The gene responsible for Peutz-Jeghers syndrome (PJS), LKB1 (also called STK11) was mapped to chromosome 19p13.3 and was found to encode a putative serine/threonine protein kinase, LKB1. As only a limited number (～10...The gene responsible for Peutz-Jeghers syndrome (PJS), LKB1 (also called STK11) was mapped to chromosome 19p13.3 and was found to encode a putative serine/threonine protein kinase, LKB1. As only a limited number (～100) of germline mutations of the gene have been reported, and because the protein function is still unclear, information about LKB1 mutations and their expression should be accumulated to understand the phenotypegenotype correlation of this disease. Here we report a patient with sporadic PJS with early-onset gastric cancer. We found a novel germline frameshift mutation (757-758insT) in the LKB1 gene and a marked reduction in LKB1 protein expression in the carcinoma cells, suggesting that the loss of LKB1 function may have led to the carcinogenesis of the gastric cancer.展开更多
Background and aims: Germline mutations in the LKB1 gene are known to cause Peutz-Jeghers syndrome, which is an autosomal dominant disorder characterised by hamartomatous polyposis and mucocutaneous pigmentation. This...Background and aims: Germline mutations in the LKB1 gene are known to cause Peutz-Jeghers syndrome, which is an autosomal dominant disorder characterised by hamartomatous polyposis and mucocutaneous pigmentation. This syndrome is associated with an increased risk of malignancies in different organs but there is a lack of data on cancer range and risk in LKB1 germline mutation carriers. Patients and methods: The cumulative incidence of cancer in 149 Peutz-Jeghers syndrome patients with germline mutation(s) in LKB1 was estimated using Kaplan-Meier time to cancer onset analyses and compared between relevant subgroups with log rank tests. Results: Thirty two cancers were found in LKB1 mutation carriers. Overall cancer risks at ages 30, 40, 50, 60, and 70 years were 6%, 18%, 31%, 41%, and 67%, respectively. There were similar overall cancer risks between male and female carriers. However, there were overall cancer risk differences for exon 6 mutation carriers versus non-exon 6 mutation carriers (log rank p = 0.022 overall, 0.56 in males, 0.0000084 in females). Most (22/32) of the cancers occurred in the gastrointestinal tract, and the overall gastrointestinal cancer risks at ages 40, 50, 60, and 70 years were 12%, 24%, 34%, and 63%, respectively. In females, the risks for developing gynaecologic cancer at ages 40 and 50 years were 13%and 18%, respectively. Conclusions: Mutations in exon 6 of LKB1 are associated with a higher cancer risk than mutations within other regions of the gene. Moreover, this study provides age related cumulative risks of developing cancer in LKB1 mutation carriers that should be useful for developing a tailor made cancer surveillance protocol for Peutz-Jeghers syndrome patients.展开更多
BACKGROUND:The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease.METHODS:Without preselection and regardless...BACKGROUND:The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease.METHODS:Without preselection and regardless of family history,we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer.We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1,MSH2,and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes.Stage 1 of the model incorporated only clinical variables;stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability.The model was validated in an independent population of patients.We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival.RESULTS:There were 38 mutations among the 870 participants(4 percent) :15 mutations in MLH1,16 in SH2,and 7 in MSH6.Carrier frequencies in men(6 percent) and women(3 percent) differed significantly(P < 0.04) .The addition of immunohistochemical analysis in stage 2 of the model had a sensitivity of 62 percent and a positive predictive value of 80 percent.There were 35 mutations in the validation series of 155 patients(23 percent) :19 mutations in MLH1,13 in MSH2,and 3 in MSH6.The performance of the model was robust among a wide range of cutoff probabilities and was superior to that of the Bethesda and Amsterdam criteria for hereditary nonpolyposis colorectal cancer.Survival among carriers was not significantly different from that among noncarriers.CONCLUSIONS:We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes.Survival was similar among carriers and noncarriers.展开更多
