BRAF mutation analysis is a valid tool to implement in Lynch syndrome diagnosis in patients classified according to the Bethesda guidelines

Francesca Molinari, Stefano Signoroni, Andrea Lampis, Claudia Bertan, Federica Perrone, Paola Sala, Patrizia Mondini, Stefano Crippa, Lucio Bertario, Milo Frattini

Research output: Contribution to journalArticle

Abstract

Aims and background. Lynch syndrome (LS) is clinically defined by the Amsterdam criteria (AC) and by germline mutations in mismatch-repair (MMR) genes leading to microsatellite instability (MSI) at the molecular level. Patients who do not fulfil AC are considered suspected-Lynch according to the less stringent Bethesda guidelines (BG) and should be tested for MSI and MMR germline mutations. BRAF mutations have been proposed as a marker to exclude LS because they are generally absent in LS patients and present in sporadic colorectal cancer (sCRC) with MSI due to promoter hypermethylation of the MLH1 gene. Our aim was to verify whether BRAF mutations may improve the criteria to select patients for germline MMR mutation assessment. Material and methods. We analyzed 303 formalin-fixed paraffin-embedded CRC samples including 174 sCRC, 28 patients fulfilling AC, and 101 suspected-Lynch patients fulfilling BG. We analyzed MSI and BRAF mutations in all CRC samples. MLH1, MSH2 and MSH6 germline mutations were investigated in MSI patients fulfilling AC or BG. Results. sCRC samples showed MSI in 20/174 (11%) cases. BRAF mutations were detected in 10/174 (6%) sCRC cases and were significantly correlated with MSI (P = 0.002). MSI was observed in 24/28 (86%) Amsterdam cases which were BRAF wildtype. MMR gene mutation was detected in 22/26 (85%) AC cases, all showing MSI. Suspected-Lynch cases carried MSI in 41/101 (40%) and BRAF mutations in 7/101 (7%) cases. MMR gene mutation was detected in 13/28 (46%) evaluable MSI patients of this group and only in cases characterized by a wild-type BRAF gene. Conclusions. The prevalence of BRAF mutations in CRC patients is not high but extremely correlated with MSI and risk categories as BG, whereas they are absent in LS patients. BRAF mutation detection can reduce the need for MMR gene analysis in a small (but not negligible) proportion of MSI patients (7%), with a positive impact on the financial and psychological costs of unnecessary tests. Copyright - Il Pensiero Scientifico Editore.

Original languageEnglish
Pages (from-to)315-320
Number of pages6
JournalTumori
Volume100
Issue number3
DOIs
Publication statusPublished - 2014

Fingerprint

Hereditary Nonpolyposis Colorectal Neoplasms
Microsatellite Instability
Guidelines
Mutation
DNA Mismatch Repair
Germ-Line Mutation
Colorectal Neoplasms
Genes
Paraffin
Formaldehyde

Keywords

  • Amsterdam criteria
  • Bethesda guidelines
  • BRAF mutations
  • Lynch syndrome
  • Microsatellite instability (MSI)
  • Mismatch repair (MMR)

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

BRAF mutation analysis is a valid tool to implement in Lynch syndrome diagnosis in patients classified according to the Bethesda guidelines. / Molinari, Francesca; Signoroni, Stefano; Lampis, Andrea; Bertan, Claudia; Perrone, Federica; Sala, Paola; Mondini, Patrizia; Crippa, Stefano; Bertario, Lucio; Frattini, Milo.

In: Tumori, Vol. 100, No. 3, 2014, p. 315-320.

