Abstract
Mismatch repair proficient hereditary non-polyposis colorectal cancer (MSS-HNPCC) encloses a heterogeneous group of families consisting of different unknown genetic syndromes and/or aggregations cases. The lack of information about the hereditability of cancer risk in these families makes it difficult to carry out an individualized Genetic Counseling. Therefore, deep description of such families becomes important for a better classification and search for underlying susceptibility causes. The aim of this study is to describe and compare the clinical, morphological features, tumor KRAS status and overall survival in MSS-HNPCC, Lynch and sporadic colorectal cancer. A total of 37 MSS-HNPCC families, 50 Lynch families and 612 sporadic CRC were included. Clinical and morphological data were evaluated by reviewing medical and pathology reports of 55, 69 and 102 tumors respectively. KRAS/BRAF status were detected by allele specific real-time PCR. Standardized incidence ratios (SIR) were calculated among 602 MSS-HNPCC relatives and 668 Lynch relatives. Main features distinguishing MSS-HNPCC were diagnosis age (55.1 ± 12.6), preferential distal location (76%), polyp detection (45%) and familial colorectal cancer incidence (SIR = 6.6). In addition, we found increased incidences rates for kidney, stomach and uterus tumors. KRAS mutation rates were similar in the study populations (48.8 ± 5.8) but higher than those described before by Sanger sequencing. MSS-HNPCC overall survival was similar to Lynch in B Dukes' stage tumors and between Lynch and sporadic in C stage tumors. Anatomical and morphological data of MSS-HNPCC are consistent with other described populations. Our studies disclose an increased HNPCC-extracolonic tumors incidence and improved overall survival in MSS-HNPCC families.
Highlights
Hereditary nonpolyposis colorectal cancer (HNPCC) has been defined as a familial syndrome with an increased incidence of colorectal cancer (CRC) and/or other extracolonic tumors [1, 2]
After Lynch diagnosis in families coming from our Genetic Counseling Unit, we found great representation of Amsterdam I families, Amsterdam II, and Amsterdam like families in Lynch positive families
Updated and increased KRAS mutation rates in microsatellite stable (MSS)-HNPCC, Lynch and sporadic CRC are given for the first time using high sensitive methodology
Summary
Hereditary nonpolyposis colorectal cancer (HNPCC) has been defined as a familial syndrome with an increased incidence of colorectal cancer (CRC) and/or other extracolonic tumors [1, 2]. Half of HNPCC cases are caused by DNA mismatch repair (MMR) pathway defects [5, 6]. Germline mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) are responsible for these cases and they are commonly referred to as Lynch syndrome. The other half of the Amsterdam families have no evidence of MMR deficiency; CRC in affected members are microsatellite stable (MSS) and MMR mutations are not found. This fact makes it difficult to carry out an individualized Genetic Counseling in all these families
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