Colon cancer in a 12-year-old girl with hypertriglyceridemia

Colorectal cancer is usually considered a disease of the elderly; however, in a small fraction of patients (2%-3% of all affected individuals), colorectal malignancies may develop earlier. The reasons whereby some individuals develop colorectal cancer at a young age are poorly understood. In a 12-year-old girl, a malignancy was diagnosed in the ascending colon. There was no familial history of Lynch syndrome or familial adenomatous polyposis. The metabolic profile of the patient revealed hypertriglyceridemia and low high-density lipoprotein cholesterol levels at nine years, then diagnosed as familial hypertriglyceridemia due to a constitutional mutation in the APOA5 gene (c.427delC). Moreover, variants possibly increasing the risk of cancer were detected in MSH6 (c.3438+11_3438+14delCTTA, intron 5) and APC (I1307K). The patient showed a rather unusual dietary pattern, since her basic alimentation from weaning consisted almost exclusively of meat homogenates and, subsequently, roasted meat or cutlets. Other foods, including fish, vegetables, sweets, and pasta, were refused. In this case, genetic and environmental factors could have acted in a particularly accelerated manner. Indeed, the genetic background of the patient (familial hypertriglyceridemia and polymorphisms predisposing to colorectal cancer) may have favored a dietary-driven colorectal carcinogenesis, resulting in an extremely early onset development of malignancy.

Cancer risk and overall survival in APC I1307K carriers.

1592 Background: The germline variant APC I1307K is one of the most commonly identified pathogenic variants on germline genetic testing panels. The purpose of the Molecular Epidemiology of Colorectal Cancer study was to quantify the risk of colorectal cancer among carriers, characterize the clinical, pathologic, and molecular features of colorectal cancers arising in patients with APC I1307K, and to describe the overall and disease-specific survival of carriers with colorectal cancer. Here, the final results of the Molecular Epidemiology of Colorectal Cancer Study are reported with respect to APC I1307K. Methods: We consented 6,006 incident, pathologically confirmed cases of colorectal adenocarcinoma and 5,023 age, sex, and ethnicity matched controls without colorectal cancer between March 31, 1998 and July 1, 2017 within a geographically defined area of Northern Israel. Comprehensive, in-person epidemiologic interviews were conducted for cases and controls, with uniform histopathologic review, detailed molecular analysis, medical record review and clinical follow-up for up to 21 years. Results: The demographic and clinical features of incident colorectal cancer cases matched the population distribution of colorectal cancer in Israel. APC I1307K was identified in 429 (7.1%) of cases and 201 (4.0%) of controls. The estimated relative risk of colorectal cancer among carriers was 1.89 (95% confidence interval, 1.59 - 2.24), p < 0.0001. The prevalence and odds ratios differed by ethnic group. Homozygous carriers were at especially high risk, with an odds ratio of 3.90 (95% confidence interval 1.11–13.71). APC I1307K carriers were significantly less likely to have microsatellite instable tumors (p = 0.04). Overall survival of APC I1307K carriers was not significantly different than survival of non-carriers, after adjustment for age, stage, sex, ethnicity, and microsatellite instability. Conclusions: APC I1307K is an actionable germline mutation that confers meaningful lifetime risk of colorectal cancer in heterozygous and homozygous carriers. APC I1307K is not an independent prognostic factor for overall survival or disease specific survival and is not associated with the MSI phenotype. Cumulative lifetime risk estimates inform genetic counseling and provide data for policies regarding the timing and frequency of screening and other preventive strategies.

Ten year experience of an integrated cancer prevention center screening for multiple cancer types.

