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PubMed1998

Germline mutations of the BRCA1 and BRCA2 genes in a breast and ovarian cancer patient.

A patient with breast carcinoma diagnosed at the age of 30 years and ovarian carcinoma diagnosed at the age of 41 years was found to have germline mutations in both the BRCA1 and the BRCA2 genes. The patient was of Ashkenazi Jewish descent and the BRCA2 mutation was 6174delT, known to be very common in this population. The BRCA1 mutation, however, was 3888delGA, a mutation not previously reported in this ethnic group. The patient's breast cancer exhibited loss of heterozygosity (LOH) at the BRCA1 locus but not at BRCA2, and her ovarian cancer sustained LOH at BRCA1 and BRCA2. The BRCA1 mutation originated from patient's father, who had no personal or family history of cancer. The patient's mother, who was found to carry the BRCA2 mutation, was affected by late-onset breast cancer and her tumor exhibited LOH at BRCA2. These findings indicate that compound heterozygotes for germline mutations of BRCA1 and BRCA2 exist and may be expected to develop normally and that either gene may contribute to breast or ovarian cancer development in such individuals. The implications of this case in regard to genetic testing and counseling are also substantial.

Adult↗
PubMed1998

Germline mutations of hMLH1 and hMSH2 genes in patients with suspected hereditary nonpolyposis colorectal cancer and sporadic early-onset colorectal cancer.

PURPOSE: The present study was designed to determine the frequency of germline mutations in the hMLH1 and hMSH2 genes in 31 families suspected of having hereditary nonpolyposis colorectal cancer who do not fulfill the criteria of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer but in whom a genetic basis for colon cancer is strongly suspected and 45 patients with sporadic early-onset colorectal cancer who developed colorectal cancer before the age of 40 years without any family history of colorectal cancer. METHODS: Genomic DNAs were prepared from peripheral blood samples of patients who were tested. All coding exons and exon-intron borders of these two genes were screened, first with the polymerase chain reaction-single-strand conformation polymorphism method, followed by sequencing of the DNA fragments displaying an abnormal single-strand conformation polymorphism pattern. RESULTS: In 31 families with suspected hereditary nonpolyposis colorectal cancer, we found six different germline mutations in seven unrelated families, including one missense mutation and three frame-shift mutations in the hMLH1 gene and one missense mutation and one frame-shift mutation in the hMSH2 gene. Totally, frequency of mutation was 23 percent, 16 percent and 7 percent in the hMLH1 and hMSH2, respectively. Only one missense mutation of the hMSH2 gene was identified in 45 patients (2 percent) with sporadic early-onset colorectal cancer. The mutation detection rate in families with suspected hereditary nonpolyposis colorectal cancer was significantly higher than that of patients with sporadic early-onset colorectal cancer (P < 0.05). CONCLUSION: Our definition of suspected hereditary nonpolyposis colorectal cancer is useful in the diagnosis of hereditary nonpolyposis colorectal cancer and for identifying those families who need genetic presymptomatic diagnosis. Our results indicate that it may be important to perform DNA testing in families suspected of having hereditary nonpolyposis colorectal cancer. On the other hand, we only detected a low mutation rate (2 percent) in 45 patients with sporadic early-onset colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Novel MLH1 and MSH2 germline mutations in the first HNPCC families identified in Slovakia.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly-inherited cancer predisposition syndrome, in which the susceptibility to cancer of the colon, endometrium and ovary is linked to germline mutations in DNA mismatch repair (MMR) genes. We have recently initiated a cancer prevention program in suspected HNPCC families in the Slovak Republic. The first ten families fulfilling Amsterdam criteria or Bethesda guidelines were screened for germline mutations in MLH1 and MSH2, two MMR genes most frequently mutated in HNPCC families. Six mutations were identified, five of which have not been reported previously. Two of the three new mutations in MLH1 (c.380+2T>A; c.307-2A>C) were absent from 100 chromosomes of healthy controls and probably cause a splicing defect, while the third was a 1 bp deletion (c.1261delA). In the MSH2 gene, one new nonsense (c.1030C>T [p.Q344X]) and one missense (c.524T>C [p.L175P]) mutation were identified. This latter variant was not found in 104 alleles of healthy control individuals. Moreover, a previously-reported pathogenic mutation (c.677G>T [p.R226L]) was found in one kindred. The clinical data and the genotypic and phenotypic evaluation of the tumors indicate that all the new alterations are pathogenic HNPCC mutations.

