169 Associations Between Cigarette Smoking and Incident Colorectal Cancer by ER Beta Protein Expression in a Population-Based Cohort of Older Women

6600 Background: A myriad of molecular markers has been proposed and tested with the promise of improving cancer care. Few have been validated and even fewer have been implemented in daily clinic. The most common hereditary colorectal cancer entity, Lynch Syndrome, can be identified in a subset of colorectal cancer patients by screening molecular markers for mismatch-repair (MMR) deficiency. We wanted to implement this screening in a Danish region, optimize quality, and describe the results. Methods: All colorectal cancer (CRC) patients diagnosed from October 2010 to September 2012 in the Region of Southern Denmark were included. Immunohistochemistry (IHC) was performed for protein expression of the MLH1, PMS2, MSH2, and MSH6 genes followed by MLH1 methylation analysis in cases with loss of pMLH1. Hereafter the indications for genetic counselling were lack of any MMR-protein – and in case missing pMLH1only those with no promoter-methylation of MLH1. Patients were included irrespectively of stage, post-mortem diagnosis, surgery, or other treatment. Accepted reasons for missed data were insufficient or autolyzed tumor material, but not data missing due to death, no surgery, or any logistic problem. Every 3-6 months the national pathology database was checked for missing data and feedback was given to the clinicians to ensure enrolling of all CRC patients. Results: CRC were diagnosed in 2,120 patients in a population of 1,200,000 with informative data for 1,932 patients at the time of analysis. 1,680 had normal protein expression of all four MMR-genes. 209 lacked pMLH1 of which 11 were not methylated. Loss of pMSH2, isolated pMSH6 or pPMS2 was seen in 23, 11, and 9 cases, respectively. Thus, the established screening program was positive in 54 patients. These patients are offered further genetic counselling and testing. Conclusions: Screening for Lynch Syndrome was feasible in a geographically defined area involving several clinical departments. Molecular screening for hereditary MMR-deficiency was positive in 54 of 1932 patients (2.8 %). Implementation of molecular markers in cancer care can be optimized by support from national databases and formalized quality feed back to the clinicians. Clinical trial information: NCT01216930.

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Altered Expression of MLH1, MSH2, and MSH6 in Predisposition to Hereditary Nonpolyposis Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2003.03.181 ◽

2003 ◽

Vol 21 (19) ◽

pp. 3629-3637 ◽

Cited By ~ 65

Author(s):

Elise Renkonen ◽

Yange Zhang ◽

Hannes Lohi ◽

Reijo Salovaara ◽

Wael M. Abdel-Rahman ◽

...

Keyword(s):

Colorectal Cancer ◽

Protein Expression ◽

Mrna Expression ◽

Messenger Rna ◽

Hereditary Nonpolyposis Colorectal Cancer ◽

Population Based ◽

Altered Expression ◽

Dna Mismatch ◽

Mmr Genes ◽

Hereditary Nonpolyposis

Purpose: A considerable fraction (30% to 70%) of families with verified or putative hereditary nonpolyposis colorectal cancer fails to show mutations in DNA mismatch repair (MMR) genes. Our purpose was to address the genetic etiology of such families. Materials and Methods: We scrutinized a population-based cohort of 26 families from Finland that had screened mutation-negative by previous techniques. Blood was tested for allelic messenger RNA (mRNA) expression of MLH1, MSH2, and MSH6 by single nucleotide primer extension (SNuPE), and tumor tissue for MMR protein expression by immunohistochemistry (IHC) as well as for microsatellite instability (MSI). Full-length cDNAs of genes implicated by SNuPE or IHC were cloned and sequenced. Results: Unbalanced mRNA expression of MLH1 alleles was evident in two families. An inherited nonsense mutation was subsequently identified in one family, and complete silencing of the mutated allele was identified in the other family. Extinct protein expression by IHC implicated MLH1 in these two and in four other families, MSH2 in four families, and MSH6 in one family. Although no unequivocal genomic mutations were detected in the latter families, haplotype and other findings provided support for heritable defects. With one exception, all tumors with IHC alterations showed MSI, in contrast to the remaining families, which showed neither IHC changes nor MSI. Conclusion: Our expression-based strategy stratified the present “mutation-negative” cohort into two discrete categories: families linked to the major MMR genes MLH1, MSH2, and MSH6 (11 [42%] of 26) and those likely to be associated with other, as yet unknown susceptibility genes (15 [58%] of 26).

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