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Background: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts., Methods: After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion., Results: We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2., Conclusion: After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objective: The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO) 2010 clinical criteria and by colorectal cancer (CRC)., Method: A retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry. Univariate and multivariate logistic regression modelling was used to determine the association between risk factors and SPS and risk factors associated with CRC in SPS., Results: Female biological sex (odds ratio (OR) = 4.54; 95%Confidence interval (CI) = 2.77-7.45), increasing body mass index (BMI) at age 20 years (OR = 1.09; 95%CI = 1.04-1.13), hormone replacement therapy (OR = 0.44; 95%CI = 0.20.98), and increasing weekly folate intake (OR = 0.82; 95%CI = 0.75-0.90) were associated with SPS by multivariate analysis. Increasing weekly calcium intake (OR = 0.79; 95%CI = 0.64-0.97) and smoking > 10 cigarettes daily (OR = 0.45; 95%CI = 0.23-0.86) were associated with WHO criterion I only. The consumption of 1-100 g of alcohol per week (OR = 0.39; 95%CI = 0.18-0.83) was associated with WHO criterion III only. Smoking 1-5 cigarettes daily (OR = 2.35; 95%CI = 1.09-5.05), weekly non-steroidal anti-inflammatory drug (NSAIDs) intake (OR = 0.88; 95%CI = 0.78-0.99), and increased height (OR = 1.09; 95% = 1.05-1.13), were associated with SPS fulfilling both WHO criteria I and III. Moreover, weekly NSAIDs intake (OR = 0.81; 95%CI = 0.67-0.98) was associated with a reduced likelihood of CRC in SPS., Conclusion: We identified novel risk and potential protective factors associated with SPS, some specific for certain WHO 2010 criteria. Weekly use of NSAIDs may reduce the risk of CRC in people with SPS., (© 2022. The Author(s).)

The Asia-Pacific region has the largest number of cases of colorectal cancer (CRC) and one of the highest levels of mortality due to this condition in the world. Since the publishing of two consensus recommendations in 2008 and 2015, significant advancements have been made in our knowledge of epidemiology, pathology and the natural history of the adenoma-carcinoma progression. Based on the most updated epidemiological and clinical studies in this region, considering literature from international studies, and adopting the modified Delphi process, the Asia-Pacific Working Group on Colorectal Cancer Screening has updated and revised their recommendations on (1) screening methods and preferred strategies; (2) age for starting and terminating screening for CRC; (3) screening for individuals with a family history of CRC or advanced adenoma; (4) surveillance for those with adenomas; (5) screening and surveillance for sessile serrated lesions and (6) quality assurance of screening programmes. Thirteen countries/regions in the Asia-Pacific region were represented in this exercise. International advisors from North America and Europe were invited to participate., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants., Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path&#95;MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path&#95;MMR carriers who were first- or second-degree relatives of Lynch syndrome probands., Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path&#95;MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path&#95;MSH2 50% and 39%; for path&#95;MSH6 13% and 17% and for path&#95;PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups., Conclusions: Prospectively observed CRC incidences (PLSD) in path&#95;MLH1 and path&#95;MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path&#95;MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path&#95;PMS2 carriers subjected to colonoscopy, but not significantly so., (© 2022. The Author(s).)

Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Genetics of Colonic Polyposis Study who had a rare germline AXIN2 gene variant identified from either clinical multi-gene panel testing (n=2) or from whole genome/exome sequencing (n=2). Variant segregation in relatives and characterisation of tumour tissue were performed where possible. Four different germline pathogenic variants in AXIN2 were identified in four families. Five of the seven carriers of the c.1049delC, p.Pro350Leufs*13 variant, two of the six carriers of the c.1994dupG, p.Asn666Glnfs*41 variant, all three carriers of c.1972delA, p.Ser658Alafs*31 variant and the single proband carrier of the c.2405G>C, p.Arg802Thr variant, which creates an alternate splice form resulting in a frameshift mutation (p.Glu763Ilefs*42), were affected by CRC and/or polyposis. Carriers had a mean age at diagnosis of CRC/polyposis of 52.5 ± 9.2 years. Colonic polyps were typically pan colonic with counts ranging from 5 to >100 (median 12.5) comprising predominantly adenomatous polyps but also serrated polyps. Two CRCs from carriers displayed evidence of a second hit via loss of heterozygosity. Oligodontia was observed in carriers from two families. Germline AXIN2 pathogenic variants from four families were associated with CRC and/or polyposis in multiple family members. These findings support the inclusion of AXIN2 in CRC and polyposis multigene panels for clinical testing., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: This review evaluated the utility of single quantitative faecal immunochemical test (FIT) as a triaging tool for patients with symptoms of possible colorectal cancer, the effect of symptoms on FIT accuracy, and the impact of triaging incorporating FIT on service provision., Methods: Five databases were searched. Meta-analyses of the extracted FIT sensitivities and specificities for detection of colorectal cancer at reported f-Hb thresholds were performed. Secondary outcomes included sensitivity and specificity of FIT for advanced colorectal neoplasia and serious bowel disease. Subgroup analysis by FIT brand and symptoms was undertaken., Results: Fifteen prospective cohort studies, including 28 832 symptomatic patients were included. At the most commonly reported f-Hb positivity threshold of ≥ 10 µg Hb/g faeces (n=13), the summary sensitivity was 88.7% (95% c.i. 85.2 to 91.4) and the specificity was 80.5% (95% c.i. 75.3 to 84.8) for colorectal cancer. At lower limits of detection of ≥ 2 µg Hb/g faeces, the summary sensitivity was 96.8% (95% c.i. 91.0 to 98.9) and the specificity was 65.6% (95% c.i. 59.0 to 71.6). At the upper f-Hb positivity thresholds of ≥ 100 µg Hb/g faeces and ≥ 150 µg Hb/g faeces, summary sensitivities were 68.1% (95% c.i. 59.2 to 75.9) and 66.3% (95% c.i. 52.2 to 78.0), with specificities of 93.4% (95% c.i. 91.3 to 95.1) and 95.1% (95% c.i. 93.6 to 96.3) respectively. FIT sensitivity was comparable between different assay brands. FIT sensitivity may be higher in patients reporting rectal bleeding., Conclusion: Single quantitative FIT at lower f-Hb positivity thresholds can adequately exclude colorectal cancer in symptomatic patients and provides a data-based approach to prioritization of colonoscopy resources., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: Colorectal cancer (CRC) is rising in incidence in young adults, and this observation is currently unexplained. We investigated whether having a personal history of type 2 diabetes mellitus (T2D) was a potential risk factor for young-onset colorectal cancer (YOCRC)., Methods: The South Australian Young Onset (SAYO) CRC study is a series of young adults with CRC below age 55. Ninety unrelated YOCRC cases were recruited to the study. Personal history and detailed family history of T2D were obtained at face-to-face interview and confirmed from medical records. Whole exome sequencing was conducted on germline DNA from each CRC case. Controls for personal history studies of T2D were 240 patients with proven clear colonoscopies and no known CRC predispositions., Results: The median age of YOCRC cases was 44 years (18-54) and of controls was 45 years (18-54), and 53% of both cases and controls were females (P = 0.99). Left-sided (distal) CRC was seen in 67/89 (75%) of cases. A personal history of T2D was confirmed in 17/90 (19%) YOCRC patients compared with controls (12/240, 5%; P < 0.001; odds ratio = 4.4; 95% confidence interval, 2.0-9.7). YOCRC patients frequently reported at least one first-degree relative with T2D (32/85, 38%). Ten of 87 (12%) of YOCRC cases had CRC-related pathogenic germline variants, however, no pathogenic variants in familial diabetes-associated genes were seen., Conclusions: Though the mechanism remains unclear, our observations suggest that there is enrichment for personal history of T2D in YOCRC patients., Impact: A diagnosis of T2D could therefore potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate., (© 2020 John Wiley & Sons Australia, Ltd.)

Background & Aims: Lynch syndrome is the most common inherited cause of colorectal cancer (CRC). Contemporary and mutation-specific estimates of CRC-risk in patients undergoing colonoscopy would optimize surveillance strategies. We performed a prospective national cohort study, using data from New Zealand, to assess overall and mutation-specific risk of CRC in patients with Lynch syndrome undergoing surveillance., Methods: We performed a prospective study of 381 persons with Lynch syndrome in New Zealand (98 with Lynch-syndrome associated variants in MLH1, 159 in MSH2, 103 in MSH6, and 21 in PMS2). Participants were offered annual colonoscopy starting at age 25 y, and those who underwent 2 or more colonoscopies before December 31, 2017 were included in the final analysis. Patients with previous colonic resection, history of CRC or diagnosis of CRC at index colonoscopy were excluded., Results: Study participants underwent 2061 colonoscopies during 2296 person-y; the median observation-period was 4.43 y and mean-age at enrollment was 43 y. Eighteen patients developed CRC (8 with variants in MLH1, 8 in MSH2, and 2 in MSH6) after a median follow-up period of 6.5 y (range 1-16 y). Eighty-three percent of patients had a surveillance colonoscopy in preceding 24 months before diagnosis of CRC; 94% were diagnosed with stage 0-II CRC and there was no CRC-related mortality. The overall-risk of developing CRC in the 5 y after first surveillance colonoscopy was 2.49% (95% CI, 1.18-5.23); cumulative risks for CRC in patients with Lynch syndrome-associated variants in MLH1, MSH2, or MSH6 by age 70 y were 17.7%, 17.8%, and 8.5%, respectively. Age-adjusted CRC-risk in patients with variants in MSH6 was lower than in MLH1 (hazard ratio, 0.2; 95% CI, 0.04-0.94; P = .02). Of patients with CRC, 33% had an adenomatous polyp resected from same segment in which a colorectal tumor later developed., Conclusions: The risk of CRC in patients with Lynch syndrome-associated mutations in MSH6 or PMS2 was significantly lower than in patients with mutations in MLH1. Incomplete adenomatous polyp resection might be responsible for one third of surveillance-detected CRCs., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Colorectal cancer (CRC) diagnosed at <50 years is predominantly located in the distal colon and rectum. Little is known about which lesion subtypes may serve as CRC precursors in young adults. The aim of this work was to document the prevalence and histological subtype of lesions seen in patients aged <50 years, and any associated clinical features., Methods: An audit of the colonoscopy database at The Queen Elizabeth Hospital in Adelaide, South Australia over a 12-month period was undertaken. Findings were recorded from both colonoscopy reports and corresponding histological examination of excised lesions., Results: Data were extracted from colonoscopies in 2064 patients. Those aged <50 comprised 485 (24%) of the total. CRC precursor lesions (including sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas, tubular adenomas ≥10 mm or with high-grade dysplasia, and conventional adenomas with villous histology) were seen in 4.3% of patients aged <50 and 12.9% of patients aged ≥50 (P <0.001). Among colonoscopies yielding CRC precursor lesions in patients under 50 years, SSA/P occurred in 52% of procedures (11/21), compared with 27% (55/204) of procedures in patients aged 50 and older (P = 0.02). SSA/P were proximally located in (10/11) 90% of patients aged under 50, and 80% (43/54) of those aged 50 and older (P = 0.46)., Conclusions: SSA/P were the most frequently observed CRC precursor lesions in patients aged <50. Most CRCs in this age group are known to arise in the distal colon and rectum suggesting that lesions other than SSA/P may serve as the precursor for the majority of early-onset CRC.

