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Genetic risk factors are important contributors to the development of colorectal cancer. Following the definition of a linkage signal at 9q22-31, we fine mapped this region in an independent collection of colon cancer families. We used a custom array of single-nucleotide polymorphisms (SNP) densely spaced across the candidate region, performing both single-SNP and moving-window association analyses to identify a colon neoplasia risk haplotype. Through this approach, we isolated the association effect to a five-SNP haplotype centered at 98.15 Mb on chromosome 9q. This haplotype is in strong linkage disequilibrium with the haplotype block containing HABP4 and may be a surrogate for the effect of this CD30 Ki-1 antigen. It is also in close proximity to GALNT12, also recently shown to be altered in colon tumors. We used a predictive modeling algorithm to show the contribution of this risk haplotype and surrounding candidate genes in distinguishing between colon cancer cases and healthy controls. The ability to replicate this finding, the strength of the haplotype association (odds ratio, 3.68), and the accuracy of our prediction model (∼60%) all strongly support the presence of a locus for familial colon cancer on chromosome 9q. Cancer Res; 70(13); 5409–18. ©2010 AACR.

Recent publications have reported that common variants on 8q24 are associated with both prostate and colorectal cancers (CRC). In addition, one of these studies (the ARCTIC study) initially observed an association with a single nucleotide polymorphism (SNP) on 9p24 that was not confirmed in some of their validation data sets. In the research described here, we conducted a case-unaffected sibling analysis using population- and clinic-based discordant sibships (N = 1,567 sibships) from the Colon Cancer Family Registry (Colon CFR) to investigate the associations between common variants at 9p24 and 8q24 and risk of CRC. We also evaluated whether these associations differed by age, family history, and tumor characteristics, including microsatellite instability and tumor site. Associations were estimated using conditional logistic regression, treating sibship as the matching factor. Analyses were adjusted for age and sex, and stratified by ascertainment source (population versus clinic). We observed an association between a SNP on 9p24 (rs719725) and risk of CRC in the population-based series (AA versus CC: odds ratios, 1.46; 95% confidence interval, 1.06–2.02; AC versus CC: odds ratios, 1.50; 95% confidence interval, 1.14–1.98; P = 0.011 on 2 df). In the population-based series, we also detected statistically significant associations between two SNPs on 8q24, rs10505477 and rs6983267, and risk of CRC (P = 0.005 and P = 0.002, respectively). There was no evidence of statistically significant heterogeneity by age at diagnosis, family history of CRC, microsatellite instability, or tumor site at either locus and no evidence of interaction between SNPs on 8q24 and 9p24. These data suggest that common variants may play important roles in the risk of CRC. [Cancer Res 2007;67(23):11128–32]

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no tumors with loss of expression of MMR proteins; no microsatellite instability (MSI)-high tumors, and no evidence of linkage to MMR genes). This represents the largest linkage analysis of proficient MMR (pMMR) familial CRC to date. Families were ascertained via the NCI-supported Colon Cancer Family Registry multi-site (Colon CFR) consortium, the City of Hope, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family, range 2-10 with an average of 2.2 affected and 2.8 unaffected individuals) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed, accounting for heterogeneity, in four chromosomal regions. The greatest lod scores were at 4q21.1 among families with mean age of diagnosis less than 50 years (dominant HLOD=4.51, α=0.84, 145.40 cM, rs10518142) and at 12q24.32 among all families (dominant HLOD=3.60, α=0.48, 285.15 cM, [rs952093][1]). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD=3.07, α=0.29; dominant HLOD=3.03, α=0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD=3.02, α=0.51, 132.52 cM, rs1319036). These linkage regions comprise previously unreported loci, supporting the hypothesis that novel loci contribute to CRC in familial pMMR cases. These loci are also largely distinct from those identified in case-control GWAS. To follow up on these findings, a custom Agilent Sure Select Target Enrichment panel has been designed for genes in three of these regions, in order to sequence probands using an Illumina HiSeq 2000. This study demonstrates the utility of family-based data and provides evidence for additional alleles for familial CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2930. doi:1538-7445.AM2012-2930 [1]: /lookup/external-ref?link_type=GEN&access_num=rs952093&atom=%2Fcanres%2F72%2F8_Supplement%2F2930.atom