Research output: Contribution to journalArticle

Molinari, F, Signoroni, S, Lampis, A, Bertan, C, Perrone, F, Sala, P, Mondini, P, Crippa, S, Bertario, L & Frattini, M 2014, 'BRAF mutation analysis is a valid tool to implement in Lynch syndrome diagnosis in patients classified according to the Bethesda guidelines', Tumori, vol. 100, no. 3, pp. 315-320. https://doi.org/10.1700/1578.17214
Molinari, Francesca ; Signoroni, Stefano ; Lampis, Andrea ; Bertan, Claudia ; Perrone, Federica ; Sala, Paola ; Mondini, Patrizia ; Crippa, Stefano ; Bertario, Lucio ; Frattini, Milo. / BRAF mutation analysis is a valid tool to implement in Lynch syndrome diagnosis in patients classified according to the Bethesda guidelines. In: Tumori. 2014 ; Vol. 100, No. 3. pp. 315-320.
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title = "BRAF mutation analysis is a valid tool to implement in Lynch syndrome diagnosis in patients classified according to the Bethesda guidelines",
abstract = "Aims and background. Lynch syndrome (LS) is clinically defined by the Amsterdam criteria (AC) and by germline mutations in mismatch-repair (MMR) genes leading to microsatellite instability (MSI) at the molecular level. Patients who do not fulfil AC are considered suspected-Lynch according to the less stringent Bethesda guidelines (BG) and should be tested for MSI and MMR germline mutations. BRAF mutations have been proposed as a marker to exclude LS because they are generally absent in LS patients and present in sporadic colorectal cancer (sCRC) with MSI due to promoter hypermethylation of the MLH1 gene. Our aim was to verify whether BRAF mutations may improve the criteria to select patients for germline MMR mutation assessment. Material and methods. We analyzed 303 formalin-fixed paraffin-embedded CRC samples including 174 sCRC, 28 patients fulfilling AC, and 101 suspected-Lynch patients fulfilling BG. We analyzed MSI and BRAF mutations in all CRC samples. MLH1, MSH2 and MSH6 germline mutations were investigated in MSI patients fulfilling AC or BG. Results. sCRC samples showed MSI in 20/174 (11{\%}) cases. BRAF mutations were detected in 10/174 (6{\%}) sCRC cases and were significantly correlated with MSI (P = 0.002). MSI was observed in 24/28 (86{\%}) Amsterdam cases which were BRAF wildtype. MMR gene mutation was detected in 22/26 (85{\%}) AC cases, all showing MSI. Suspected-Lynch cases carried MSI in 41/101 (40{\%}) and BRAF mutations in 7/101 (7{\%}) cases. MMR gene mutation was detected in 13/28 (46{\%}) evaluable MSI patients of this group and only in cases characterized by a wild-type BRAF gene. Conclusions. The prevalence of BRAF mutations in CRC patients is not high but extremely correlated with MSI and risk categories as BG, whereas they are absent in LS patients. BRAF mutation detection can reduce the need for MMR gene analysis in a small (but not negligible) proportion of MSI patients (7{\%}), with a positive impact on the financial and psychological costs of unnecessary tests. Copyright - Il Pensiero Scientifico Editore.",
keywords = "Amsterdam criteria, Bethesda guidelines, BRAF mutations, Lynch syndrome, Microsatellite instability (MSI), Mismatch repair (MMR)",
author = "Francesca Molinari and Stefano Signoroni and Andrea Lampis and Claudia Bertan and Federica Perrone and Paola Sala and Patrizia Mondini and Stefano Crippa and Lucio Bertario and Milo Frattini",
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T1 - BRAF mutation analysis is a valid tool to implement in Lynch syndrome diagnosis in patients classified according to the Bethesda guidelines

