Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer
Previous studies have determined that the frequency of germ-line p53 mutations in familial breast cancer patients is 1% or less, but these reports have not investigated the importance of polymorphic intron base changes in the p53 gene. Therefore, we investigated the frequency of both exon and intron...
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creator | LEHMAN, T. A HAFFTY, B. G CARBONE, C. J BISHOP, L. R GUMBS, A. A KRISHNAN, S SHIELDS, P. G MODALI, R TURNER, B. C |
description | Previous studies have determined that the frequency of germ-line p53 mutations in familial breast cancer patients is 1% or less, but these reports have not investigated the importance of polymorphic intron base changes in the p53 gene. Therefore, we investigated the frequency of both exon and intron germ-line p53 base changes in 42 breast cancer patients with a strong family history of breast cancer. The mean age of presentation of these patients was 44.0 years (range, 29-69), and 12 of 42 (29%) were of known Ashkenazi ancestry. Purified DNA obtained from the 42 index cases was screened for germ-line p53 mutations in exons 2-11 and surrounding introns using a combination of intron based primers for PCR-single strand conformation polymorphism analysis, direct sequencing, and microarray sequencing using the Affymetrix p53 gene chip methodology. Morphological analysis of apoptosis and cell survival determination were performed on EBV-immortalized lymphoblastoid cell lines from two patients with the p53 intron 6 mutation. A germ-line mutation in the p53 gene at nucleotide 13964 with a G to C base change (13964GC) was identified in 3 of 42 (7.1%) hereditary breast cancer patients. Two patients were heterozygous for this mutation, and one patient had a homozygous mutation. In comparison, 0 of 171 (0%) of sporadic breast cancer patients had the p53 13964GC mutation (P = 0.0003). We found that 0 of 42 (0%) of these hereditary breast cancer patients had other germ-line p53 mutation in exons 2-11. However, pedigree analysis demonstrated that all three patients had strong family histories of multiple types of cancers consistent with Li-Fraumeni syndrome but with late age of onset. Comprehensive BRCA1 and BRCA2 nucleotide analysis from patients with the p53 13964GC mutation revealed no concomitant deleterious BRCA1 or BRCA2 mutations, although they were found in the other hereditary breast cancer patients. Functional analysis of two immortalized lymphoblastoid cell lines derived from patients with the p53 13964GC mutation demonstrated prolonged in vitro survival in response to cisplatinum treatment and showed decreased chemotherapy-induced apoptosis. Immunohistochemical analysis of breast tumors from these patients revealed high levels of mutant p53 protein, suggesting a functional mutation in the p53 gene. In summary, we have identified a single p53 intron mutation in familial breast cancer patients that is present at elevated frequency and has functional activity. |
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A ; HAFFTY, B. G ; CARBONE, C. J ; BISHOP, L. R ; GUMBS, A. A ; KRISHNAN, S ; SHIELDS, P. G ; MODALI, R ; TURNER, B. C</creator><creatorcontrib>LEHMAN, T. A ; HAFFTY, B. G ; CARBONE, C. J ; BISHOP, L. R ; GUMBS, A. A ; KRISHNAN, S ; SHIELDS, P. G ; MODALI, R ; TURNER, B. C</creatorcontrib><description>Previous studies have determined that the frequency of germ-line p53 mutations in familial breast cancer patients is 1% or less, but these reports have not investigated the importance of polymorphic intron base changes in the p53 gene. Therefore, we investigated the frequency of both exon and intron germ-line p53 base changes in 42 breast cancer patients with a strong family history of breast cancer. The mean age of presentation of these patients was 44.0 years (range, 29-69), and 12 of 42 (29%) were of known Ashkenazi ancestry. Purified DNA obtained from the 42 index cases was screened for germ-line p53 mutations in exons 2-11 and surrounding introns using a combination of intron based primers for PCR-single strand conformation polymorphism analysis, direct sequencing, and microarray sequencing using the Affymetrix p53 gene chip methodology. Morphological analysis of apoptosis and cell survival determination were performed on EBV-immortalized lymphoblastoid cell lines from two patients with the p53 intron 6 mutation. A germ-line mutation in the p53 gene at nucleotide 13964 with a G to C base change (13964GC) was identified in 3 of 42 (7.1%) hereditary breast cancer patients. Two patients were heterozygous for this mutation, and one patient had a homozygous mutation. In comparison, 0 of 171 (0%) of sporadic breast cancer