Background: Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC) and an evolving management approach. The aims of this study were to assess the polyp burden reduction over time, and the incidence of CRC in serrated polyposis patients undergoing community surveillance., Methods: This is an observational study based on prospectively collected data. A total of 96 SPS patients with no personal history of CRC were prospectively enrolled in a surveillance program under the guidance of a tertiary center. Patients underwent surveillance colonoscopy in multiple centres across New Zealand., Results: Patients underwent a median of four colonoscopies with a median interval of 15 months over a median follow-up period of 4.8 years. Five of 96 patients (5%) were referred for surgery, and the remaining 91 were managed by colonoscopy alone. In patients referred for surgery, 92% of the surveillance intervals to the fourth colonoscopy had been ≤12 months compared to 33% (P<0.001) in the colonoscopy only group, and all five (100%) had ≥20 pancolonic polyps after four procedures compared with only 5/91 (5%) in those managed by colonoscopy alone. In patients successfully managed by colonoscopy, 86% had <10 pancolonic polyps, >75% no longer had polyps ≥10mm and >90% no longer had proximal serrated polyps ≥10mm after the fourth colonoscopy. No patients were found to develop CRC during the study time period., Conclusions: Patients with SPS were managed by proactive surveillance colonoscopy in wider hospital settings under tertiary centre guidance, with only 5% requiring surgical management. No CRC was diagnosed in any patient during surveillance., Competing Interests: Dr Burt reports personal fees from Thetis Pharma outside the submitted work.

Background: People with germline mutation in one of the DNA mismatch repair (MMR) genes have increased colorectal cancer risk. For these high-risk people, study findings of the relationship between alcohol consumption and colorectal cancer risk have been inconclusive. Methods: 1,925 MMR gene mutations carriers recruited into the Colon Cancer Family Registry who had completed a questionnaire on lifestyle factors were included. Weighted Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between alcohol consumption and colorectal cancer. Results: Colorectal cancer was diagnosed in 769 carriers (40%) at a mean (SD) age of 42.6 (10.3) years. Compared with abstention, ethanol consumption from any alcoholic beverage up to 14 g/day and >28 g/day was associated with increased colorectal cancer risk (HR, 1.50; 95% CI, 1.09-2.07 and 1.69; 95% CI, 1.07-2.65, respectively; P trend = 0.05), and colon cancer risk (HR, 1.78; 95% CI, 1.27-2.49 and 1.94; 95% CI, 1.19-3.18, respectively; P trend = 0.02). However, there was no clear evidence for an association with rectal cancer risk. Also, there was no evidence for associations between consumption of individual alcoholic beverage types (beer, wine, spirits) and colorectal, colon, or rectal cancer risk. Conclusions: Our data suggest that alcohol consumption, particularly more than 28 g/day of ethanol (∼2 standard drinks of alcohol in the United States), is associated with increased colorectal cancer risk for MMR gene mutation carriers. Impact: Although these data suggested that alcohol consumption in MMR carriers was associated with increased colorectal cancer risk, there was no evidence of a dose-response, and not all types of alcohol consumption were associated with increased risk. Cancer Epidemiol Biomarkers Prev; 26(3); 366-75. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Background and Aim: We conducted a systematic review and meta-analysis to identify personal, lifestyle, and tumor-related risk factors for metachronous colorectal cancer (CRC) and polyp., Methods: Relevant studies were identified by searching MEDLINE, Web of Science and Cochrane Central Register through 15 May 2016. Estimates for associations were summarized using random effects models., Results: Fifty-five studies were included in the review. For individuals who had a CRC resection, having a synchronous polyp was a risk factor for metachronous CRC or polyp (relative risk [RR], 2.04; 95% confidence interval [CI], 1.48-2.82) and having a synchronous CRC (RR, 1.90; 95% CI, 1.25-2.91) and proximally located CRC (RR, 2.12; 95% CI, 1.24-3.64) were risk factors for metachronous CRC. For individuals who had a polypectomy, larger size (RR, 4.26; 95% CI, 2.11-8.57) or severe dysplasia of the initial polyp (RR, 5.15; 95% CI, 2.02-13.14), and having a synchronous polyp (RR, 2.52; 95% CI, 1.35-4.73) were risk factors for metachronous CRC; and a family history of CRC (RR, 1.90; 95% CI, 1.26-2.87), having a synchronous polyp (RR, 2.47; 95% CI, 1.74-3.50) and a larger size (RR, 1.49; 95% CI, 1.03-2.15) and proximal location of the initial polyp (RR, 1.20; 95% CI, 1.02-1.40) were risk factors for metachronous polyp. Meta-regression showed duration of follow-up was not a source of heterogeneity for most associations. There was no evidence that lifestyle factors were associated with metachronous CRC or polyp risk., Conclusion: A comprehensive list of risk factors identified for metachronous CRC or polyp may have important clinical implications., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Purpose/objectives: To ascertain individual experiences of extended bowel resection as treatment for colorectal cancer (CRC) in those with a high metachronous CRC risk, including the self-reported adequacy of information received at different time points of treatment and recovery.
., Research Approach: Qualitative.
., Setting: Participants were recruited through the Australasian Colorectal Cancer Family Registry and two hospitals in Melbourne, Australia.
., Participants: 18 individuals with a high metachronous CRC risk who had an extended bowel resection from 6-12 months ago.
., Methodologic Approach: Semistructured interviews. Data were analyzed thematically.
., Findings: In most cases, the treating surgeon decided on the best option regarding surgical treatment. Participants felt well informed about the surgical procedure. Information related to surgical outcomes, recovery, and lifestyle adjustment from surgery was not always adequate. Many participants described ongoing worry about developing another cancer. 
., Conclusions: Patients undergoing an extended resection to reduce metachronous CRC risk require detailed information delivered at more than one time point and relating to several different aspects of the surgical procedure and its outcomes.
., Interpretation: An increased emphasis should be given to the provision of patient information on surgical outcomes, recovery, and lifestyle adjustment. Colorectal nurses could provide support for some of the reported unmet needs.

