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Background: Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics. Methods: The population-based study included individuals diagnosed with CRC between 1998–2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status. Results: Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13–1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS- or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival. Conclusion: Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC.

Lynch syndrome, historically known as hereditary non-polyposis colorectal cancer (Jass, 2006), refers to colorectal and other cancers caused by germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 (Vasen et al, 1999). Approximately 1 in 3000 people in the general population carry a mutation in an MMR gene (Dunlop et al, 2000). These MMR gene mutation carriers are at substantially increased risk of colorectal cancer (CRC) with an estimated cumulative risk to age 70 years between 40% and 70% depending on the carrier's sex and the MMR gene that is mutated (Chen et al, 2006; Jenkins et al, 2006; Senter et al, 2008; Baglietto et al, 2010). Physical characteristics or environmental exposures of the mutation carriers could also modify their risks of developing CRC (Jenkins et al, 2007). Identifying modifiers of CRC risk for carriers of MMR gene mutations is important for understanding carcinogenesis. Identifying potentially protective or harmful and avoidable risk factors also creates opportunities for mutation carriers to reduce their risks of life-threatening diseases. Previous studies have provided evidence for the existence of modifiers of CRC risk for MMR gene mutation carriers. For example, CRC risk for carriers is positively associated with alcohol consumption (Watson et al, 2004) and negatively associated with fruit consumption and dietary fibre intake (Diergaarde et al, 2007). For smoking, CRC risk for carriers is positively associated with current smoking (Diergaarde et al, 2007; Pande et al, 2010), but negatively or not associated with former smoking (Diergaarde et al, 2007; Pande et al, 2010). However, the association between body size and CRC risk for MMR gene mutation carriers is yet to be established. One CRC risk factor for people in the general population is body size, a collective term for body mass index (BMI), waist circumference and height (Dai et al, 2007; Larsson and Wolk, 2007; Moghaddam et al, 2007; Renehan et al, 2008). Previous case–control studies of CRC cases with a family history (therefore, likely to be enriched for MMR gene mutation carriers) compared with population-based controls who were unselected for family history, have shown that current BMI is positively associated with CRC risk (Slattery et al, 2003; Campbell et al, 2007). However, studies that have examined the association between current BMI and the occurrence of tumours with microsatellite instability (MSI), a common characteristic of CRCs caused by MMR defects, have reported no statistically significant associations with this form of disease (Slattery et al, 2000; Campbell et al, 2010). One study that examined the association between BMI and colorectal adenoma risk for MMR gene mutation carriers observed a positive association for males but not females (Botma et al, 2010). Identifying an association of BMI in early adulthood on subsequent cancer risk would be important for MMR gene mutation carriers who learn their mutation status as adults in their 20s, an increasingly common occurrence because of increased systematic testing in the population, with the consequent opportunity to reduce their risk of disease. In this study, we estimated an association between BMI at age 20 years and CRC risk for MMR gene mutation carriers. As a comparison, we also estimated the association for non-carriers to investigate whether BMI has a differential effect on risk for CRC by mutation status.

The autosomal recessive polycystic kidney disease (ARPKD) gene, PKHD1, has been implicated in the genesis or growth of colorectal adenocarcinoma, as a high level of somatic mutations was found in colorectal tumor tissue. To determine whether carriers of a single PKHD1 mutation are at increased risk of colorectal carcinoma, we assessed the prevalence of the commonest European mutation, T36M. First, we assayed a European cohort of ARPKD patients and found T36M was responsible for 13.1% of mutations. We then investigated two European cohorts with colorectal adenocarcinoma versus two control cohorts of similar age and gender. Screening for the most common PKHD1 mutation, T36M, we detected 15:3,603 (0.42%) controls versus 1:3,767 (0.027%) colorectal cancer individuals, indicating that heterozygous PKHD1 mutations are not a risk factor and are protective (p = 0.0002). We also show that the carriage rate for PKHD1 mutations in the European population is higher than previous accepted at 3.2% (1:31 genomes).

Multivitamin use has been related to a modest reduced risk of colorectal cancer (CRC), but evidence on its use after diagnosis in relation to survival has been limited. Incident, invasive CRC cases were identified through cancer registries from 1997–2008 and enrolled in four population-based sites of the Colon Cancer Family Registry (Fred Hutchinson Cancer Research Center, Cancer Care Ontario, Mayo Clinic, and the Universities of Queensland and Melbourne). At enrollment, a standardized interview ascertained multivitamin use in the year prior to diagnosis. A follow-up questionnaire was administered approximately 5 years after baseline, with 2,586 participants providing information on their multivitamin use at both time points. Survival outcomes were identified through linkage to national death registries. Delayed-entry Cox regression was used to estimate the association between patterns of multivitamin use and overall or CRC-specific survival (Hazard Ratio (HR) and 95% Confidence Interval (CI)), with survival time beginning at the 5-year follow-up survey. Models were adjusted for age at diagnosis, sex, body mass index, smoking history, stage, study center, and number of days from diagnosis to baseline survey. Over a median 4.8 years after the follow-up survey, 397 participants died (103 from CRC). Multivitamin use was common: at the 5-year follow-up, 37% reported continued use since before diagnosis, 12% had initiated use, 17% had discontinued use, and only 34% participants reported never using multivitamins. Compared to never use of multivitamins, continued use was significantly associated with increased subsequent overall survival (HR = 0.71, 95% CI: 0.55–0.91). However, this association did not reach statistical significance for CRC-specific survival (HR = 0.76, 95% CI: 0.47–1.24). No significant association was observed for discontinuing (HR = 0.92, 95% CI: 0.68–1.25) or initiating (HR = 0.80, 95% CI: 0.55–1.13) multivitamin use from baseline to follow-up, compared to never users, though initiating use trended towards increased survival. These findings suggest that continuing multivitamin use after a CRC diagnosis may increase survival; replication and details on the specific micronutrients included are needed.

