Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts.
OBJECTIVE
Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches.


METHODS
Colorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600Esomatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs.


RESULTS
Of the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 25.2% of the MMR-deficient CRCs for the ACCFR and MCCS, respectively.


CONCLUSIONS
Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR-deficient CRCs will have unknown etiology (Lynch-like) proving problematic for clinical management.
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
Daniel D
DD
Buchanan
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
Mark
M
Clendenning
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.|Envoi Specialist Pathologists, Herston, Queensland, Australia.|School of Medicine, The University of Queensland, Herston, Queensland, Australia.
Christophe
C
Rosty
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
Stine V
SV
Eriksen
Department of Histopathology, Sullivan Nicolaides Pathology, Brisbane, Queensland, Australia.
Michael D
MD
Walsh
Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, Queensland, Australia.
Rhiannon J
RJ
Walters
Molecular Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Stephen N
SN
Thibodeau
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
Jenna
J
Stewart
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
Susan
S
Preston
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
Aung Ko
AK
Win
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
Louisa
L
Flander
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
Driss Ait
DA
Ouakrim
Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.|Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia.|Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Finlay A
FA
Macrae
Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.|Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
Alex
A
Boussioutas
Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.|Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia.
Ingrid M
IM
Winship
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
Graham G
GG
Giles
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.|Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea.
John L
JL
Hopper
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
Melissa C
MC
Southey
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
Dallas
D
English
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
Mark A
MA
Jenkins
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000235:genetics; D055815:Young Adult
Colorectal cancer; Lynch syndrome; immunohistochemistry; microsatellite instability, MLH1, MSH2, MSH6, PMS2, MLH1 methylation, BRAFV600E; mismatch repair protein expression