Background: New screening tests for colorectal cancer continue to emerge, but the evidence needed to justify their adoption in screening programs remains uncertain., Methods: A review of the literature and a consensus approach by experts was undertaken to provide practical guidance on how to compare new screening tests with proven screening tests., Results: Findings and recommendations from the review included the following: Adoption of a new screening test requires evidence of effectiveness relative to a proven comparator test. Clinical accuracy supported by programmatic population evaluation in the screening context on an intention-to-screen basis, including acceptability, is essential. Cancer-specific mortality is not essential as an endpoint provided that the mortality benefit of the comparator has been demonstrated and that the biologic basis of detection is similar. Effectiveness of the guaiac-based fecal occult blood test provides the minimum standard to be achieved by a new test. A 4-phase evaluation is recommended. An initial retrospective evaluation in cancer cases and controls (Phase 1) is followed by a prospective evaluation of performance across the continuum of neoplastic lesions (Phase 2). Phase 3 follows the demonstration of adequate accuracy in these 2 prescreening phases and addresses programmatic outcomes at 1 screening round on an intention-to-screen basis. Phase 4 involves more comprehensive evaluation of ongoing screening over multiple rounds. Key information is provided from the following parameters: the test positivity rate in a screening population, the true-positive and false-positive rates, and the number needed to colonoscope to detect a target lesion., Conclusions: New screening tests can be evaluated efficiently by this stepwise comparative approach., (© 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

The average age at diagnosis for colorectal cancer (CRC) in Australia is 69, and the age-specific incidence rises rapidly after age 50 years. The incidence has stabilized or is declining in older age groups in Australia during recent decades, possibly related to the increased uptake of screening and high-risk surveillance. In the same time frame, a rising incidence of CRC in younger adults has been well-documented in the United States. This rise in incidence in the young has not been reported from other countries that share long-term exposure to westernised urban lifestyles. Using data from the Australian Institute of Health and Welfare, we examined trends in national incidence rates for CRC under age 50 years and observed that rates in people under age 40 years have been rising for the last two decades. We further performed a review of the literature regarding CRC in young adults to outline the extent of current understanding, explore potential risk factors such as obesity, alcohol, and sedentary lifestyles, and to identify the questions remaining to be addressed. Although absolute numbers might not justify a population screening approach, the dispersal of young adults with CRC across the primary health-care system decreases probability of their recognition. Patient and physician awareness, aided by stool and emerging blood-screening tests and risk profiling tools, have the potential to aid in identification of those young adults who would most benefit from a colonoscopy through early detection of CRCs or by removal of advanced polyps., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: There is controversy regarding the optimum surgical treatment of patients presenting with colorectal cancer with known or suspected genetic cancer syndromes. Although standard segmental resection may be curative, a high risk of metachronous malignancy leads many to advocate extended surgery. The current study was designed to assess whether or not extended surgery adversely impacts quality of life compared to segmental surgery., Methods: Records at The Royal Melbourne Hospital Family Cancer Clinic were searched in order to identify patients with suspected high risk familial colon cancer. Patients who underwent surgery were identified and mailed two Standardized Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-CR38)., Results: Fifty respondents met the inclusion criteria. None of the 15 patients whose primary operation was an extended procedure developed a metachronous cancer. Seventeen of the 35 (48.67%) who had an initial segmental resection had subsequent surgery for metachronous cancer. At the time of the questionnaire, 27 had extended surgery and 23 had segmental operations. The overall global health status and quality of life was very similar between the two groups., Conclusion: This study confirms that there is a high rate of metachronous cancer for patients undergoing segmental resection for hereditary colon cancer. Quality of life following either segmental or extended resection is not significantly different. Consequently, it is reasonable to recommend extended surgery for most patients with high risk hereditary colon cancer., (© 2013 Royal Australasian College of Surgeons.)

