Germline TP53 mutations in patients with early-onset colorectal cancer in the colon cancer family registry

Matthew B. Yurgelun, Serena Masciari, Victoria A. Joshi, Rowena C. Mercado, Noralane Morey Lindor, Steven Gallinger, John L. Hopper, Mark A. Jenkins, Daniel D. Buchanan, Polly A. Newcomb, John D. Potter, Robert W. Haile, Raju Kucherlapati, Sapna Syngal

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)214-221
Number of pages8
JournalJAMA oncology
Volume1
Issue number2
DOIs
StatePublished - May 1 2015

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Germ-Line Mutation
Colonic Neoplasms
Registries
Colorectal Neoplasms
Li-Fraumeni Syndrome
DNA Mismatch Repair
Hereditary Neoplastic Syndromes
Microsatellite Instability
Mutation
p53 Genes
Genetic Testing
New Zealand
Computer Simulation
Population
Canada
Virulence
Neoplasms
Cohort Studies
Cross-Sectional Studies
Immunohistochemistry

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yurgelun, M. B., Masciari, S., Joshi, V. A., Mercado, R. C., Lindor, N. M., Gallinger, S., ... Syngal, S. (2015). Germline TP53 mutations in patients with early-onset colorectal cancer in the colon cancer family registry. JAMA oncology, 1(2), 214-221. https://doi.org/10.1001/jamaoncol.2015.0197

Germline TP53 mutations in patients with early-onset colorectal cancer in the colon cancer family registry. / Yurgelun, Matthew B.; Masciari, Serena; Joshi, Victoria A.; Mercado, Rowena C.; Lindor, Noralane Morey; Gallinger, Steven; Hopper, John L.; Jenkins, Mark A.; Buchanan, Daniel D.; Newcomb, Polly A.; Potter, John D.; Haile, Robert W.; Kucherlapati, Raju; Syngal, Sapna.

In: JAMA oncology, Vol. 1, No. 2, 01.05.2015, p. 214-221.

Research output: Contribution to journalArticle

Yurgelun, MB, Masciari, S, Joshi, VA, Mercado, RC, Lindor, NM, Gallinger, S, Hopper, JL, Jenkins, MA, Buchanan, DD, Newcomb, PA, Potter, JD, Haile, RW, Kucherlapati, R & Syngal, S 2015, 'Germline TP53 mutations in patients with early-onset colorectal cancer in the colon cancer family registry', JAMA oncology, vol. 1, no. 2, pp. 214-221. https://doi.org/10.1001/jamaoncol.2015.0197
Yurgelun, Matthew B. ; Masciari, Serena ; Joshi, Victoria A. ; Mercado, Rowena C. ; Lindor, Noralane Morey ; Gallinger, Steven ; Hopper, John L. ; Jenkins, Mark A. ; Buchanan, Daniel D. ; Newcomb, Polly A. ; Potter, John D. ; Haile, Robert W. ; Kucherlapati, Raju ; Syngal, Sapna. / Germline TP53 mutations in patients with early-onset colorectal cancer in the colon cancer family registry. In: JAMA oncology. 2015 ; Vol. 1, No. 2. pp. 214-221.
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abstract = "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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AU - Yurgelun, Matthew B.

AU - Masciari, Serena

AU - Joshi, Victoria A.

AU - Mercado, Rowena C.

AU - Lindor, Noralane Morey

AU - Gallinger, Steven

AU - Hopper, John L.

AU - Jenkins, Mark A.

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AU - Newcomb, Polly A.

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AU - Haile, Robert W.

AU - Kucherlapati, Raju

AU - Syngal, Sapna

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N2 - 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.

AB - 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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