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New approaches in genetic analysis to predict for CRC risk.

ABSTRACT: Interventions: The aim of this research is to find the undiscovered gene or genes responsible for hereditary colorectal cancer, and to understand how the gene(s) cause colorectal cancer. One of the best approaches used to find the answers to these questions is to study families where there are several family members affected with colorectal cancer. Case probands and their relatives (affected and unaffected) will be recruited (20 ml) of blood will be obtained on one occasion from each participant Where tissues from affected family members have already been obtained (paraffin embedded tumour tissue in blocks) we will seek permission to access this material for DNA extraction. The duration of study will be approximately 48 months. Primary outcome(s): To identify molecular markers of potential value in understanding predisposition to CRC by their association with gene variants that increase the risk of CRC. The study will be a family based analysis of SNP genotypes for cases and controls within families and between families. Transmission of disease associated SNPs will be assessed to determine within-family association and linkage and then to calculate across-family associations.[2-3 blood samples per week over 36 months approx] Study Design: Purpose: Natural history;Duration: Cross-sectional;Selection: Defined population;Timing: Both

DISEASE(S): Bowel Cancer,Cancer-bowel-anal,Cancer-bowel-small Bowel (duodenum And Ileum,Cancer-bowel-back Passage (rectum) Or Large Bowel (colon)

PROVIDER: 2452082 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar pathophysiological mechanisms. Grouping into molecularly homogeneous subsets may therefore be of potential value for further genetic analysis in order to identify new high penetrance breast cancer genes. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer patients within the same family. By analyzing a collection of 70 breast tumor biopsies from 58 families, we show that distinct functional subgroupings, similar to the intrinsic molecular breast cancer subtypes, exist. The distribution of subtypes was markedly different from the distribution found among BRCA1/2 mutation carriers. From 11 breast cancer families, breast tumor biopsies from more than one affected family member were included in the study. Notably, in 8 of these families we found that patients from the same family shared the same tumor subtype, showing a tendency of familial aggregation of tumor subtypes (p-value = 1.7e-3). Our finding indicates involvement of hereditary factors in these families in which family members may carry genetic susceptibility not just to breast cancer but to a particular subtype of breast cancer. Using our previously developed BRCA1/2-signatures, we identified 7 non-BRCA1/2 tumors with a BRCA1-like molecular phenotype and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. This is the first study to provide a biological link between breast cancers from family members of high risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly homogeneous subtypes in order to identify new high penetrance susceptibility genes.

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New approaches in genetic analysis to predict for CRC risk.

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