Risk of cancer in cases of suspected lynch syndrome without germline mutation.
OBJECTIVE
Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS.


METHODS
We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups.


RESULTS
The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P < .001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P < .001).


CONCLUSIONS
The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.
Unidad de Gastroenterología, Hospital General Universitario de Alicante, Alicante, Spain.
María
M
Rodríguez-Soler
Lucía
L
Pérez-Carbonell
Carla
C
Guarinos
Pedro
P
Zapater
Adela
A
Castillejo
Victor M
VM
Barberá
Miriam
M
Juárez
Xavier
X
Bessa
Rosa M
RM
Xicola
Juan
J
Clofent
Luis
L
Bujanda
Francesc
F
Balaguer
Josep-Maria
JM
Reñé
Luisa
L
de-Castro
José C
JC
Marín-Gabriel
Angel
A
Lanas
Joaquín
J
Cubiella
David
D
Nicolás-Pérez
Alejandro
A
Brea-Fernández
Sergi
S
Castellví-Bel
Cristina
C
Alenda
Clara
C
Ruiz-Ponte
Angel
A
Carracedo
Antoni
A
Castells
Montserrat
M
Andreu
Xavier
X
Llor
José L
JL
Soto
Artemio
A
Payá
Rodrigo
R
Jover
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics; D053843:DNA Mismatch Repair; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011159:Population Surveillance; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology
D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1