Macrae FA 1, Good N 3, Young GP, Bampton P 2, Lane J 2, St John DJB 1, Diehl R 3, J O Dwyer 3, Slattery M 1.

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1 Macrae FA 1, Good N 3, Young GP, Bampton P 2, Lane J 2, St John DJB 1, Diehl R 3, J O Dwyer 3, Slattery M 1. Colorectal Medicine and Genetics, and University of Melbourne Dept of Medicine The Royal Melbourne Hospital 1, Flinders Centre for Cancer Prevention and Control, Flinders University, Adelaide 2, CSIRO phealth Flagship, Adelaide 3 Australia

2 Introduction International guidelines recognize age of onset and multiplicity of colorectal cancers on the same side of the family as risk factors for familial colorectal cancer. Information on screening outcomes where CRC is present on both sides of the family is unavailable and would be explicable in a recessive model of inheritance. We instituted colonoscopic screening for family members where both parents had developed CRC compared the outcomes with other groups in our program.

3 Aim To compare screening outcomes screenees who have both parents affected with colorectal cancer, with moderate risk groups defined by Australian NHMRC criteria.

4 Methods Data on screening outcomes was derived from The Royal Melbourne Hospital (BCSP) and Southern Adelaide Health Services (SAHS) Bowel Cancer Screening Programs, who have been prospectively planning and documenting screening in familial bowel cancer for 29 and 16 years respectively. We evaluated the outcomes of the worst findings during screening in the patients stratified by density of family history of colorectal cancer and age of onset. Screening frequency was scheduled at 5 yearly intervals for all groups except those with HNPCC where screening was annual (gene carriers) or bi-ennial (Amsterdam positive, no mutation).

5 Definitions of Risk Groups: RELS A RELS B RELS C RELS D RELS E RELS F RELS G RELS H RELS Q RELS R RELS S CCC HNPCC Suspected HNPCC Definite Both parents with CRC Two siblings with CRC Parent + sibling with CRC Parent + grandparent with CRC One sibling and distant relative with CRC Parent and Parent's Sibling with CRC One 1 Relative with CRC <55 yr Identical twin with CRC Adenoma(s) in 1 o relative One 1 Relative >55 yr with CRC One or more CRC 2 or 3 Relative(s) with CRC More than two 1 st or second degree relatives (same side of the family) with CRCs. Age of onset (for all affecteds) >50 years More than One first degree relative with CRC or syndrome associated cancer with at least one affected 50 years of age or younger OR Three first degree relatives over two generations including at least one CRC and/or other syndromic cancer, all diagnosed over 50 years BUT Not Amsterdam I OR II Amsterdam II or II i.e. Three or more family members with CRC or syndromic cancers, at least one of whom is a first degree relative of the other two At least one affected at 50 years of age or younger Two generations affected OR MMR mutation in the family.

6 Collapsing of risk groups for analysis (see second figure) R0 R1 R2 R3 R4 No family history= Adenoma or Cancer Follow up RELS A,B,C,H (CRC Both Parents; CRC 2 Siblings; CRC Parent and sibling; CRC Twins) RELS D,E,F (CRC Parent and Grandparent; 1x 1 Relative +other family members with CRC; CRC Parent and Parent's Sibling) RELS G (CRC 1 Relative <55yr) RELS R,S,Q (CRC 1 Relative >55yr; CRC 2 or 3 Relative; Adenomas)

7 Results 83 screenees had a family history with both parents developing bowel cancer; In addition, there were 38 with 2 siblings affected with CRC, 105 with parent and sibling affected with CRC, 360 with one 1 st degree relative affected with CRC at <55years and 264 definite HNPCC (cancer-affected Amsterdam family members or MMR mutation positive individuals). Over the 30 year duration of our register, advanced adenomas or cancer occurred in 10.8% of the both parents group, compared with 18.4% in those with 2 siblings, 10.4% with a parent and sibling, 6.4% with parent and grandparent, and 10.2% for the group with a single 1 st relative affected under 55 years. In the definite HNPCC group who had annual or bi-ennial screening, advanced adenomas or cancer occurred in 13.7% of the cohort. In a logistic regression taking into account sex and age in addition to risk group, these differences were not statistically significantly different

8

9 Outcome at first worse colonoscopy by familial risk group

10 Results

11 Results

12 Conclusion Screening should be considered in families where both parents have developed CRC, regardless of age of onset of the cancer, as the outcome for advanced neoplasia is comparable to other established risk groups.

13 Acknowledgements With thanks to all the many generations of managers who have contributed to this information The RMH Bowel Cancer Surveillance Program is funded by donations of screenees and the public The merge and data analysis were funded through Australian BioGrid, with support from the Australian CSIRO and Victorian Government

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