Adaptor Proteins, Signal Transducing↗
PubMed2003

[Germline mutation of BRCA1 gene in Polish families with strong aggregation of breast and/or ovarian cancer based on coding sequence analysis using the SSCP method].

The aim of the study was to identify possible BRCA1 germline mutations in Polish families with strong aggregation of breast and/or ovarian cancer. Identification was based on analysis of the entire coding region using SSCP--"Phast System" technique. The study group consisted of 34 women with breast or/and ovarian cancer from families with aggregation of breast and/or ovarian cancer referred from the Oncology Center in Szczecin. Breast and ovarian cancer cases were revealed in 16 families, breast cancer in 17 and ovarian cancer in 1 family. Blood samples for genetic analyses were taken from at least one affected woman from each family. As a rule, samples were taken from the youngest woman. Genomic DNA was prepared from peripheral blood leukocytes with the nonenzymatic rapid method described by Lahiri and Nurnberger. The entire coding region of the BRCA1 gene was screened for the presence of germline mutations by use of Single Stranded Conformation Polymorphism (SSCP) followed by direct sequencing of variants. Primers used for PCR amplification of the BRCA1 gene have been described in the Breast Cancer Information Core (BIC) database. Samples were sequenced with the use of fluorescent dideoxy-chain terminators from the ABI Prism Kit (PE Biosystems) and model 373 automated sequencer (PE Biosystems). Four mutations were found in exon 5 (4/9) and three in exon 11 (3/9) of the BRCA1 gene. The two mutations in exon 20--5382insC (2/9) could not be identified using SSCP and required sequencing. Three BRCA1 abnormalities--C61G, 3819de15 and 5382insC, were the most frequent mutations detected in Polish families with strong aggregation of breast and/or ovarian cancers. These three abnormalities were most frequent in hereditary breast-ovarian cancer syndrome (6/9), followed by hereditary breast cancer-site specific syndrome (3/9). The present study and literature data suggest that the most effective strategy for DNA testing for cancer susceptibility genes is to identify the type and frequency of mutations in families with strong familial aggregation of cancers.

Adult↗
PubMed1999

No evidence of germline mutation or somatic deletion of the MEN1 gene in a case of familial multiple endocrine neoplasia type 1 (MEN1).

The MEN1 gene has recently been cloned as the gene responsible for multiple endocrine neoplasia type 1 (MEN1) and its germline mutations have been identified in a number of familial MEN1 patients. However, mutation-negative cases have also been reported in some MEN1 families. We report here a Japanese MEN1 family, including a proband with no evidence of MEN1 gene mutation. The proband (51 y.o., female) had three major MEN1 lesions, including primary hyperparathyroidism (HP), prolactinoma, and pancreatic tumor. Her father and brother had HP, and her daughter had both HP and prolactinoma. When we analyzed the proband for a germline mutation of the MEN1 gene, the direct sequencing analysis showed no mutation in the coding region, on the promoter, 5' and 3' untranslated regions of the MEN1 gene. We next examined the loss of heterozygosity (LOH) in the proband's parathyroid tumors using two benign polymorphisms (C2249G in intron 1 and 2248del3 in exon 10) in the MEN1 gene to detect LOH. LOH was not found in any of the four separate regions of the tumor tissues.

DNA↗
PubMed2006

High incidence of BRCA1-2 germline mutations, previous breast cancer and familial cancer history in Jewish patients with uterine serous papillary carcinoma.

OBJECTIVE: To test the carrier status of the three germline founder mutations in Jewish patients with uterine serous papillary carcinoma (USPC) and to evaluate its association to their personal and familial cancer records. METHODS: Retrospective analysis of histologically confirmed USPC Jewish patients diagnosed between April 1, 1997 and December 31, 2003. All cases were genetically tested for the three BRCA1-2 founder germline mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). The analysis was performed on genomic DNA extracted from whole blood or paraffin embedded normal tissue of these patients, employing PCR amplification of target sequences and differential digestion with restriction enzymes. The carrier frequency was compared to the known population frequency of these mutations. RESULTS: The study group comprised 22 Jewish patients with USPC diagnosed within this timeframe. The mean age was 71.8 years (range 56-79). FIGO surgical stage distribution revealed 59% at stages III-IV. Seven USPC patients (32%) with a previous diagnosis of breast cancer were identified. Familial cancer history was recorded in 23% of the patients (four with breast cancer and one with ovarian cancer). DNA analysis revealed six BRCA1-2 germline mutation carriers (27%) as follows: three with BRCA2-6174delT, two with BRCA1-185delAG, and one with BRCA1-5382insC mutation. Three of the carriers had a previous diagnosis of breast cancer. Four carriers had familial cancer history in first-degree relative (three with breast cancer and one with ovarian cancer). CONCLUSIONS: The high rate of BRCA germline mutations in USPC patients observed in the present study, coupled with the strong personal and familial cancer history as well as the histological and clinical resemblance to the ovarian cancer, may indicate that USPC is a part or an expression of the hereditary breast-ovarian cancer syndrome. This option may have implications in our clinical recommendations for non-affected BRCA1-2 carriers.