Background: Debate continues as to the usefulness of testing adenomas for loss of mismatch repair (MMR) proteins to identify individuals with suspected Lynch syndrome. Several studies have suggested that it is only worthwhile testing large, proximal adenomas exhibiting high grade dysplasia while others report disappointing “hit rates” even from known mutation carriers. Screening of unselected early-onset adenomas for MMR deficiency has yielded disappointing results. Design: We tested 88 adenomas from 49 proven mutation carriers (23 female and 26 male) from 37 Lynch syndrome families (12 MLH1, 21 MSH2, 3 MSH6 and 1 PMS2) enrolled in the Australasian Colorectal Cancer Family Study which is part of the Colon Collaborative Family Registry (C-CFR). The average age of diagnosis of first polyp studied was 49.1 ± 9.6 years (ranging from 30.3 to 72.0 years). All polyps were tested by immunohistochemistry (IHC) for the four MMR proteins MLH1, MSH2, MSH6 and PMS2. In addition, microsatellite instability testing using a panel of 10 markers (incorporating the standard NCI panel) was performed on 69 adenomas. All polyps were subjected to a standard review by one specialist pathologist (JJ). The majority of adenomas included in the present study were tubular adenomas (n = 61), with 22 tubulovillous adenomas, 1 villous adenoma, and 4 traditional serrated adenomas. Results: Overall, abnormal immunohistochemical results (loss of expression) were noted for 73/88 (82.9%) of the adenomas from MMR gene mutation carriers. In all instances, loss of expression was consistent with the underlying germline mutation. MSI testing was concordant with immunohistochemistry in 66/69 (95.6%) cases. There was no statistical difference in patient ages at the time of polypectomy between MMR deficient and intact adenomas (49.6 ± 9.5 yrs vs. 49.8 ± 11.6 yrs). 15/88 (17.1%) polyps demonstrated normal MMR IHC. Six of these polyps came from four individuals who had other polyps which demonstrated abnormal IHC), whilst the remaining nine adenomas came from nine individuals for whom other adenomas had not been tested. Of these 9 cases, however, three had been diagnosed with Lynch syndrome-spectrum tumours which showed appropriate loss of MMR protein(s) Conclusions: Diagnostic testing of adenomas from patients from Lynch syndrome families is a useful alternative in cases where cancers are unavailable. The overwhelming majority (82.9%) of adenomas from carriers show appropriate loss of MMR proteins and a high level of concordant microsatellite instability. We were unable to demonstrate an association between adenoma grade, size or site and MMR deficiency. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 798.

Background: Lynch Syndrome is an autosomal dominant condition which predisposes to early-onset cancer of the colorectum, endometrium, and to a lesser extent, stomach, ureter and renal pelvis, ovary, brain and small bowel. It is thought, however, that there is no significant increase in risk of developing breast cancer. The aim of this study was to determine the prevalence and clinicopathological features of breast cancers arising in families with a history of both colorectal and breast malignancy. Design: 107 cases of breast carcinoma (BC) from 90 families were identified from the Australasian Colorectal Cancer Family Registry. Comprehensive cancer histories were available for all families: 53 (59%) families met the modified Amsterdam criteria, and the remainder had multiple cancers including at least one early onset ( Results: Loss of one or more MMR proteins was seen in 18/107 tumors (17%): five cancers showed loss of MLH1 and PMS2, twelve tumors MSH2 and MSH6, and one tumor MSH6 alone. IHC and MSI results were concordant in 85/89 (96%) tumors tested. Invasive MMR-deficient BCs were more likely to be poorly differentiated (p=0.005), steroid hormone receptor negative (p Conclusion: DNA mismatch repair protein deficiency was identified in 18/107 cases (17%) of breast cancer arising in a familial setting of colorectal and breast carcinoma. The MMR-deficient BCs were more likely to be high grade, steroid hormone receptor negative, have areas of solid growth, confluent necrosis and high mitotic index than MMR-proficient tumors. The study suggests that breast cancer arising in a setting of Lynch syndrome commonly demonstrates evidence of MMR deficiency and that breast cancers may represent a valid tissue option for the detection of MMR deficiency where colorectal or other spectrum tumors are difficult to obtain. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 32.