PURPOSE: PTEN (phosphatase and tensin homologue deleted in chromosome 10) is a candidate tumor suppressor gene. Mutations of this gene are responsible for PTEN hamartoma tumor syndromes, including Cowden syndrome, Ban...PURPOSE: PTEN (phosphatase and tensin homologue deleted in chromosome 10) is a candidate tumor suppressor gene. Mutations of this gene are responsible for PTEN hamartoma tumor syndromes, including Cowden syndrome, Bannayan- Riley- Ruvalcaba syndrome, Proteus syndrome, and Proteus - like syndromes. Recently, PTEN mutations were identified in several human neoplasms. We analyzed the DNA of various organs and lesions in Korean patients with Cowden syndrome, their family members, and patients with familial adenomatous polyposis for germline or somatic PTEN mutations. METHODS: The 11 patients included in this study were 5 patients with Cowden syndrome, 4 of their family members, and 2 patients with familial adenomatous polyposis. Deletions and mutations in exons 1 to 9 of the PTEN gene were evaluated by polymerase chain reaction- single strand conformation polymorphism and sequencing analysis in esophageal acanthosis, gastric polyps, colonic polyps, skin lesions, and peripheral blood mononuclear cells. To exclude common polymorphisms, 240 controls were tested. RESULTS: All patients with Cowden syndrome showed several to numerous polyps in the gastrointestinal tract. A missense mutation at codon 217 (GTC to GAC,Val to Asp) in exon 7 was identified in one Cowden syndrome patient, and a nonsense mutation at codon 211 (TGC to TGA, Cys to stop) in exon 6 was identified in a second patient. Identical mutations were found in all tissue samples, including colonic polyps, from each patient. No PTEN mutations were found in their family members or in any patient with familial adenomatous polyposis. None of tested controls contained a mutation. CONCLUSIONS: We have identified two new germline PTEN mutations in Korean patients with Cowden syndrome. Mutations in the introns and regulatory regions of the PTEN gene may be present in additional patients with Cowden syndrome and polyposis syndrome.展开更多
Background & Aims:MYH-associated polyposis is a recently described disease that is characterized by multiple colorectal adenomas and a recessive pattern of inheritance. Individuals with MYH-associated polyposis ha...Background & Aims:MYH-associated polyposis is a recently described disease that is characterized by multiple colorectal adenomas and a recessive pattern of inheritance. Individuals with MYH-associated polyposis have biallelic mutations in MYH, a base excision repair gene, and are negative for germline mutations in the APC gene. In this study, the 2 most prevalent MYH mutations in white persons, Y165C and G382D, were analyzed for their presence in 984 subjects selected from 3 groups: 400 undergoing screening colonoscopy and found to have 0-3 polyps, 444 with colorectal cancer (CRC), and 140 referred for APC mutation analysis in which a germline mutation was not identified. Methods: Genotyping for Y165C and G382D was performed by Pyrosequencing. Results: Biallelic mutations for Y165C and/or G382D were not found in any of those undergoing screening colonoscopy with 0-3 polyps (n =400), in those APC-negative patients with < 20 adenomatous polyps (n = 26), or in those with CRC who were older than 50 years (n = 328). Furthermore, these 2 MYH mutations were not found among patients whose tumors showed the presence of defective DNA mismatch repair (n = 62). However, the presence of biallelic germline MYH mutations correlated with the presence of ≥ 20 adenomatous polyps. Interestingly, 2 of the 116 individuals with CRC diagnosed at 50 years of age or younger also presented with biallelic germline mutations in MYH. Conclusions: These data suggest that screening of MYH should be considered not only in patients with multiple polyps but also in patients with early-onset CRC.展开更多
Background: Up to 5% of patientswith melanoma have a family history of a first-degree relative also being affected. Objectives: To study such families for germline mutations, to help clarify the gene-environment inter...Background: Up to 5% of patientswith melanoma have a family history of a first-degree relative also being affected. Objectives: To study such families for germline mutations, to help clarify the gene-environment interaction in melanoma aetiology. Methods: Thirty-two families in Scotland with melanoma in two or more first-degree relatives are reported for the first time. Peripheral blood DNA was extracted, and denaturing high-performance liquid chromatography analysis performed on exons 1 α and 2 of the CDKN2A gene and their splice junctions. The coding sequences and splice junctions of these exons were sequenced in all samples as confirmation of the chromatographic pattern observed. Results: Seven of the 32 melanoma families (22% ) have CDKN2A mutations. One mutation, H83N, which has not previously been described in melanoma families, was found in one family. In addition, two families have R112G mutations, one family has a G67R mutation, one has an exon 1 α 24-bp duplication where bases 9- 32 are duplicated between bases 32 and 33, and two families have M53I mutations, bringing the total of known Scottish families with the M53I mutation to six. Conclusions: This study brings the total of Scottish families investigated for germlinemutations to 48, and strongly suggests that the M53I mutation originated in Scotland.