Aged↗
PubMed1999

Novel germline mutations of the MEN1 gene in Japanese patients with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroid glands, the pancreatic islet cells, and the anterior pituitary. Germline mutations of the MEN1 gene in three independent Japanese cases with MEN1 were analyzed. Case 1 has revealed a 2-bp (TA) insertion at nucleotide position 341 (341insTA) in exon 2, which shifts the reading frame such that the mutant protein has a completely different amino acid sequence from codon 78 to the premature stop codon at 119. In case 2, a nucleotide substitution, i.e., TAG in place of TGG, which encodes tryptophan at codon 198 was identified (nonsense mutation). These mutations were heterozygously present and have not been reported previously. Case 3 showed no mutations in the protein-coding exons and exon-intron junctions of the MEN1 gene by single-strand conformation polymorphism or direct sequencing of the polymerase chain reaction (PCR) fragments. We confirmed the finding that patients with MEN1 carry heterozygous germline mutations in the MEN1 gene, which is compatible with the idea that the MEN1 gene is a tumor suppressor gene. The reason why mutations in the coding region of the MEN1 gene could not be detected by PCR-based analysis in some of the MEN1 patients, e.g. case 3, needs to be clarified further.

Adult↗
PubMed2006

A rare extracellular D631Y germline mutation of the RET proto-oncogene in two Korean families with multiple endocrine neoplasia 2A.

A mutation in codon 631 of exon 11 of the RET proto-oncogene is extremely rare in the patients with multiple endocrine neoplasia type 2A (MEN 2A). We report here on a rare extracellular mutation of the RET gene that led to the substitution of a tyrosine for an aspartate in codon 631 (D631Y, GAC to TAC) in two Korean families with MEN 2A. Eleven individuals from two unrelated families were found to have the D631Y germline mutation. Among them, medullary thyroid carcinoma (MTC) was identified in five patients: four of them had MEN 2A and one had familial MTC. They had tumors 2 cm or less in the greatest dimension that were limited to the thyroid, and they had a relatively old age above 30 at the time of diagnosis. Pheochromocytoma was detected in six patients including the four patients who had MEN 2A. All had adrenal tumors greater than 3 cm in the greatest dimension, and four of them had bilateral tumors. Two of six patients suffering with pheochromocytoma had no clinical evidence of MTC at the time of diagnosis. None had any evidence of hyperparathyroidism. This genetic profile might be related to the less vigorous clinical disease behavior and the late onset of MTC. In addition, pheochromocytoma might be the first manifestation prior to the development of MTC in some patients with the D631Y mutation. This report is the first description of the clinical characteristics of the D631Y germline mutation in the families with MEN 2A.

Adult↗
PubMed1994

A common hot spot for somatic and germline mutations in rat mitochondrial DNA: analysis by fluorescence-based SSCP.

To estimate the degree of sequence heterogeneity of mtDNA, we have developed an efficient system for mutant detection using fluorescence-based single strand conformational polymorphism (F-SSCP). The F-SSCP analysis 200 clones from Wistar rat and sequencing of 2 clones from each 40 inbred Wistar rats at the age of 7 weeks detected no sequence differences, suggesting that the mtDNA sequence heterogeneity is low in young rat hearts. One of the 387 clones isolated from a Donryu rat showed a different mobility in the F-SSCP from other clones. Sequencing of the mutant clone revealed double contiguous TT-->CC transitions at nucleotide positions 15443 and 15444, compared with the normal Donryu clone. The nucleotide at 15444 was different between the Wistar and Donryu rats, indicating that this is the site of germline mutation. These results suggest that the somatic and germline mutations can occur at a common hot spot.

Animals↗
PubMed2002

Prevalence of germline mutations of MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer families from Spain.

