Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome
Background Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without MLH1 methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the...
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crjcrbmj:10.1136/jmedgenet-2018-105698 2024-09-15T18:13:40+00:00 Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome Pearlman, Rachel Haraldsdottir, Sigurdis de la Chapelle, Albert Jonasson, Jon G Liyanarachchi, Sandya Frankel, Wendy L Rafnar, Thorunn Stefansson, Kari Pritchard, Colin C Hampel, Heather National Cancer Institute Pelotonia 2019 http://dx.doi.org/10.1136/jmedgenet-2018-105698 https://syndication.highwire.org/content/doi/10.1136/jmedgenet-2018-105698 en eng BMJ Journal of Medical Genetics volume 56, issue 7, page 462-470 ISSN 0022-2593 1468-6244 journal-article 2019 crjcrbmj https://doi.org/10.1136/jmedgenet-2018-105698 2024-07-25T04:14:49Z Background Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without MLH1 methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts. Methods We included patients with CRC from Ohio 2013–2016 and Iceland 2000–2009. All had microsatellite instability testing and/or immunohistochemistry (IHC) of MMR proteins, and MLH1 methylation testing when indicated. Germline next-generation sequencing was performed for all with dMMR tumours; tumour sequencing followed for patients with unexplained dMMR. Clinical characteristics of DS patients and patients with LS were compared. Results Of the 232 and 51 patients with non-methylated dMMR tumours in the Ohio and Iceland cohorts, respectively, 57.8% (n=134) and 45.1% (n=23) had LS, 32.8% (n=76) and 31.4% (n=16) had DS PVs, 6% (n=14) and 9.8% (n=5) were unexplained and 4.3% (n=10) and 13.7% (n=7) had incorrect IHC. Age of diagnosis for DS patients was older than patients with LS (p=3.73×10 −4 ) in the two cohorts. Patients with LS were more likely to meet Amsterdam II criteria (OR=15.81, p=8.47×10 −6 ) and have multiple LS-associated tumours (OR=6.67, p=3.31×10 −5 ). Absence of MLH1/PMS2 was predictive of DS PVs; isolated MSH6 and PMS2 absence was predictive of LS in both cohorts. Conclusions Individuals with LS are 15× more likely to meet Amsterdam II criteria and >5× more likely to have multiple cancers as compared with those with DS tumours. Furthermore, isolated loss of MSH6 or PMS2 protein predicts LS. Article in Journal/Newspaper Iceland The BMJ Journal of Medical Genetics 56 7 462 470 |
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Background Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without MLH1 methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts. Methods We included patients with CRC from Ohio 2013–2016 and Iceland 2000–2009. All had microsatellite instability testing and/or immunohistochemistry (IHC) of MMR proteins, and MLH1 methylation testing when indicated. Germline next-generation sequencing was performed for all with dMMR tumours; tumour sequencing followed for patients with unexplained dMMR. Clinical characteristics of DS patients and patients with LS were compared. Results Of the 232 and 51 patients with non-methylated dMMR tumours in the Ohio and Iceland cohorts, respectively, 57.8% (n=134) and 45.1% (n=23) had LS, 32.8% (n=76) and 31.4% (n=16) had DS PVs, 6% (n=14) and 9.8% (n=5) were unexplained and 4.3% (n=10) and 13.7% (n=7) had incorrect IHC. Age of diagnosis for DS patients was older than patients with LS (p=3.73×10 −4 ) in the two cohorts. Patients with LS were more likely to meet Amsterdam II criteria (OR=15.81, p=8.47×10 −6 ) and have multiple LS-associated tumours (OR=6.67, p=3.31×10 −5 ). Absence of MLH1/PMS2 was predictive of DS PVs; isolated MSH6 and PMS2 absence was predictive of LS in both cohorts. Conclusions Individuals with LS are 15× more likely to meet Amsterdam II criteria and >5× more likely to have multiple cancers as compared with those with DS tumours. Furthermore, isolated loss of MSH6 or PMS2 protein predicts LS. |
author2 |
National Cancer Institute Pelotonia |
format |
Article in Journal/Newspaper |
author |
Pearlman, Rachel Haraldsdottir, Sigurdis de la Chapelle, Albert Jonasson, Jon G Liyanarachchi, Sandya Frankel, Wendy L Rafnar, Thorunn Stefansson, Kari Pritchard, Colin C Hampel, Heather |
spellingShingle |
Pearlman, Rachel Haraldsdottir, Sigurdis de la Chapelle, Albert Jonasson, Jon G Liyanarachchi, Sandya Frankel, Wendy L Rafnar, Thorunn Stefansson, Kari Pritchard, Colin C Hampel, Heather Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome |
author_facet |
Pearlman, Rachel Haraldsdottir, Sigurdis de la Chapelle, Albert Jonasson, Jon G Liyanarachchi, Sandya Frankel, Wendy L Rafnar, Thorunn Stefansson, Kari Pritchard, Colin C Hampel, Heather |
author_sort |
Pearlman, Rachel |
title |
Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome |
title_short |
Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome |
title_full |
Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome |
title_fullStr |
Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome |
title_full_unstemmed |
Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome |
title_sort |
clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with lynch syndrome |
publisher |
BMJ |
publishDate |
2019 |
url |
http://dx.doi.org/10.1136/jmedgenet-2018-105698 https://syndication.highwire.org/content/doi/10.1136/jmedgenet-2018-105698 |
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Iceland |
genre_facet |
Iceland |
op_source |
Journal of Medical Genetics volume 56, issue 7, page 462-470 ISSN 0022-2593 1468-6244 |
op_doi |
https://doi.org/10.1136/jmedgenet-2018-105698 |
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Journal of Medical Genetics |
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56 |
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7 |
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462 |
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470 |
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1810451430286295040 |