patients had the p53 13964GC mutation (P = 0.0003). We found that 0 of 42 (0%) of these hereditary breast cancer patients had other germ-line p53 mutation in exons 2-11. However, pedigree analysis demonstrated that all three patients had strong family histories of multiple types of cancers consistent with Li-Fraumeni syndrome but with late age of onset. Comprehensive BRCA1 and BRCA2 nucleotide analysis from patients with the p53 13964GC mutation revealed no concomitant deleterious BRCA1 or BRCA2 mutations, although they were found in the other hereditary breast cancer patients. Functional analysis of two immortalized lymphoblastoid cell lines derived from patients with the p53 13964GC mutation demonstrated prolonged in vitro survival in response to cisplatinum treatment and showed decreased chemotherapy-induced apoptosis. Immunohistochemical analysis of breast tumors from these patients revealed high levels of mutant p53 protein, suggesting a functional mutation in the p53 gene. In summary, we have identified a single p53 intron mutation in familial breast cancer patients that is present at elevated frequency and has functional activity.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 10706125</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adult ; Biological and medical sciences ; Breast Neoplasms - genetics ; Female ; Genes, p53 ; Genotype ; Germ-Line Mutation ; Gynecology. Andrology. Obstetrics ; Humans ; Introns ; Li-Fraumeni Syndrome - genetics ; Mammary gland diseases ; Medical sciences ; Middle Aged ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2000-02, Vol.60 (4), p.1062-1069</ispartof><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1343319$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10706125$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LEHMAN, T. A</creatorcontrib><creatorcontrib>HAFFTY, B. G</creatorcontrib><creatorcontrib>CARBONE, C. J</creatorcontrib><creatorcontrib>BISHOP, L. R</creatorcontrib><creatorcontrib>GUMBS, A. A</creatorcontrib><creatorcontrib>KRISHNAN, S</creatorcontrib><creatorcontrib>SHIELDS, P. G</creatorcontrib><creatorcontrib>MODALI, R</creatorcontrib><creatorcontrib>TURNER, B. C</creatorcontrib><title>Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Previous studies have determined that the frequency of germ-line p53 mutations in familial breast cancer patients is 1% or less, but these reports have not investigated the importance of polymorphic intron base changes in the p53 gene. Therefore, we investigated the frequency of both exon and intron germ-line p53 base changes in 42 breast cancer patients with a strong family history of breast cancer. The mean age of presentation of these patients was 44.0 years (range, 29-69), and 12 of 42 (29%) were of known Ashkenazi ancestry. Purified DNA obtained from the 42 index cases was screened for germ-line p53 mutations in exons 2-11 and surrounding introns using a combination of intron based primers for PCR-single strand conformation polymorphism analysis, direct sequencing, and microarray sequencing using the Affymetrix p53 gene chip methodology. Morphological analysis of apoptosis and cell survival determination were performed on EBV-immortalized lymphoblastoid cell lines from two patients with the p53 intron 6 mutation. A germ-line mutation in the p53 gene at nucleotide 13964 with a G to C base change (13964GC) was identified in 3 of 42 (7.1%) hereditary breast cancer patients. Two patients were heterozygous for this mutation, and one patient had a homozygous mutation. In comparison, 0 of 171 (0%) of sporadic breast cancer patients had the p53 13964GC mutation (P = 0.0003). We found that 0 of 42 (0%) of these hereditary breast cancer patients had other germ-line p53 mutation in exons 2-11. However, pedigree analysis demonstrated that all three patients had strong family histories of multiple types of cancers consistent with Li-Fraumeni syndrome but with late age of onset. Comprehensive BRCA1 and BRCA2 nucleotide analysis from patients with the p53 13964GC mutation revealed no concomitant deleterious BRCA1 or BRCA2 mutations, although they were found in the other hereditary breast cancer patients. Functional analysis of two immortalized lymphoblastoid cell lines derived from patients with the p53 13964GC mutation demonstrated prolonged in vitro survival in response to cisplatinum treatment and showed decreased chemotherapy-induced apoptosis. Immunohistochemical analysis of breast tumors from these patients revealed high levels of mutant p53 protein, suggesting a functional mutation in the p53 gene. In summary, we have identified a single p53 intron mutation in familial breast cancer patients that is present at elevated frequency and has functional activity.