HNPCC is an autosomal dominantly inherited cancer-susceptibility syndrome that confers an increased risk for colorectal cancer and endometrial cancer at a young age. It also entails an increased risk of a variety of other tumors, such as ovarian, gastric, uroepithelial and biliary tract cancers. The underlying pathogenic mutation lies in 1 of the 5 known DNA MMR genes (MSH2, MLH1, PMS1, PMS2 and MSH6). We screened a total of 140 individuals from 56 Spanish families with suspected HNPCC for mutations in the DNA mismatch repair genes MLH1 and MSH2, using DGGE and direct DNA sequencing. Families were selected on the basis of a history of HNPCC-related tumors or the occurrence of other associated tumors in members besides the index case affected with colorectal cancer. We detected 14 definite pathogenic germline mutations, 9 in MLH1 and 5 in MSH2 in 13 unrelated families selected by the Amsterdam criteria and Bethesda guidelines (1 family carries 2 mutations) and 3 missense mutations in 3 unrelated families selected by the Amsterdam criteria. Among the 17 germline mutations noted in the Spanish cohort, 10 are novel, 7 in MLH1 and 3 in MSH2, perhaps demonstrating different mutational spectra in the Spanish population, where no founder mutation has been identified. Based on our results, we suggest that in the Spanish population not only HNPCC families fulfilling the Amsterdam criteria but also those following Bethesda guidelines should undergo genetic testing for MSH2 and MLH1 mutations.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome.

BACKGROUND AND AIMS: Juvenile polyps occur in several Mendelian disorders, whether in association with gastrointestinal cancer alone (juvenile polyposis syndrome, JPS) or as part of known syndromes (Cowden, Gorlin, and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in the SMAD4 (DPC4) gene, providing further evidence for the importance of the TGFbeta signalling pathway in colorectal cancer. There remains, however, considerable, unexplained genetic heterogeneity in JPS. Other members of the SMAD family are excellent candidates for JPS, especially SMAD2 (which, like SMAD4, is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when "knocked out" in mice), SMAD5, and SMAD1. METHODS: SMAD1, SMAD2, SMAD3, and SMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4 mutations. RESULTS: No mutations were found in any of these genes. A G-A C89Y polymorphism with possible effects on protein function was found in SMAD3, but the frequencies of the G and A alleles did not differ between patients with JPS and controls. CONCLUSIONS: It remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas. SMAD4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.

Adenomatous Polyposis Coli↗
PubMed1998

Intestinal cancer in patients with a germline mutation in the down-regulated in adenoma (DRA) gene.

A recent study has revealed that germline mutations of the down-regulated in adenoma (DRA) gene are a likely cause of a recessive intestinal absorption defect, congenital chloride diarrhea. This finding was in accordance with previous works showing that DRA encodes a sodium independent transporter for sulfate and oxalate. Although DRA was originally reported as a candidate tumor suppressor, these studies have questioned the relevance of DRA in cancer. To evaluate whether further studies on the role of DRA in tumorigenesis are still of interest, we examined whether individuals carrying germline DRA mutations have an excess of intestinal cancer. Cancer status of 229 members of 36 Finnish congenital chloride diarrhea families (44 homozygous patients, 70 heterozygous parents, and 115 grandparents at 50% risk of being a DRA mutation carrier) was checked at the Finnish Cancer Registry and the risk of intestinal cancer was found slightly elevated (standardized incidence ratio 3.4, 95% confidence interval 1.4-7.0, P < 0.05). While this result does not unambiguously demonstrate an increased intestinal cancer risk in DRA mutation carriers, it should promote further studies to determine the possible role of DRA in cancer.

Adenoma↗
PubMed2000

Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study.

