Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.
OBJECTIVE
Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history.


METHODS
Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants.


RESULTS
Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1).


CONCLUSIONS
This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.|Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
Anne M L
AM
Jansen
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Marije A
MA
Geilenkirchen
Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
Tom
T
van Wezel
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Shantie C
SC
Jagmohan-Changur
Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
Dina
D
Ruano
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Heleen M
HM
van der Klift
Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
Brendy E W M
BE
van den Akker
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Jeroen F J
JF
Laros
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Michiel
M
van Galen
Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Anja
A
Wagner
Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
Tom G W
TG
Letteboer
Department of Clinical Genetics, University Hospital Maastricht, Maastricht, The Netherlands.
Encarna B
EB
Gómez-García
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Carli M J
CM
Tops
Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
Hans F
HF
Vasen
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Peter
P
Devilee
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Frederik J
FJ
Hes
Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
Hans
H
Morreau
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.|Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Juul T
JT
Wijnen
D015331:Cohort Studies; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006801:Humans; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D000070957:MutL Protein Homolog 1 / Q000235:genetics; D012007:Rectum / Q000378:metabolism / Q000473:pathology
D000070957:MutL Protein Homolog 1