Approximately 15% of colorectal cancers exhibit instability of short nucleotide repeat regions, microsatellites. These tumors display a unique clinicopathologic profile and the microsatellite instability status is increasingly used to guide clinical management as it is known to predict better prognosis as well as resistance to certain chemotherapeutics. A panel of five repeats determined by the National Cancer Institute, the Bethesda panel, is currently the standard for determining the microsatellite instability status in colorectal cancer. Recently, a quasimonomorphic mononucleotide repeat 16T/U at the 3' untranslated region of the Ewing sarcoma breakpoint region 1 gene was reported to show perfect sensitivity and specificity in detecting mismatch repair deficient colorectal, endometrial, and gastric cancers in two independent populations. To confirm this finding, we replicated the analysis in 213 microsatellite unstable colorectal cancers from two independent populations, 148 microsatellite stable colorectal cancers, and the respective normal samples by PCR and fragment analysis. The repeat showed nearly perfect sensitivity for microsatellite unstable colorectal cancer as it was altered in 212 of the 213 microsatellite unstable (99.5%) and none of the microsatellite stable colorectal tumors. This repeat thus represents the first potential single marker for detecting microsatellite instability.
The prevalence of desmoid tumors among patients with familial adenomatous polyposis (FAP) is at least 10%, and the prevalence of FAP among desmoid patients varies between 7.5-16%.
Data included 106 desmoid patients identified from the database of the Department of Pathology, Helsinki University Hospital, years 2000-2012. We evaluated the risk of FAP among patients by using endoscopy and we identified individuals with attenuated FAP by APC gene mutation test. We compared sporadic desmoid patients' and FAP patients' clinical characteristics.
Ten of 106 patients already had FAP diagnosis before the desmoid. Eleven patients had had FAP screening already earlier due to desmoid and three of them were found to have FAP. Total of 52 patients participated into prospective screening of FAP. No new cases of FAP were found. The risk of FAP among desmoid tumor patients was 4.8%. In the FAP desmoid group, there were more males and patients were younger than in the sporadic group. Intra-abdominal desmoids were more common in the FAP group.
Patients with desmoid carry an elevated risk of FAP and therefore screening is indicated. Asymptomatic patients with desmoid situated in extra truncal region may not need to be screened.
Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p?=?2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p?=?1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate?
The estimated lifetime risk for endometrial carcinoma (EC) in hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is 32-60%, thus supporting surveillance. The survival rate of EC patients is, however, favourable questioning the need for surveillance. Yet, the effectiveness of gynecological surveillance remains to be shown. The 2 previously published studies were based on transvaginal ultrasound (TVUS) alone. Intrauterine biopsy has not been tested in surveillance for EC in HNPCC families. The effect of gynecological surveillance was evaluated among 175 Finnish mutation carriers. During 759 person years at risk, there were 503 surveillance visits including TVUS and intrauterine biopsy of endometrium at 94% and 74% of the visits, respectively. EC occurred in 14 cases, 11 of which were diagnosed by surveillance, 8 by intrauterine biopsies. TVUS indicated only 4 EC patients but missed 6 other cases. Intrauterine sampling detected 14 additional cases of potentially premalignant hyperplasia. The stage distribution and survival tended to be more favorable in the 14 EC cases of the surveilled group (no deaths) than in the group of 83 symptomatic mutation carriers of whom 6 died of EC, but with no statistical significance. Four cases of ovarian cancer occurred but none was detected by surveillance in TVUS examinations. In conclusion, EC surveillance in HNPCC seems more effective with endometrial biopsies than with TVUS alone. A definite improvement in survival remains to be shown. The detection of early cancer stages and premalignant lesions offers the opportunity to avoid extensive adjuvant treatment.