Papillary thyroid carcinoma (PTC) is one extracolonic manifestation affecting about 1-2% of patients with familial adenomatous polyposis (FAP). Ninety-seven patients with FAP-associated PTC have previously been reported, including 6 pairs of siblings. During a European collaborative study, 15 patients with FAP-associated PTC were collected. All 15 patients were females. The mean age at thyroidectomy was 24.9 yr (range, 19-39 yr). In 13 subjects, APC germline mutations had been detected; they were at codons 140, 593, 778, 976, 993, 1061 (n = 5), 1105 (n = 1), and 1309 (n = 2), respectively. A review of the literature added 11 other patients with FAP-associated PTC and detection of germline APC mutations; they were at codons 313 (n = 2), 698 (n = 3), 848 (n = 2), 1209 (n = 2), 1061 (n = 1), and 1105 (n = 1), respectively. The latter led to formation of the same stop codon (TAA) at 1125-1126 as the mutation at codon 1061. Therefore, 21 of 24 mutations were in exon 15 in the genomic area usually associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE), i.e. codons 463-1387. Typical CHRPE was found in 17 of 18 affected patients who had specific screening. Interestingly, 22 of the 24 patients had their mutation out of the mutation cluster region (codons 1286-1513), which is currently considered the hot spot mutation area, in particular for extracolonic manifestations of FAP. The difference in the incidence of germline mutations before and after codon 1220 between PTC and non-PTC FAP patients was statistically significant (P<0.05) for both patients and kindreds (P = 0.005 and P = 0.049, respectively). Even if most mutations were scattered throughout the entire 5'-portion of exon 15, 8 of 23 patients (6 with mutation at 1061 and 2 with mutation at 1105; i.e. more than one third) had the same truncated protein product. The awareness that patients with PTC usually have APC mutations that cluster in a well defined genomic area, in addition to giving a deeper insight into gene function, could facilitate both earlier diagnosis and better treatment. In particular, intensive screening for thyroid nodules after age 15 yr is recommended when a single patient or an entire kindred have CHRPE and/or mutations in the 5'-portion of exon 15.

Adenomatous Polyposis Coli↗
PubMed2006

Von Hippel-Lindau disease germline mutations in Mexican patients with cerebellar hemangioblastoma.

OBJECT: Central nervous system (CNS) hemangioblastomas are benign vascular tumors arising either sporadically or as a manifestation of von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome. The authors studied a series of patients with CNS hemangioblastomas and their families to identify germline mutations in the VHL tumor suppressor gene and to establish a predictive testing and screening protocol. METHODS: Patients admitted between 2002 and 2004 to the Instituto Nacional de Neurología y Neurocirugía for hemangioblastoma were prospectively enrolled, together with their at-risk family members. The authors performed the molecular analysis of the VHL gene by using polymerase chain reaction and direct genetic sequencing. All asymptomatic mutation carriers underwent genetic counseling and tumor surveillance. Ninety-eight individuals were tested for VHL mutations--23 symptomatic and 75 asymptomatic individuals belonging to 16 families. Seven of the families had definite clinical criteria of VHL disease, five had sporadic hemangioblastoma, and four had CNS hemangioblastoma combined with minor visceral signs. Molecular genetic testing identified five germline mutations in six of the definite VHL families (sensitivity 85%), but none in the possible VHL and sporadic hemangioblastoma cases; four of these mutations had been previously described and one is a novel mutation present in two unrelated families. After patients carrying the mutation were identified, they underwent clinical screening and asymptomatic VHL-related lesions were identified in 43%. CONCLUSIONS: Genetic testing for mutations in the VHL gene is crucial in patients with CNS hemangioblastoma. The prompt identification of patients carrying the genetic mutation allows for a multidisciplinary screening protocol to decrease morbidity and mortality rates in these patients, while avoiding costly and invasive procedures for noncarriers.

Adolescent↗
PubMed1999

Molecular pathology of multiple endocrine neoplasia type I: two novel germline mutations and updated classification of mutations affecting MEN1 gene.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined development of tumors in several endocrine glands and other tissues. The MEN1 gene was recently identified and isolated by positional cloning. This gene was screened in two unrelated MEN1 Spanish kindreds (with four affected members and seven asymptomatic members) using single-strand conformation polymorphism, DNA sequencing, and restriction enzyme analysis. Two novel germline mutations were identified: a missense in exon 2 (H139R) and a splice-site in intron 9 (1461-2A>C). These findings allowed us to identify the MEN1 carriers among the seven asymptomatic members analyzed. An updated review of the mutations and polymorphisms found in the analysis of the MEN1 gene is provided. The report of all germline mutations causing MEN1 and easy access to this updated information are both of special diagnostic interest, because this greatly facilitates the task of attributing the disorder to a specific mutation found in a given MEN1 family. This is especially helpful in the critical differentiation of missense mutations from nonsynonymous polymorphisms that fit the pattern of segregation of the disease, but do not cause it.

Adolescent↗
PubMed2001

Microsatellite instability, PTEN and p53 germline mutations in glioma families.