Mismatch repair-deficient breast cancers may be identified in Lynch syndrome mutation carriers, and have clinicopathological features in common with mismatch repair-deficient colorectal and endometrial cancers such as tumour-infiltrating lymphocytes and poor differentiation. Mismatch repair-deficient colorectal cancers frequently show mucinous differentiation associated with upregulation of chromosome 11 mucins. The aim of this study was to compare the protein expression of these mucins in mismatch repair-deficient and -proficient breast cancers. Cases of breast cancer (n=100) were identified from families where (1) both breast and colon cancer co-occurred and (2) families met either modified Amsterdam criteria or had at least one early-onset (<50 years) colorectal cancer. Tumour sections were stained for the epithelial mucins, MUC2, MUC5AC, MUC5B and MUC6, and the homeobox protein CDX2, a regulator of MUC2 expression. In all, 16 mismatch repair-deficient Lynch syndrome breast cancers and 84 non-Lynch breast cancers were assessed for altered mucin expression. No significant difference in the expression of MUC2, MUC5AC or MUC6 was observed between the mismatch repair-deficient and mismatch repair-proficient breast cancers; however, there was a trend for mismatch repair-deficient tumours to express high levels of MUC5B less frequently (P=0.07, OR=0.2 (0.0-1.0)). Co-expression of two or more gel-forming mucins was common. Ectopic expression of CDX2 was associated with expression of MUC2 (P=0.035, OR=8.7 (1.3-58.4)). Mismatch repair-deficient breast cancers do not show differential expression of the mucins genes on chromosome 11 when compared with mismatch repair-proficient breast cancers, in contrast with mismatch repair-deficient colorectal and endometrial cancers, which frequently have increased mucin protein expression when compared with their mismatch repair-proficient counterparts. In addition, ectopic CDX2 expression is positively associated with de novo MUC2 expression.

Background: Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a proctectomy for index rectal cancer., Methods: This retrospective cohort study comprised 79 carriers of germline mutation in a MMR gene (18 MLH1, 55 MSH2, 4 MSH6, and 2 PMS2) from the Colon Cancer Family Registry who had had a proctectomy for index rectal cancer. Cumulative risks of metachronous colon cancer were calculated using the Kaplan-Meier method., Results: During median 9 years (range 1-32 years) of observation since the first diagnosis of rectal cancer, 21 carriers (27 %) were diagnosed with metachronous colon cancer (incidence 24.25, 95 % confidence interval [CI] 15.81-37.19 per 1,000 person-years). Cumulative risk of metachronous colon cancer was 19 % (95 % CI 9-31 %) at 10 years, 47 (95 % CI 31-68 %) at 20 years, and 69 % (95 % CI 45-89 %) at 30 years after surgical resection. The frequency of surveillance colonoscopy was 1 colonoscopy per 1.16 years (95 % CI 1.01-1.31 years). The AJCC stages of the metachronous cancers, where available, were 72 % stage I, 22 % stage II, and 6 % stage III., Conclusions: Given the high metachronous colon cancer risk for MMR gene mutation carriers diagnosed with an index rectal cancer, proctocolectomy may need to be considered.

KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O(6)-methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wild-type carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; P<0.001), demonstrated mucinous differentiation (46 vs 31%; P=0.001) and were associated with different MSI status (P<0.001) and with MGMT methylation (47 vs 21%; P=0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P=0.001), mucinous differentiation (46 vs 25%; P<0.001), presence of a contiguous polyp (38 vs 22%; P<0.001), MGMT methylation (47 vs 26%; P=0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P=0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P=0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.

We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available., (© 2012 Wiley Periodicals, Inc.)

Muir-Torre syndrome is a variant of Lynch syndrome, characterised by sebaceous neoplasia and/or keratoacanthomas associated with visceral malignancies. Muir-Torre syndrome is caused by germline mutations of one of the mismatch repair genes, frequently MSH2 and less frequently MLH1 and MSH6. Visceral malignancies associated with Muir-Torre syndrome and Lynch syndrome include colorectal, endometrial and other gastrointestinal, urological and gynaecological malignancies. Small numbers of Lynch syndrome-associated soft tissue sarcomas have been reported, but there are no reported cases of soft tissue sarcomas in Muir-Torre syndrome. In this study, we report a 74-year-old man with known Muir-Torre syndrome with confirmed MSH2 germline mutation, diagnosed with pleomorphic liposarcoma of the right buttock in a previous radiation field. The tumour showed loss of expression of MSH2 and MSH6 on immunohistochemistry. Immunohistochemistry on another pleomorphic liposarcoma in a different patient with no previous history of Muir-Torre syndrome or Lynch syndrome showed no loss of expression of mismatch repair proteins. This is the first report of Muir-Torre syndrome-associated sarcoma and the first case of post-radiation sarcoma in Lynch syndrome.

Aim: To estimate the colonoscopy burden of introducing population screening for colorectal cancer in New Zealand., Methods: Screening for colorectal cancer using biennial immunochemical faecal occult blood tests offered to people aged 50-74 years of age was modelled using population estimates from Statistics New Zealand for 2011-2031. Modelling to determine colonoscopy requirements was based on participation and test positivity rates from published results of screening programmes. Estimates of the number of procedures required for ongoing adenoma surveillance were calculated using screening literature results of adenoma yield, and New Zealand Guidelines for Adenoma Surveillance. Sensitivity analysis was undertaken on key parameters., Results: For a test positivity of 6.4%, biennial screening using immunochemical faecal occult blood testing with a 60% participation rate, would require 18,000 colonoscopies nationally, increasing to 28,000 by 2031. The majority of procedures are direct referrals from a positive FOBT, with surveillance colonoscopy numbers building over time., Conclusion: Colonoscopy requirements for immunochemical faecal occult blood based population screening for colorectal cancer are high. Significant expansion of services is required and careful management of surveillance procedures to ensure timely delivery of initial colonoscopies whilst maintaining symptomatic services. A model re-run informed by data from the screening pilot will allow improved estimates for the New Zealand setting.