AU - Molinari, Francesca

AU - Signoroni, Stefano

AU - Lampis, Andrea

AU - Bertan, Claudia

AU - Perrone, Federica

AU - Sala, Paola

AU - Mondini, Patrizia

AU - Crippa, Stefano

AU - Bertario, Lucio

AU - Frattini, Milo

PY - 2014

Y1 - 2014

N2 - Aims and background. Lynch syndrome (LS) is clinically defined by the Amsterdam criteria (AC) and by germline mutations in mismatch-repair (MMR) genes leading to microsatellite instability (MSI) at the molecular level. Patients who do not fulfil AC are considered suspected-Lynch according to the less stringent Bethesda guidelines (BG) and should be tested for MSI and MMR germline mutations. BRAF mutations have been proposed as a marker to exclude LS because they are generally absent in LS patients and present in sporadic colorectal cancer (sCRC) with MSI due to promoter hypermethylation of the MLH1 gene. Our aim was to verify whether BRAF mutations may improve the criteria to select patients for germline MMR mutation assessment. Material and methods. We analyzed 303 formalin-fixed paraffin-embedded CRC samples including 174 sCRC, 28 patients fulfilling AC, and 101 suspected-Lynch patients fulfilling BG. We analyzed MSI and BRAF mutations in all CRC samples. MLH1, MSH2 and MSH6 germline mutations were investigated in MSI patients fulfilling AC or BG. Results. sCRC samples showed MSI in 20/174 (11%) cases. BRAF mutations were detected in 10/174 (6%) sCRC cases and were significantly correlated with MSI (P = 0.002). MSI was observed in 24/28 (86%) Amsterdam cases which were BRAF wildtype. MMR gene mutation was detected in 22/26 (85%) AC cases, all showing MSI. Suspected-Lynch cases carried MSI in 41/101 (40%) and BRAF mutations in 7/101 (7%) cases. MMR gene mutation was detected in 13/28 (46%) evaluable MSI patients of this group and only in cases characterized by a wild-type BRAF gene. Conclusions. The prevalence of BRAF mutations in CRC patients is not high but extremely correlated with MSI and risk categories as BG, whereas they are absent in LS patients. BRAF mutation detection can reduce the need for MMR gene analysis in a small (but not negligible) proportion of MSI patients (7%), with a positive impact on the financial and psychological costs of unnecessary tests. Copyright - Il Pensiero Scientifico Editore.

AB - Aims and background. Lynch syndrome (LS) is clinically defined by the Amsterdam criteria (AC) and by germline mutations in mismatch-repair (MMR) genes leading to microsatellite instability (MSI) at the molecular level. Patients who do not fulfil AC are considered suspected-Lynch according to the less stringent Bethesda guidelines (BG) and should be tested for MSI and MMR germline mutations. BRAF mutations have been proposed as a marker to exclude LS because they are generally absent in LS patients and present in sporadic colorectal cancer (sCRC) with MSI due to promoter hypermethylation of the MLH1 gene. Our aim was to verify whether BRAF mutations may improve the criteria to select patients for germline MMR mutation assessment. Material and methods. We analyzed 303 formalin-fixed paraffin-embedded CRC samples including 174 sCRC, 28 patients fulfilling AC, and 101 suspected-Lynch patients fulfilling BG. We analyzed MSI and BRAF mutations in all CRC samples. MLH1, MSH2 and MSH6 germline mutations were investigated in MSI patients fulfilling AC or BG. Results. sCRC samples showed MSI in 20/174 (11%) cases. BRAF mutations were detected in 10/174 (6%) sCRC cases and were significantly correlated with MSI (P = 0.002). MSI was observed in 24/28 (86%) Amsterdam cases which were BRAF wildtype. MMR gene mutation was detected in 22/26 (85%) AC cases, all showing MSI. Suspected-Lynch cases carried MSI in 41/101 (40%) and BRAF mutations in 7/101 (7%) cases. MMR gene mutation was detected in 13/28 (46%) evaluable MSI patients of this group and only in cases characterized by a wild-type BRAF gene. Conclusions. The prevalence of BRAF mutations in CRC patients is not high but extremely correlated with MSI and risk categories as BG, whereas they are absent in LS patients. BRAF mutation detection can reduce the need for MMR gene analysis in a small (but not negligible) proportion of MSI patients (7%), with a positive impact on the financial and psychological costs of unnecessary tests. Copyright - Il Pensiero Scientifico Editore.

KW - Amsterdam criteria

KW - Bethesda guidelines

KW - BRAF mutations

KW - Lynch syndrome

KW - Microsatellite instability (MSI)

KW - Mismatch repair (MMR)

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