Rare inherited syndromes that to some extent explain familial glioma include Turcot's syndrome, Li-Fraumeni syndrome and neurofibromatosis types I and II. The majority of families with glioma do not meet the clinical criteria for any of these syndromes. In order to study the genetic origin of familial glioma, tumour DNA (n = 35) or blood samples (n = 8) were collected from 25 families. The glioma tumours were tested for microsatellite instability (MSI) with two markers, BAT25 and BAT26, since glioma is associated with hereditary non-polyposis colon cancer (HNPCC) in Turcot's syndrome. Furthermore, p53 was screened from blood DNA (exons 2-11) with temporal temperature gradient electrophoresis (TTGE) since germline mutations in p53 are seen in Li-Fraumeni syndrome. In gliomas, there is a wide variety of somatic mutations, such as, for instance, in p53, the epidermal growth factor receptor (EGFR) and p16. The tumour suppressor gene PTEN is also often somatically mutated in glioma, therefore it is attractive as a candidate gene for germline mutations in familial glioma. Blood DNA was directly sequenced for mutations in PTEN exons 1-9. The analysis showed that no mutations were found in either of the studied tumour suppressor genes, and no MSI-positive tumours were found. A common polymorphism in p53 at codon 72 (arginine/proline) was found in 6/8 of the patients. Apparently, mutation in the tested tumour suppressor genes or DNA mismatch repair genes does not explain the familial glioma observed in these families.

Brain Neoplasms↗
PubMed2001

Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene.

We describe 2 siblings with multiple gastrointestinal stromal tumors (GISTs) and cutaneous hyperpigmentation. Both had a point mutation of the c-kit gene. The patients were sisters who had exhibited cutaneous hyperpigmentation since their late teens, but the diagnosis of multiple gastrointestinal submucosal tumors was not made until they were 41 and 45 years old. Histologic examination showed that these tumors were GISTs expressing CD34 and Kit protein. Both patients died of GISTs. Single-strand conformation polymorphism analysis showed a mutation of c-kit in tumor DNA extracted from paraffin-embedded specimens. Direct sequencing analysis showed that the point mutation occurred at codon 559 of exon 11 (Val-->Ala). The same single-point mutation was detected in DNA extracted from peripheral leukocytes obtained from the younger sister and her 2 children (who had similar general hyperpigmentation) as well as in DNA from a skin biopsy specimen taken from the older sister. The germline mutation at codon 559 of the c-kit gene found in the present familial GISTs differed from that in a previously reported case of familial GISTs. We propose that GISTs caused by a germline mutation of the c-kit gene should be referred to as GIST-cutaneous hyperpigmentation disease.

Adult↗
PubMed1999

Survival in hereditary breast cancer associated with germline mutations of BRCA2.

PURPOSE: Breast cancer in BRCA1 and BRCA2 gene-mutation carriers may differ from so-called sporadic breast cancer in clinical features and behavior. These potential differences may be of importance for the prevention, screening, and, ultimately, treatment of breast cancer in women with such germline mutations. Thus far, there have been very few studies on the survival of BRCA2-associated breast cancer patients. PATIENTS AND METHODS: We determined the disease-free and overall survival of 28 breast cancer patients from 14 consecutive families with eight different BRCA2 germline mutations. These patients' survival and tumor characteristics were compared with those of a control group of 112 sporadic breast cancer patients matched to them by age and year of diagnosis. RESULTS: The 5-year disease-free survival was 52% for each group (P =.91); the overall survival was 74% for BRCA2 carriers and 75% for sporadic cases (P =.50). At the time of diagnosis, tumors from the BRCA2 carriers were borderline significantly larger in comparison to the tumors in sporadic cases (P =.05), but axillary nodal status was not significantly different in the two groups (node-negativity, 63% v 52. 8%, respectively; P =.34). With respect to steroid receptor status, BRCA2-associated tumors were more likely to be steroid receptor-positive, especially regarding progesterone receptor status (100% v 76.7% positive, respectively; P =.06). Stage-adjusted recurrence and death rates were nonsignificantly better for BRCA2 cases (hazard ratios of 0.84 and 0.59 [P =.61 and P =.19], respectively). In contrast, after 5 years, the rate of metachronous contralateral breast cancer in BRCA2 patients was 12% (v 2% in controls; P =.02). CONCLUSION: Patients with hereditary breast cancer due to BRCA2 have a similar prognosis when compared with age-matched sporadic breast cancer patients. Contrary to our previous observation regarding BRCA1-associated breast cancer, BRCA2 tumors tended to be steroid receptor-positive, instead of steroid receptor-negative.

Actuarial Analysis↗