast-ovarian cancer families have been screened for BRCA1 coding region mutations and none were detected. Conformation-sensitive gel electrophoresis (CSGE) analysis of PCR-amplified DNA followed by direct sequencing was used to detect sequence variants. Three of eleven individuals carry the same mutation, all are of Ashkenazi Jewish descent, supporting the observation by Neuhausen et al. in this issue that there is a common mutation in this population. Eleven truncating mutations and nine polymorphisms were identified -- all were coding region variants. No loss-of-transcript mutations were identified in the sixteen samples for which this analysis was possible. Seven of the nine disease-associated mutations were detected in the 50 men with breast cancers; for thus in our series, BRCA2 mutations account for 14% of male breast cancer, all but one of which had a family history of male and/or female breast cancer.

BRCA2 Protein↗
PubMed1996

Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer.

The lifetime risk of breast cancer may approach 80-90% in women who have germline mutations of either of two genes, BRCA1 or BRCA2. A single BRCA1 mutation, 185delAG, has been noted in approximately 20% of Ashkenazi Jewish women with early onset breast cancer and in 0.9% of the Ashkenazi population. We recently detected a 6174delT frameshift mutation in BRCA2 in an hereditary breast cancer kindred of Ashkenazi Jewish ancestry. Here, we investigated the frequency of this mutation in 200 women with early-onset breast cancer. Six of 80 Ashkenazi Jewish women (8%) diagnosed with breast cancer before the age of 42, wer heterozygous for the 6174delT mutation, compared to none of 93 non-Jewish women diagnosed with breast cancer at the same age (P = .005). These cases were ascertained without regard to family history. Two of 27 (7%) additional Jewish families in which the proband was diagnosed with breast cancer at age 42 to 50 and had a family history of breast or ovarian cancer had germline 6174delT mutations. The results of this report suggest that a recurrent mutation of BRCA1 and a recurrent mutation BRCA2 together may account for over a quarter of all early-onset breast cancer in the setting of a personal or family history of ovarian cancer in Ashkenazi Jewish women.

Adult↗