Debate continues as to the usefulness of assessing adenomas for loss of mismatch repair protein expression to identify individuals with suspected Lynch syndrome. We tested 109 polyps from 69 proven mutation carriers (35 females and 34 males) belonging to 49 Lynch syndrome families. All polyps were tested by immunohistochemistry for four mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. Detailed pathology review was performed by specialist gastrointestinal pathologists. The majority of polyps (86%) were conventional adenomas (n=94), with 65 tubular and 28 tubulovillous adenomas and a single villous adenoma. The remaining 15 lesions (14%) were serrated polyps. Overall, loss of mismatch repair expression was noted for 78/109 (72%) of polyps. Loss of mismatch repair expression was seen in 74 of 94 (79%) conventional adenomas, and 4 of 15 (27%) serrated polyps from mismatch repair gene mutation carriers. In all instances, loss of expression was consistent with the underlying germline mutation. Mismatch repair protein expression was lost in 27 of 29 adenomas with a villous component compared with 47 of 65 adenomas without this feature (93 vs 73%; P=0.028). A strong trend was observed for high-grade dysplasia. Mismatch repair deficiency was observed in 12 of 12 conventional adenomas with high-grade dysplasia compared with 60 of 79 with low-grade dysplasia (100 vs 76%; P=0.065). We were unable to demonstrate a significant association between conventional adenoma size or site and mismatch repair deficiency. All (4/4 or 100%) of the serrated polyps demonstrating mismatch repair deficiency were traditional serrated adenomas from a single family. Diagnostic testing of adenomas in suspected Lynch syndrome families is a useful alternative in cases where cancers are unavailable. The overwhelming majority of conventional adenomas from mutation carriers show loss of mismatch repair protein expression concordant with the underlying germline mutation.

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 loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) 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 assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). 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 previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated.

Background: Surgical management of colon cancer for patients with Lynch syndrome who carry a mismatch repair (MMR) gene mutation is controversial. The decision to remove more or less of the colon involves the consideration of a relatively high risk of metachronous colorectal cancer (CRC) with the impact of more extensive surgery., Objective: To estimate and compare the risks of metachronous CRC for patients with Lynch syndrome undergoing either segmental or extensive (subtotal or total) resection for first colon cancer., Design: Risk of metachronous CRC was estimated for 382 MMR gene mutation carriers (172 MLH1, 167 MSH2, 23 MSH6 and 20 PMS2) from the Colon Cancer Family Registry, who had surgery for their first colon cancer, using retrospective cohort analysis. Age-dependent cumulative risks of metachronous CRC were calculated using the Kaplan-Meier method. Risk factors for metachronous CRC were assessed by a Cox proportional hazards regression., Results: None of 50 subjects who had extensive colectomy was diagnosed with metachronous CRC (incidence rate 0.0; 95% CI 0.0 to 7.2 per 1000 person-years). Of 332 subjects who had segmental resections, 74 (22%) were diagnosed with metachronous CRC (incidence rate 23.6; 95% CI 18.8 to 29.7 per 1000 person-years). For those who had segmental resections, incidence was statistically higher than for those who had extensive surgery (P <0.001). Cumulative risk of metachronous CRC was 16% (95% CI 10% to 25%) at 10 years, 41% (95% CI 30% to 52%) at 20 years and 62% (95% CI 50% to 77%) at 30 years after segmental colectomy. Risk of metachronous CRC reduced by 31% (95% CI 12% to 46%; p=0.002) for every 10 cm of bowel removed., Conclusions: Patients with Lynch syndrome with first colon cancer treated with more extensive colonic resection have a lower risk of metachronous CRC than those receiving less extensive surgery. This finding will better inform decision-making about the extent of primary surgical resection.

Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.

Objective: To investigate the association of body mass index (BMI) in early adulthood and endometrial cancer risk for carriers of a germline mutation in a DNA mismatch repair gene., Methods: We estimated the association between BMI at age 18-20 years and endometrial cancer risk for mismatch repair gene mutation carriers and, as a comparison group, noncarriers using 601 female carriers of a germline mutation in a mismatch repair gene (245 MLH1, 299 MSH2, 38 MSH6, and 19 PMS2) and 533 female noncarriers from the Colon Cancer Family Registry using a weighted Cox proportional hazards regression., Results: During 51,693 person-years of observation, we observed diagnoses of endometrial cancer for 126 carriers and eight noncarriers. For carriers, there was no evidence of an association between BMI at age 20 years and endometrial cancer (adjusted hazard ratio 0.73 per 5 kg/m²; 95% confidence interval [CI], 0.40-1.34; P=.31). For noncarriers, endometrial cancer risk increased by 74% for each 5-kg/m² increment in BMI (adjusted hazard ratio 1.74; 95% CI 1.27-2.37; P<.001). The hazard ratio for BMI and endometrial cancer for noncarriers was greater than for carriers (P=.04)., Conclusion: The effect of body mass on endometrial cancer risk depends on the woman's mismatch repair gene mutation carrier status, suggesting obesity-independent endometrial carcinogenesis for carriers., Level of Evidence: II.

