Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families

Arcand, Suzanna L.; Maugard, Christine M.; Ghadirian, Parviz; Robidoux, André; Perret, Chantal; Zhang, Phil; Fafard, Eve; Mes-Masson, Anne-Marie; Foulkes, William D.; Provencher, Diane; Narod, Steven A.; Tonin, Patricia N.

doi:10.1007/s10549-007-9608-6

Cited by 34 publications

(55 citation statements)

References 29 publications

(46 reference statements)

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“…The primers for CYGB were designed as described previously (22). The RT-PCR-based assays were performed essentially as previously described (43). The PCR conditions were 3 min at 95˚C, 30 cycles of 94˚C for 30 sec, annealing temperatures for 30 sec and 72˚C for 30 sec.…”

Section: Gene Expression Analysesmentioning

confidence: 99%

“…The primers were designed using Primer3 software (42). The PCR assays were carried out as previously described (43). Primer sequences and PCR annealing temperatures are found in Table II.…”

Section: Gene Expression Analysesmentioning

confidence: 99%

“…Primer sequences and PCR annealing temperatures are found in Table II. The PCR products were sequenced in both directions using the 3730XL capillary DNA Analyzer system platform from Applied Biosystems at the McGill University and Genome Quebec Innovation Center, Montreal, Canada as previously described (43). Sequence chromatograms from both directions were aligned and compared with the RHBDF2 and CYGB reference sequences.…”

Section: Gene Expression Analysesmentioning

confidence: 99%

“…The primers for RHBDF2 were also designed using MethPrimer, based on a putative CpG island that maps 123 Kb upstream of the gene, and overlaps the first exon (39). The PCR reactions were carried out as previously described (43). In the absence of CYGB and RHBDF2 methylated control, CDKN2A was investigated to assess bisulfite conversion in all assays as it has been shown methylated in the TOV-112D EOC cell line (13).…”

Section: Gene Expression Analysesmentioning

confidence: 99%

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Chromosome 17q25 genes, RHBDF2 and CYGB, in ovarian cancer

et al. 2012

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Abstract. It has been proposed that the frequent loss of heterozygosity (LOH) of an entire chromosome 17 contig in epithelial ovarian cancers (EOC) is the consequence of the inactivation of multiple tumour suppressor genes on this chromosome. We report the characterization of a 453 Kb 17q25 locus shown previously to exhibit a high frequency of LOH in EOC samples. LOH analysis further defined the minimal region of deletion to a 65 Kb interval flanked by D17S2239 and D17S2244, which contains RHBDF2, CYGB and PRCD as tumour suppressor gene candidates. Tissue specific expression excluded PRCD as a candidate. RHBDF2 was expressed at low levels in the majority of benign and low malignant potential (LMP) tumours, and in a subset of malignant ovarian tumour samples, as compared with primary cultures of normal ovarian surface epithelial cell (NOSE) samples. CYGB was expressed at low levels in the majority of LMP and malignant samples compared with benign and NOSE samples. In contrast to CYGB expression, RHBDF2 was expressed at low or undetectable levels in EOC cell lines exhibiting tumourigenic characteristics and up-regulated in a genetically modified EOC cell line rendered non-tumourigenic. DNA sequence analysis identified variants but no apparent deleterious mutations in either gene. Methylation-specific PCR analysis suggested that promoter methylation of CYGB but not RHBDF2 occurred in 6 of 31 malignant samples. The results combined suggest that RHBDF2 and CYGB may play distinctive roles in ovarian cancer and could be added to the growing roster of chromosome 17 genes implicated in this disease.

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Section: Gene Expression Analysesmentioning

confidence: 99%

“…The primers were designed using Primer3 software (42). The PCR assays were carried out as previously described (43). Primer sequences and PCR annealing temperatures are found in Table II.…”

Section: Gene Expression Analysesmentioning

confidence: 99%

Section: Gene Expression Analysesmentioning

confidence: 99%

Section: Gene Expression Analysesmentioning

confidence: 99%

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Chromosome 17q25 genes, RHBDF2 and CYGB, in ovarian cancer

et al. 2012

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“…Mutations were initially screened by single-strand conformation polymorphism analysis of exons 5 to 9 of DNA samples as previously described (14). Then, DNA sequencing of exons 2 to 11, which corresponds to all protein-encoding regions of the gene, was then performed to identify mutations missed by this initial screen, as previously described (15). The primer sets and conditions for DNA sequencing are shown in Supplementary Table S2.…”