The heritability of colorectal cancer (CRC) is incompletely understood, and the contribution of undiscovered rare variants may be important. In search of rare disease-causing variants, we exome sequenced 22 CRC patients who were diagnosed before the age of 40 years. Exome sequencing data from 95 familial CRC patients were available as a validation set. Cases with known CRC syndromes were excluded. All patients were from Finland, a country known for its genetically homogenous population. We searched for rare nonsynonymous variants with allele frequencies below 0.1% in 3,374 Finnish and 58,112 non-Finnish controls. In addition, homozygous and compound heterozygous variants were studied. No genes with rare loss-of-function variants were present in more than one early-onset CRC patient. Three genes (ADAMTS4, CYTL1, and SYNE1) harbored rare loss-of-function variants in both early-onset and familial CRC cases. Five genes with homozygous variants in early-onset CRC cases were found (MCTP2, ARHGAP12, ATM, DONSON, and ROS1), including one gene (MCTP2) with a homozygous splice site variant. All discovered homozygous variants were exclusive to one early-onset CRC case. Independent replication is required to associate the discovered variants with CRC. These findings, together with a lack of family history in 19 of 22 (86%) early-onset patients, suggest genetic heterogeneity in unexplained early-onset CRC patients, thus emphasizing the requirement for large sample sizes and careful study designs to elucidate the role of rare variants in CRC susceptibility.
Colonoscopies with polypectomies and endometrial biopsies with transvaginal ultrasonography, repeated at 2- to 3-year intervals, are performed for prevention or early detection of cancer in patients with DNA mismatch repair gene mutation causing Lynch syndrome. The long-term effectiveness of surveillance was evaluated in Lynch syndrome family members tested approximately 10 years ago.
Cancer incidence and survival were determined after an 11.5-year follow-up in 242 mutation-positive and 367 mutation-negative participants. These participants in 57 Lynch syndrome families with 14 different mutations were at 50% risk. The median age was 36 years (range, 18 to 72 years) in mutation carriers and 42 years (range, 18 to 72 years) in mutation-negative participants, and none had had cancer of the Lynch syndrome type.
Compliance was 95.9% for the colonic surveillance and 97.1% for the gynecologic surveillance. Colorectal cancer (CRC) occurred in 30 mutation-positive participants, and 74 participants had adenomas removed. Three patients died of CRC. Endometrial cancer (EC) occurred in 19 of 103 women at risk, and 48 women had prophylactic hysterectomy. Six of 112 women at risk had ovarian cancer. The overall cancer risk ratio (RR) in mutation carriers was 5.80 (95% CI, 3.4 to 9.5). Cancer mortality rate (RR = 2.28; 95% CI, 0.82 to 6.31) and overall death rate (RR = 1.26; 95% CI, 0.65 to 2.46) were not significantly increased.
Long-term compliance in surveillance for CRC and EC exceeded 95% in Lynch syndrome. All CRC deaths were not prevented as a result of noncompliance or missed lesions. Still, after 10 years of surveillance, no significant increase in mortality had occurred compared with mutation-negative relatives.
Computed tomographic colonography (CTC) is suggested to be an alternative to colonoscopy as a surveillance tool in subjects with a high risk for colorectal cancer (CRC). To evaluate the utility of CTC we successively examined 78 subjects, all with a DNA mismatch repair gene mutation, by CTC and colonoscopy. We detected altogether 37 polyps or tumors in 28 subjects (prevalence 35.9%), adenomas in 13 subjects (16.7%), CRC in two (2.6%), and hyperplastic polyps in 13 (16.7%). A great majority of the polyps were diminutive. The per-patient sensitivity for detecting all lesions with CTC was 0.25 and 0.29 by two radiologists and the specificities 0.82 and 0.76. For lesions of 10 mm or larger the sensitivities were 0.6 and 1.0 and the specificities 0.96 by each examiner. Each diagnosed the two cancers correctly. We concluded that CTC has an acceptable accuracy for large lesions in the colon but the detection rate for small polyps is not comparable to that in colonoscopy. Therefore CTC remains a second choice in surveillance for use when colonoscopy for some reason is incomplete or unsuitable.