Background: New Zealand (NZ) has a high incidence of colorectal cancer (CRC). Maori have a documented incidence that is approximately half that found in NZ Europeans, possibly the result of under-reporting., Aim: To determine and compare the prevalence of colorectal adenomas in Maori and NZ European patients., Methods: Colonoscopy records from the Middlemore Colonoscopy Audit Database between 1 July 2001 and 31 December 2005 were reviewed. Studies performed for indications associated with an increased risk of colorectal polyps were excluded from the analysis. Patient demographics, including self-identified ethnicity, and number and location of colonic polyps were recorded. All polyp histology was reviewed., Results: Data was analysed from 2842 colonoscopies--2523 were NZ Europeans (mean age 67 yrs) and 319 were Maori patients (mean age 60.6 yrs). To adjust for age, a comparison of data between 40 and 59 years was undertaken. In 643 (81.2%) NZ Europeans, polyps were identified in 213 (33.1%). In the 149 (18.8%) Maori patients, polyps were identified in 35 (23.5%) p=0.029. The comparative rates of adenomas in NZ Europeans and Maori were 16.7% and 8.7% respectively (p=0.019; 8% difference, CI=2.3-13.9%)., Conclusion: The prevalence of colorectal adenomas in Maori is approximately half that found in NZ Europeans. This mirrors the reported difference in CRC incidence between these groups and lends support to this being a real finding and not a bias in the manner in which the data has been collected.

Objective: Hyperplastic polyposis is a colonic polyposis condition of unknown aetiology. The purpose of this study was to examine the spectrum of phenotypic variation in patients with multiple serrated polyps as a basis for gene discovery., Methods: One hundred and twenty-six patients with multiple (> or = 5) serrated polyps were recruited to the study. Polyp counts were extracted from histology and colonoscopy reports. Ethnicity was self-reported. Family history of cancer data were derived from pedigrees. Ascertainment status was classified as either index case or identified by screening., Results: The average reported polyp count was 39. Patients with highest polyp numbers were more likely to be male (P = 0.02). Colorectal cancer (CRC) was identified in 49 of 119 patients (41%) and 28% of these patients had multiple CRC. Young onset patients had higher polyp numbers (P = 0.03) and were more likely to have their CRC in the distal colon (P = 0.02). CRC was significantly associated with the presence of adenomas (P = 0.03). Patients were divided into moderate polyposis (5-79 serrated polyps) and dense polyposis (80 or more) categories. The dense polyposis category was associated with a lack of family history for CRC (P = 0.034) and male gender (P = 0.014), independent of ascertainment status and recruitment site., Conclusion: Multiple serrated polyps were associated with an increased personal risk of CRC. A subset of patients with the highest polyp numbers was more likely to be male and to have no family history of CRC. This result suggests heterogeneous modes of inheritance and has implications for studies investigating the genetic basis of multiple serrated polyps.

Background: Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain., Methods: We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment., Results: For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7)., Conclusion: We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.

The identification of Lynch syndrome has been greatly assisted by the advent of tumour immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and by the recognition of the role of acquired somatic BRAF mutation in sporadic MMR-deficient colorectal cancer (CRC). However, somatic BRAF mutation may also be present in the tumours in families with a predisposition to develop serrated polyps in the colorectum. In a subgroup of affected members in these families, CRCs emerge which demonstrate clear evidence of MMR deficiency with absent MLH1 staining and high-level microsatellite instability (MSI). This may result in these families being erroneously classified as Lynch syndrome, or conversely, an individual is considered "sporadic" due to the presence of a somatic BRAF mutation in a tumour. In this report, we describe two Lynch syndrome families who demonstrated several such inconsistencies. In one family, IHC deficiency of both MSH2 and MLH1 was demonstrated in tumours from different affected family members, presenting a confusing diagnostic picture. In the second family, MLH1 loss was observed in the lesions of both MLH1 mutation carriers and those who showed normal MLH1 germline sequence. Both families had Lynch syndrome complicated by an independently segregating serrated neoplasia phenotype, suggesting that in families such as these, tumour and germline studies of several key members, rather than of a single proband, are indicated to clarify the spectrum of risk.

Aim: The hyperplastic polyposis syndrome (HPS) has been described in a subset of patients with multiple or large hyperplastic polyps. HPS is associated with an increased risk of colorectal cancer (CRC). In this report, we review the presentation and management of a series of individuals with HPS., Methods: From 2001, gastroenterologists, surgeons, and histopathologists at Middlemore Hospital were asked to report cases of HPS. Clinical records were retrospectively reviewed to confirm the number and size of polyps and the age at diagnosis, site of involvement in the colon, and nature of surgical procedures performed in cases with CRC., Results: HPS was identified in 24 patients: 14 females and 10 males. Though 46% of patients attending our gastroenterology department are non-Europeans, all HPS cases had European ancestry. A family history of CRC was identified in four patients (16.6%). All patients had small polyps (<5mm) however 15 (63%) had at least one polyp > or =10 mm, the largest being 45 mm. There were 21 CRCs in 14 patients with a mean age at diagnosis of 61 years. The tumour site was known in 19 CRC, and 16 of these (84%) occurred in the proximal colon. Synchronous cancers were identified in four patients and metachronous tumours in two patients. Twenty-two surgical procedures were performed in 17 patients. Three patients underwent prophylactic surgery due to polyp burden or dysplasia., Conclusion: HPS is rarely encountered but is associated with a significant risk of CRC and is found in the European component of the New Zealand population. Identification of this syndrome has implications regarding management and surveillance for both the individual patient and their first-degree relatives.