Section: Tp53 Sequencing and Allelic Imbalance Analysismentioning

confidence: 99%

Breast Carcinoma–Associated Fibroblasts Rarely Contain p53 Mutations or Chromosomal Aberrations

Hosein

Arcand

et al. 2010

Cancer Research

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It has become increasingly clear that the cells within the tumor microenvironment play a critical role in cancer growth and metastasis. Studies in experimental models suggest that carcinoma-associated fibroblasts (CAF) differ from normal fibroblasts and are capable of promoting cancer progression through a variety of mechanisms. At present, a definitive view is lacking on whether genomic abnormalities are present and whether they might underlie the observed phenotypic differences. This study reports the molecular analysis of the largest series of breast CAFs reported to date, with an array comparative genomic hybridization-based DNA copy number analysis of cultured CAFs derived from 25 freshly resected human breast cancers. We found DNA copy number changes consisting of the whole arm of chromosomes 6p and 9p plus interstitial 4q loss in only one sample. No abnormalities were observed in non-tumor-associated fibroblast counterparts. Karyotyping of the same CAF revealed further chromosomal abnormalities, which included clonal loss of chromosomes, chromosomal duplications, and less frequent chromosomal rearrangements. These abnormalities were not associated with alterations in the global gene expression profile of this particular CAF, relative to its nontumor-associated fibroblast counterpart. Moreover, this particular patient's CAF also displayed the only p53 mutation in the cohort, the first time such a mutation has been reported in freshly cultured human CAFs. These findings argue that the procancerous effects of CAFs are unlikely to be due to DNA copy number-type genomic abnormalities in the CAFs themselves. As such, breast CAFs should be mainly regarded as genomically stable cellular constituents that exist within complex cancer microenvironments.

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GermlineTP53Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry

et al. 2015

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IMPORTANCE Li-Fraumeni syndrome, usually characterized by germline TP53 mutations, is associated with markedly elevated lifetime risks of multiple cancers, and has been linked to an increased risk of early-onset colorectal cancer. OBJECTIVE To examine the frequency of germline TP53 alterations in patients with early-onset colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter cross-sectional cohort study of individuals recruited to the Colon Cancer Family Registry (CCFR) from 1998 through 2007 (genetic testing data updated as of January 2015). Both population-based and clinic-based patients in the United States, Canada, Australia, and New Zealand were recruited to the CCFR. Demographic information, clinical history, and family history data were obtained at enrollment. Biospecimens were collected from consenting probands and families, including microsatellite instability and DNA mismatch repair immunohistochemistry results. A total of a 510 individuals diagnosed as having colorectal cancer at age 40 years or younger and lacking a known hereditary cancer syndrome were identified from the CCFR as being potentially eligible. Fifty-three participants were excluded owing to subsequent identification of germline mutations in DNA mismatch repair genes (n = 47) or biallelic MUTYH mutations (n = 6). INTERVENTIONS Germline sequencing of the TP53 gene was performed. Identified TP53 alterations were assessed for pathogenicity using literature and international mutation database searches and in silico prediction models. MAIN OUTCOMES AND MEASURES Frequency of nonsynonymous germline TP53 alterations. RESULTS Among 457 eligible participants (314, population-based; 143, clinic-based; median age at diagnosis, 36 years [range, 15–40 years]), 6 (1.3%; 95%CI, 0.5%–2.8%) carried germline missense TP53 alterations, none of whom met clinical criteria for Li-Fraumeni syndrome. Four of the identified TP53 alterations have been previously described in the literature in probands with clinical features of Li-Fraumeni syndrome, and 2 were novel alterations. CONCLUSIONS AND RELEVANCE In a large cohort of patients with early-onset colorectal cancer, germline TP53 mutations were detected at a frequency comparable with the published prevalence of germline APC mutations in colorectal cancer. With the increasing use of multigene next-generation sequencing panels in hereditary cancer risk assessment, clinicians will be faced with the challenge of interpreting the biologic and clinical significance of germline TP53 mutations in families whose phenotypes are atypical for Li-Fraumeni syndrome.

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Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families

Cited by 34 publications

References 29 publications

Chromosome 17q25 genes, RHBDF2 and CYGB, in ovarian cancer

Chromosome 17q25 genes, RHBDF2 and CYGB, in ovarian cancer

Breast Carcinoma–Associated Fibroblasts Rarely Contain p53 Mutations or Chromosomal Aberrations

GermlineTP53Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry

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