Background: Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and ‘non-familial' (non-AC1) CRC cases. Methods: From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression. Results: Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage. Conclusions: FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) is a newly described, rare autosomal dominant syndrome, characterized by fundic gland polyposis with occasional hyperplastic and adenomatous polyps. We diagnosed GAPPS in a large Australian (Family 1) and two smaller North American families (Family 2 and 3). Mutations in APC, MUTYH, CDH1, SMAD4, BMPR1A, STK11 and PTEN were excluded in all families by sequence analysis of exons and flanking regions, as well as by assays for deletion or duplication of exons. We mapped the GAPPS gene in Family 1 by linkage analysis (LOD score 4.21) to a 20Mb region which contains about 60 genes. Short tandem repeat genotyping showed that the affected members of Family 2 share a haplotype in this 20Mb region, but analysis of Affymetrix SNP 6.0 data from three affected members of Family 2 showed that they also shared several other regions of the genome. However, both Family 2 and 3 are too small for definitive linkage analysis. We have carried out full exome sequencing for three affected individuals in Family 1 (and targeted sequencing of the linked region in another individual), and of three affected members of Family 2. We did not find any rare coding or splice site variants in the linked region that were shared by all affected members of Family 1; nor any from the same region in both affected members of Family 2. All coding exons and miR genes in the linked region have been sequenced at least 30X at every base, or by Sanger sequencing, except for seven exons for which Sanger sequencing is yet to be completed. We will also use Sanger sequencing to improve the coverage of exons in the linked region in Family 2. However, our current hypothesis is that non-coding mutations in the linked region are responsible for the GAPPS syndrome in both Families 1 and 2 and so whole genome sequence analysis for two affected members in Family 1 has been performed and analysis is underway.

Objective Pirfenidone (Deskar, Marnac Inc., Dallas, TX), 5-methyl-1-phenyl-2-(1H)-pyridone, is a broad-spectrum, noncytotoxic, oral antifibrotic agent that is reported to inhibit or block the action of cytokine growth factors: transforming growth factor β1, platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor, and to prevent formation of new fibrotic lesions. Methods We enrolled 10 women and four men with extensive familial adenomatous polyposis (FAP)-associated desmoid disease in a 2-yr open-label treatment trial with oral pirfenidone. Imaging of desmoids was conducted at baseline and 6, 12, and 24 months. Results No drug toxicity or drug intolerance was encountered. Seven patients dropped out (three because of progressive disease), and seven continued for at least 18 months. Of those that continued, two had partial but significant reduction in the size of all desmoids beginning in the first 6 months of treatment, and two others experienced relief of symptoms without change in desmoid size. Three patients experienced no change in tumor size or symptoms. Conclusion Pirfenidone is well tolerated by patients with FAP-associated desmoid tumors. Some patients with FAP/desmoid tumors treated with pirfenidone had regression of tumors, some had progression, and some had no response. Patients with rapidly growing tumors did not respond to pirfenidone. A placebo-controlled trial is needed to determine whether there is a subset of patients for whom pirfenidone may result in partial shrinkage of desmoid tumors, because the natural history of desmoid tumors is not predictable or understood.

Methods We studied 167 MLH1 and 225 MSH2 mutation-carrying families comprising 17,352 members from the Colon Cancer Family Registry. Probands were recruited either because they had a family history of cancer (n=274) or from cancer registries independently of family history (n=118). Hazard ratios (HRs) of cancer risks for carriers compared with the general population and age-specific cumulative risks for carriers (penetrance) were estimated using modified segregation analysis conditioned on ascertainment. Heterogeneity in risks for carriers was modelled with a polygenic risk modifier (as in the BOADICEA model).

Background It is known that metachronous colorectal cancer risk for Lynch syndrome patients with primary colon cancer is high and total colectomy is the preferred option [1]. However if the index primary cancer is in the rectum, management advice is complicated by considerations of worsening bowel function or stoma formation. To aid surgical decision-making, we estimated the risk of metachronous colon cancer for Lynch syndrome patients who underwent either anterior resection or abdominoperineal resection for primary rectal cancer.

3538 Background: Lynch syndrome is caused by a germ-line mutation in a DNA mismatch repair (MMR) gene. Carriers are at high risks of colorectal (CRC), endometrial and some other cancers. To date, t...

1521 Background: Women with an inherited mutation in a mismatch repair (MMR) gene have a substantially increased risk of endometrial cancer (EC) during their lifetime. In the general population, ri...

3515 Background: Appropriate surgical management of colorectal cancers (CRC) in Lynch syndrome patients, i.e., carriers of a mutation in a mismatch repair (MMR) gene, is still controversial. The de...

1501 Background: Lynch syndrome, a hereditary cancer syndrome characterized by germline mutations in mismatch repair (MMR) genes, is associated with an elevated lifetime risk of cancer development, predominantly endometrial, colorectal and ovarian. To date, no increased risk of cervical cancer for mutation carriers has been reported. Methods: Families with an identified pathologic mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2 were obtained from Colon Cancer Family Registry (Australasia, USA and Canada). Families were ascertained via a population- based colorectal cancer case or via family cancer clinics. Attempts were made to obtain pathology reports for cases of cervical cancer. Modified segregation analyses incorporating rigorous corrections for ascertainment were used to estimate relative and cumulative risks of cervical cancer for mutation carriers. Binomial tests and t-tests and were used to compare observed histology and ages of diagnosis to population norms. Results: A total of 66 cases...