Aims: Population screening for colorectal cancer (CRC) in New Zealand is under review and would increase demand for colonoscopy. This National Screening Unit commissioned survey aimed to determine the current level of colonoscopy provision in New Zealand's public hospitals, the gap in demand and provision for diagnostic and surveillance procedures, and factors limiting colonoscopy capacity., Method: A survey, based on the United States SECAP study, was posted to all public endoscopy units within New Zealand in April 2005., Results: The overall survey response rate was 86% (24/28). Only 3 of 7 large centres, and 11 of 17 small centres, are able to offer a diagnostic colonoscopy to patients with symptoms suggestive of CRC within 3 months of referral--and at the time of the survey, 828 patients had been waiting greater than 6 months. The majority (85%) of public hospitals offer surveillance colonoscopy for most indications, and at the time of the survey, 2550 patients had been waiting greater than 6 months. Availability of endoscopy nurses and endoscopists are the main factors limiting colonoscopy provision., Conclusion: In New Zealand's public hospitals a significant gap exists between colonoscopy demand and provision. Population screening for CRC would require a significant increase in colonoscopy capacity to ensure waiting times for symptomatic patients do not increase.

Aim: In 2005 the National Screening Unit of the Ministry of Health appointed a Colorectal Screening Advisory Group to provide independent strategic advice and recommendations on population screening for colorectal cancer (CRC) in New Zealand., Method: Evidence-based review of relevant literature and assessment of CRC screening using the New Zealand Criteria to Assess Screening Programmes., Results: Guaiac faecal occult blood test (FOBTg), immunochemical FOBT (FOBTi), flexible sigmoidoscopy, colonoscopy, and CT colonography were considered. FOBTg is the only test supported by high quality evidence from randomised controlled trials but has limited sensitivity and achieves modest CRC mortality reduction over time. FOBTi has higher analytical sensitivity than FOBTg and would be assumed to achieve greater mortality reduction. A CRC screening programme requires substantial planning and resources. Currently public hospitals cannot deliver timely diagnostic or surveillance colonoscopy., Conclusion: The Advisory Group recommends that a feasibility study of CRC screening using FOBTi be undertaken. This would help determine the performance of the FOBTi in the New Zealand population and whether the New Zealand health system could support an acceptable, effective and economically efficient CRC screening programme. To optimise the diagnosis and treatment of colorectal cancer there is an immediate need to expand colonoscopy services and to ensure that throughout New Zealand the treatment outcomes for CRC, both surgical and oncological, meet international standards.

Aims: The optimal management of familial bowel cancer is thought to involve specialised familial cancer units and registries that facilitate a multidisciplinary approach. We studied the impact this approach had on the investigation and management of affected families in our register., Method: A review of the outcomes of assessment for 25 families was undertaken. These families have completed assessment by the Northern Regional Genetic Service Familial Bowel Cancer Registry because of the possibility of a hereditary bowel cancer syndrome. Details of the cancer history and screening advice known at the time of initial referral to the genetic service, and at the end of assessment, were compared., Results: Detailed family history revealed 130 cancers, 90 of which were known at referral. Eighty-four cancers were confirmed, of which 73 belonged to the spectrum of cancers associated with hereditary nonpolyposis colorectal cancer (HNPCC). The mean age of diagnosis was 56.3 years. Eight families met the modified Amsterdam Criteria for the diagnosis of HNPCC, compared to four families at the time of referral. Familial hyperplastic polyposis was diagnosed in one family. 164 asymptomatic at-risk first-degree relatives were identified, 48 from families who met the Amsterdam criteria and were thereby recommended to have intensive colonoscopic screening., Conclusion: Assessment by the Familial Bowel Cancer Registry increased the number of cancers identified in families, thus facilitating a diagnosis of HNPCC in a third of the referred families and a diagnosis of hyperplastic polyposis in one other. Consequently specialised genetic testing and intensive colonoscopic surveillance could be targeted to the asymptomatic first-degree relatives most at risk. Ongoing coordination of colonoscopic surveillance by the registry for those individuals identified to have disease causing mutations or to be at-risk, is anticipated to reduce the number of deaths from colorectal cancer in these families.

Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome defined by germline mutation of the E-cadherin gene (CDH-1). The cumulative risk for advanced gastric cancer in HDGC is 67% in men and 83% in women by 80 years of age. Early HDGC is characterized by multiple microscopic foci of intramucosal signet-ring cell carcinoma. The time to progression of these foci appears to be variable and currently is not predictable--the carcinoma foci may remain confined to the mucosa for many years. The management options for mutation carriers include prophylactic gastrectomy or surveillance gastroscopy. The only extensive published surveillance experience used chromogastroscopy, which detected early HDGC foci not visible on white-light endoscopy. The use of new techniques such as confocal microscopy, spectroscopy, or autofluorescence may prove useful, but have not been studied in HDGC. In patients up to 20 years of age, the risk for gastric cancer is less than 1%; this risk is outweighed by the mortality and morbidity associated with total gastrectomy. It is therefore recommended that genetic testing should occur at 16 years of age and that annual surveillance chromogastroscopy also should begin at age 16 in identified CDH-1 mutation carriers. After 20 years of age, delaying prophylactic gastrectomy carries significant risk, particularly if the alternative is surveillance by white-light gastroscopy. Surveillance chromogastroscopy (Congo red/methylene blue technique) should be considered for individuals younger than 20 years and patients unwilling to undergo prophylactic gastrectomy. Sufficient evidence for an increased risk for lobular breast cancer in CDH-1 carriers exists to justify breast screening in female carriers older than 35 years of age, however, evidence is insufficient to recommend prophylactic mastectomy.