</description><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - genetics</subject><subject>Female</subject><subject>Genes, p53</subject><subject>Genotype</subject><subject>Germ-Line Mutation</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Introns</subject><subject>Li-Fraumeni Syndrome - genetics</subject><subject>Mammary gland diseases</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE9LAzEUxIMotla_guQg3haSTbKbPUqpf6Dgpffykk00ks2uSbbQb2_EikdPbwZ-b2DmDC2pYLJqORfnaEkIkZXgbb1AVyl9FCsoEZdoQUlLGlqLJZo23hwgmx7baD5nE_QRQyhuDjq7MYDHUMTB5SMeLQacJqOddRq_mThU3gWDJ8GwCzmOAQ9zhu-34rGFwXlXAlQ0kDLWELSJ1-jCgk_m5nRXaPe42a2fq-3r08v6YVu9M0Jy1SmwDNq-UUVRS2xfa6Yl5bzWvQRom8ZwqXgvOqUlV0xrUUvDlGl6KzVbofuf2CmOpVbK-8ElbbyHYMY57VvSSVo37F-QtoJL1nYFvD2BsxpMv5-iGyAe979bFuDuBEDS4G0sfV364xhnjHbsC_2ef98</recordid><startdate>20000215</startdate><enddate>20000215</enddate><creator>LEHMAN, T. A</creator><creator>HAFFTY, B. G</creator><creator>CARBONE, C. 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R</creatorcontrib><creatorcontrib>GUMBS, A. A</creatorcontrib><creatorcontrib>KRISHNAN, S</creatorcontrib><creatorcontrib>SHIELDS, P. G</creatorcontrib><creatorcontrib>MODALI, R</creatorcontrib><creatorcontrib>TURNER, B. C</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>LEHMAN, T. A</au><au>HAFFTY, B. G</au><au>CARBONE, C. J</au><au>BISHOP, L. R</au><au>GUMBS, A. A</au><au>KRISHNAN, S</au><au>SHIELDS, P. G</au><au>MODALI, R</au><au>TURNER, B. C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2000-02-15</date><risdate>2000</risdate><volume>60</volume><issue>4</issue><spage>1062</spage><epage>1069</epage><pages>1062-1069</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Previous studies have determined that the frequency of germ-line p53 mutations in familial breast cancer patients is 1% or less, but these reports have not investigated the importance of polymorphic intron base changes in the p53 gene. Therefore, we investigated the frequency of both exon and intron germ-line p53 base changes in 42 breast cancer patients with a strong family history of breast cancer. The mean age of presentation of these patients was 44.0 years (range, 29-69), and 12 of 42 (29%) were of known Ashkenazi ancestry. Purified DNA obtained from the 42 index cases was screened for germ-line p53 mutations in exons 2-11 and surrounding introns using a combination of intron based primers for PCR-single strand conformation polymorphism analysis, direct sequencing, and microarray sequencing using the Affymetrix p53 gene chip methodology. Morphological analysis of apoptosis and cell survival determination were performed on EBV-immortalized lymphoblastoid cell lines from two patients with the p53 intron 6 mutation. A germ-line mutation in the p53 gene at nucleotide 13964 with a G to C base change (13964GC) was identified in 3 of 42 (7.1%) hereditary breast cancer patients. Two patients were heterozygous for this mutation, and one patient had a homozygous mutation. In comparison, 0 of 171 (0%) of sporadic breast cancer patients had the p53 13964GC mutation (P = 0.0003). We found that 0 of 42 (0%) of these hereditary breast cancer patients had other germ-line p53 mutation in exons 2-11. However, pedigree analysis demonstrated that all three patients had strong family histories of multiple types of cancers consistent with Li-Fraumeni syndrome but with late age of onset. Comprehensive BRCA1 and BRCA2 nucleotide analysis from patients with the p53 13964GC mutation revealed no concomitant deleterious BRCA1 or BRCA2 mutations, although they were found in the other hereditary breast cancer patients. Functional analysis of two immortalized lymphoblastoid cell lines derived from patients with the p53 13964GC mutation demonstrated prolonged in vitro survival in response to cisplatinum treatment and showed decreased chemotherapy-induced apoptosis. Immunohistochemical analysis of breast tumors from these patients revealed high levels of mutant p53 protein, suggesting a functional mutation in the p53 gene. In summary, we have identified a single p53 intron mutation in familial breast cancer patients that is present at elevated frequency and has functional activity.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>10706125</pmid><tpages>8</tpages></addata></record> |
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subjects | Adult Biological and medical sciences Breast Neoplasms - genetics Female Genes, p53 Genotype Germ-Line Mutation Gynecology. Andrology. Obstetrics Humans Introns Li-Fraumeni Syndrome - genetics Mammary gland diseases Medical sciences Middle Aged Tumors |
title | Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer |
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