展开更多
文摘The gene responsible for Peutz-Jeghers syndrome (PJS), LKB1 (also called STK11) was mapped to chromosome 19p13.3 and was found to encode a putative serine/threonine protein kinase, LKB1. As only a limited number (～100) of germline mutations of the gene have been reported, and because the protein function is still unclear, information about LKB1 mutations and their expression should be accumulated to understand the phenotypegenotype correlation of this disease. Here we report a patient with sporadic PJS with early-onset gastric cancer. We found a novel germline frameshift mutation (757-758insT) in the LKB1 gene and a marked reduction in LKB1 protein expression in the carcinoma cells, suggesting that the loss of LKB1 function may have led to the carcinogenesis of the gastric cancer.
文摘Background and aims: Germline mutations in the LKB1 gene are known to cause Peutz-Jeghers syndrome, which is an autosomal dominant disorder characterised by hamartomatous polyposis and mucocutaneous pigmentation. This syndrome is associated with an increased risk of malignancies in different organs but there is a lack of data on cancer range and risk in LKB1 germline mutation carriers. Patients and methods: The cumulative incidence of cancer in 149 Peutz-Jeghers syndrome patients with germline mutation(s) in LKB1 was estimated using Kaplan-Meier time to cancer onset analyses and compared between relevant subgroups with log rank tests. Results: Thirty two cancers were found in LKB1 mutation carriers. Overall cancer risks at ages 30, 40, 50, 60, and 70 years were 6%, 18%, 31%, 41%, and 67%, respectively. There were similar overall cancer risks between male and female carriers. However, there were overall cancer risk differences for exon 6 mutation carriers versus non-exon 6 mutation carriers (log rank p = 0.022 overall, 0.56 in males, 0.0000084 in females). Most (22/32) of the cancers occurred in the gastrointestinal tract, and the overall gastrointestinal cancer risks at ages 40, 50, 60, and 70 years were 12%, 24%, 34%, and 63%, respectively. In females, the risks for developing gynaecologic cancer at ages 40 and 50 years were 13%and 18%, respectively. Conclusions: Mutations in exon 6 of LKB1 are associated with a higher cancer risk than mutations within other regions of the gene. Moreover, this study provides age related cumulative risks of developing cancer in LKB1 mutation carriers that should be useful for developing a tailor made cancer surveillance protocol for Peutz-Jeghers syndrome patients.
文摘BACKGROUND:The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease.METHODS:Without preselection and regardless of family history,we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer.We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1,MSH2,and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes.Stage 1 of the model incorporated only clinical variables;stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability.The model was validated in an independent population of patients.We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival.RESULTS:There were 38 mutations among the 870 participants(4 percent) :15 mutations in MLH1,16 in SH2,and 7 in MSH6.Carrier frequencies in men(6 percent) and women(3 percent) differed significantly(P < 0.04) .The addition of immunohistochemical analysis in stage 2 of the model had a sensitivity of 62 percent and a positive predictive value of 80 percent.There were 35 mutations in the validation series of 155 patients(23 percent) :19 mutations in MLH1,13 in MSH2,and 3 in MSH6.The performance of the model was robust among a wide range of cutoff probabilities and was superior to that of the Bethesda and Amsterdam criteria for hereditary nonpolyposis colorectal cancer.Survival among carriers was not significantly different from that among noncarriers.CONCLUSIONS:We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes.Survival was similar among carriers and noncarriers.
