Incorporation of somatic <Emphasis Type="Italic">BRAF</Emphasis> mutation testing into an algorithm for the investigation of hereditary non-polyposis colorectal cancer |
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Authors: | M B Loughrey P M Waring A Tan M Trivett S Kovalenko V Beshay M-A Young G McArthur A Boussioutas A Dobrovic |
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Institution: | (1) Molecular Pathology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;(2) Department of Pathology, Royal Group of Hospitals, Belfast, N. Ireland, UK;(3) Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;(4) Genentech Inc., South San Francisco, CA, USA;(5) Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;(6) Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;(7) Trescowthick Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;(8) Department of Medicine, University of Melbourne, Melbourne, VIC, Australia;(9) Department of Pathology, University of Melbourne, Melbourne, VIC, Australia |
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Abstract: | Patients suspected on clinical grounds to have hereditary non-polyposis colorectal cancer (HNPCC) may be offered laboratory
testing in order to confirm the diagnosis and to facilitate screening of pre-symptomatic family members. Tumours from an affected
family member are usually pre-screened for microsatellite instability (MSI) and/or loss of immunohistochemical expression
of mismatch repair (MMR) genes prior to germline MMR gene mutation testing. The efficiency of this triage process is compromised
by the more frequent occurrence of sporadic colorectal cancer (CRC) showing high levels of MSI (MSI-H) due to epigenetic loss
of MLH1 expression. Somatic BRAF mutations, most frequently V600E, have been described in a significant proportion of sporadic MSI-H CRC but not in HNPCC-associated
cancers. BRAF mutation testing has therefore been proposed as a means to more definitively identify and exclude sporadic MSI-H CRC cases
from germline MMR gene testing. However, the clinical validity and utility of this approach have not been previously evaluated
in a familial cancer clinic setting. Testing for the V600E mutation was performed on MSI-H CRC samples from 68 individuals
referred for laboratory investigation of suspected HNPCC. The V600E mutation was identified in 17 of 40 (42%) tumours showing
loss of MLH1 protein expression by immunohistochemistry but in none of the 28 tumours that exhibited loss of MSH2 expression
(P < 0.001). The assay was negative in all patients with an identified germline MMR gene mutation. Although biased by the fact
that germline testing was not pursued beyond direct sequencing in many cases lacking a high clinical index of suspicion of
HNPCC, BRAF V600E detection was therefore considered to be 100% specific and 48% sensitive in detecting sporadic MSI-H CRC amongst those
cases showing loss of MLH1 protein expression, in a population of patients with MSI-H CRC and clinical features suggestive
of HNPCC. Accordingly, we recommend the incorporation of BRAF V600E mutation testing into the laboratory algorithm for pre-screening patients with suspected HNPCC, whose CRCs show loss
of expression of MLH1. In such tumours, the presence of a BRAF V600E mutation indicates the tumour is not related to HNPCC and that germline testing of MLH1 in that individual is not warranted. We also recommend that in families where the clinical suspicion of HNPCC is high, germline
testing should not be performed on an individual whose CRC harbours a somatic BRAF mutation, as this may compromise identification of the familial mutation. |
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Keywords: | Hereditary non-polyposis colorectal cancer BRAF Allele-specific PCR Microsatellite instability |
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