1549 Background: Cancer is the leading cause of mortality worldwide. Prevention and early detection are pivotal tools for reducing cancer burden. Methods: We describe the 10 year experience (2006-2016) of an integrated cancer prevention center that provides screening for prevention and early detection of 11 most common cancer types. Healthy individuals (20-80 yr) were included. Extensive clinical and epidemiological data was obtained. DNA was extracted from all participants and genotyped for APC I1307K and E1317Q. Patients were examined by specialists in internal medicine, surgery, plastic surgery, OBGYN, urology, oncology, oral surgery, gastroenterology, and others. Women underwent vaginal US and pap smear and (40yr) mammography and US/MRI with a clinical indication. PSA and free PSA for Men ( > 40yr). LDCT for heavy smokers. Colonoscopy was recommended to all subjects ( > 40yr). Results: A total of 6258 (49%) men and 6461 (51%) women mean age 47.0±11.5 year were screened. New malignant lesions were detected in 389 (1.75%) of screeners. The most common cancers were of skin (74, 0.6%), prostate (62, 0.5%), thyroid (51, 0.4%), breast (36, 0.3%), colorectal (22, 0.2%), ovarian (19, 0.1%), uterus (14, 0.1%), testis (12, 0.09%) urinary (9, 0.07%) and lung (10, 0.08%). In 28 patients (0.22%) more than one cancer was detected. Twenty eight of the cancer patients (7.2%) died after 32.4±28.1 months at a mean age of 69.4±14.2 years. Significantly, better than the expected cancer mortality. The APC I1307K and E1317Q variants were detected in 572 (4.8%) and 182 (1.5%) subjects respectively. First degree family member with cancer (OR = 2.02), I1307K carrier ship (OR = 1.53), female gender (OR = 1.23) and advanced age (OR = 1.06) were all associated with statistically significant (P < 0.05) increased cancer risk. Advanced age and first degree family history were also associated with detection of more than one cancer types. Conclusions: One stop shop screening, in the setting of a multidisciplinary outpatient clinic, is feasible and can prevent and detect cancer at an early stage. It significantly improve morbidity and mortality. Impressively the APC I1307K carries an overall increase cancer risk.

APC I1307K polymorphism as a predictive factor for colorectal neoplasia recurrence.

1526 Background: The use of surveillance colonoscopy to detect disease recurrence after initial colorectal neoplasia resection has increased significantly in the past decade. Currently, predictive factors at index colonoscopy include only histo-pathologic characteristics such as adenoma number, size, type and dysplasia. The goal of the current study is to identify additional factors (i.e., genetic markers) that increase the risk of subsequent lesions and may optimize the use of surveillance colonoscopies. Methods: A prospective analysis of 383 consecutive Israeli subjects with an initial neoplastic finding in screening colonoscopy. The participants were followed over a period of 10 years, and underwent up to five surveillance colonoscopies. Clinical data regarding potential risk factors for colorectal cancer as well as blood samples were collected. Genetic polymorphisms were detected using real-time PCR from DNA extracted from peripheral mononuclear cells. Results: The overall prevalence of recurrent Colorectal carcinoma and adenoma was 9.4% (36/383) and 69% (268/383) respectively, with a median of 4.8 years from index colonoscopy. In a univariate analysis, subjects with recurrent lesions had significantly higher number of adenomas at index colonoscopy (3.9 Vs 1.1, p=0.001), increased rate of high grade dysplasia (65.8% Vs 50%, p=0.018), and a non-significant trend for larger adenomas and villous histology. The APC I1307K gene variant was detected in 11.8% of subjects with recurrent lesions compared to 3.8% of subjects with normal follow-up colonoscopies (p=0.03). In a multivariate logistic regression (adjusted to age, sex, family history of CR neoplasia, time to recurrence and number of colonoscopies performed), the I1307K variant and the presence of dysplasia were the only significant predictive factors for recurrent neoplasia with an OR of 3.27 (1-11.02, p=0.05) and 1.72 (1.02-2.89, p=0.04) respectively. Conclusions: The APC I1307K gene variant is an important predictive factor for recurrent colorectal neoplasia after a positive index colonoscopy and should be considered as part of the criteria for high risk subjects among Israeli Jews.