文摘PURPOSE: PTEN (phosphatase and tensin homologue deleted in chromosome 10) is a candidate tumor suppressor gene. Mutations of this gene are responsible for PTEN hamartoma tumor syndromes, including Cowden syndrome, Bannayan- Riley- Ruvalcaba syndrome, Proteus syndrome, and Proteus - like syndromes. Recently, PTEN mutations were identified in several human neoplasms. We analyzed the DNA of various organs and lesions in Korean patients with Cowden syndrome, their family members, and patients with familial adenomatous polyposis for germline or somatic PTEN mutations. METHODS: The 11 patients included in this study were 5 patients with Cowden syndrome, 4 of their family members, and 2 patients with familial adenomatous polyposis. Deletions and mutations in exons 1 to 9 of the PTEN gene were evaluated by polymerase chain reaction- single strand conformation polymorphism and sequencing analysis in esophageal acanthosis, gastric polyps, colonic polyps, skin lesions, and peripheral blood mononuclear cells. To exclude common polymorphisms, 240 controls were tested. RESULTS: All patients with Cowden syndrome showed several to numerous polyps in the gastrointestinal tract. A missense mutation at codon 217 (GTC to GAC,Val to Asp) in exon 7 was identified in one Cowden syndrome patient, and a nonsense mutation at codon 211 (TGC to TGA, Cys to stop) in exon 6 was identified in a second patient. Identical mutations were found in all tissue samples, including colonic polyps, from each patient. No PTEN mutations were found in their family members or in any patient with familial adenomatous polyposis. None of tested controls contained a mutation. CONCLUSIONS: We have identified two new germline PTEN mutations in Korean patients with Cowden syndrome. Mutations in the introns and regulatory regions of the PTEN gene may be present in additional patients with Cowden syndrome and polyposis syndrome.
文摘Background & Aims:MYH-associated polyposis is a recently described disease that is characterized by multiple colorectal adenomas and a recessive pattern of inheritance. Individuals with MYH-associated polyposis have biallelic mutations in MYH, a base excision repair gene, and are negative for germline mutations in the APC gene. In this study, the 2 most prevalent MYH mutations in white persons, Y165C and G382D, were analyzed for their presence in 984 subjects selected from 3 groups: 400 undergoing screening colonoscopy and found to have 0-3 polyps, 444 with colorectal cancer (CRC), and 140 referred for APC mutation analysis in which a germline mutation was not identified. Methods: Genotyping for Y165C and G382D was performed by Pyrosequencing. Results: Biallelic mutations for Y165C and/or G382D were not found in any of those undergoing screening colonoscopy with 0-3 polyps (n =400), in those APC-negative patients with < 20 adenomatous polyps (n = 26), or in those with CRC who were older than 50 years (n = 328). Furthermore, these 2 MYH mutations were not found among patients whose tumors showed the presence of defective DNA mismatch repair (n = 62). However, the presence of biallelic germline MYH mutations correlated with the presence of ≥ 20 adenomatous polyps. Interestingly, 2 of the 116 individuals with CRC diagnosed at 50 years of age or younger also presented with biallelic germline mutations in MYH. Conclusions: These data suggest that screening of MYH should be considered not only in patients with multiple polyps but also in patients with early-onset CRC.
文摘Background: Up to 5% of patientswith melanoma have a family history of a first-degree relative also being affected. Objectives: To study such families for germline mutations, to help clarify the gene-environment interaction in melanoma aetiology. Methods: Thirty-two families in Scotland with melanoma in two or more first-degree relatives are reported for the first time. Peripheral blood DNA was extracted, and denaturing high-performance liquid chromatography analysis performed on exons 1 α and 2 of the CDKN2A gene and their splice junctions. The coding sequences and splice junctions of these exons were sequenced in all samples as confirmation of the chromatographic pattern observed. Results: Seven of the 32 melanoma families (22% ) have CDKN2A mutations. One mutation, H83N, which has not previously been described in melanoma families, was found in one family. In addition, two families have R112G mutations, one family has a G67R mutation, one has an exon 1 α 24-bp duplication where bases 9- 32 are duplicated between bases 32 and 33, and two families have M53I mutations, bringing the total of known Scottish families with the M53I mutation to six. Conclusions: This study brings the total of Scottish families investigated for germlinemutations to 48, and strongly suggests that the M53I mutation originated in Scotland.
