Survey of germline variants in cancer-associated genes in young adults with colorectal cancer.

Colorectal cancer (CRC) incidence in young adults is rising. Identifying genetic risk factors is fundamental for the clinical management of patients and their families. This study aimed to identify clinically significant germline variants among young adults with CRC. Whole-exome sequencing data of blood-derived DNA from 133 unrelated young CRC patients (<55 years of age) underwent a comprehensive analysis of 133 cancer-predisposition/implicated genes. All patient tumors were evaluated for mismatch repair deficiency (dMMR). Among 133 patients (aged 16-54 years), 15% (20/133) had clinically actionable pathogenic or likely pathogenic (P/LP) variants in at least 1 well established cancer-predisposing gene: dMMR genes (6), MUTYH [bi-allelic (2), mono-allelic (3)], RNF43 (1), BMPR1A (1), BRCA2 (4), ATM (1), RAD51C (1), and BRIP1 (1). Five patients (4%) had variants in genes implicated in cancer but where the significance of germline variants in CRC risk is uncertain: GATA2 (1), ERCC2 (mono-allelic) (1), ERCC4 (mono-allelic) (1), CFTR (2). Fourteen (11%) had dMMR tumors. Eighteen (14%) reported a first-degree relative with CRC, but only three of these carried P/LP variants. Three patients with variants in polyposis-associated genes showed no polyposis (one each in MUTYH [bi-allelic], RNF43, and BMPR1A). Approximately one in five young adults in our series carried at least one P/LP variant in a cancer-predisposing/implicated gene; 80% of these variants are currently considered clinically actionable in a familial cancer setting. Family history and phenotype have limitations for genetic risk prediction; therefore multigene panel testing and genetic counseling are warranted for all young adults with CRC regardless of those two factors.

RNF43 pathogenic Germline variant in a family with colorectal cancer.

The role of RNF43 as a cause of an inherited predisposition to colorectal cancer (CRC) is yet to be fully explored. This report presents our findings of two individuals with CRC from a single family carrying a likely-pathogenic inherited germline variant in RNF43. The proband (III:1) and the proband's mother (II:2) were diagnosed with mismatch repair proficient CRCs at the age of 50 years and 65 years, respectively. Both patients had BRAFV600E mutated colon tumours, indicating that the CRCs arose in sessile serrated lesions. The germline variant RNF43:c.375+1G>A was identified in both patients. RNA studies showed that this variant resulted in an aberrantly spliced transcript, which was predicted to encode RNF43:p.Ala126Ilefs*50 resulting in premature termination of protein synthesis and was classified as a likely-pathogenic variant. Our report adds further evidence to the hereditary role of RNF43 as a tumour suppressor gene in colorectal tumorigenesis and supports the inclusion of RNF43 as a gene of interest in the investigation of CRC predispositions outside the setting of serrated polyposis.

Immunohistochemistry features and molecular pathology of appendiceal neoplasms.

Primary appendiceal neoplasms (ANs) comprise a heterogeneous group of tumors. The pathology and classification of ANs have been controversial, and thus, a new classification of these neoplasms was published in the World Health Organization (WHO) classification of tumors (5th edition, 2019). However, immunohistochemistry (IHC) features of epithelial ANs are not explained in this edition and the limited data on the molecular pathology of these tumors shows inconsistent findings in various studies. It would be useful to identify biomarkers appropriate for each subtype to better aid in treatment selection. Therefore, we reviewed the literature to investigate what is known of the molecular pathology and IHC features of the most frequently diagnosed pathological subtypes of epithelial ANs based on the recent classification. The inconsistencies in research findings regarding the IHC features and molecular pathology of ANs could be due to differences in the number of samples and their collection and preparation as well as to the lack of a universally accepted classification system for these neoplasms. However, the literature shows that epithelial ANs typically stain positive for MUC2, CK20, and CDX2 and that the expression of SATB2 protein could be used as a biomarker for appendix tumor origin. Low-grade appendiceal mucinous neoplasms tend to have mutations in KRAS and GNAS but are usually wild-type for BRAF, APC, and P53. Conversely, appendiceal adenocarcinomas are frequently found with mutations in KRAS, GNAS, P53, PIK3CA, and APC, and have significant nuclear expression of ß-catenin, loss of nuclear or nuclear and cytoplasmic expression of SMAD4, and loss of cytoplasmic membranous expression of E-cadherin. Goblet cell carcinomas (GCCs) typically stain positive for keratin and mucin markers and are frequently mutated in P53 and chromatin-modifier genes, but they tend to be wild-type for KRAS, GNAS, APC, and PIK3CA. The expression of CK7 and SATB2 proteins is usually negative in appendiceal neuroendocrine neoplasms and they lack the mutations in common cancer-associated genes including APC, BRAF, SMAD4, and PIK3C. The available data suggest that GCCs have distinct molecular and immunohistochemical features and that they have characteristics more in common with adenocarcinoma than classical neuroendocrine tumors. In addition, MSI does not seem to have a role in the pathogenesis of epithelial ANs because they are rarely detected in these tumors. Finally, hereditary predisposition may have a role in the development of ANs because heterozygous CTNNß1, NOTCH1, and NOTCH4 germline mutations have recently been identified in low and high grades ANs.

Age-Specific Differences in the Risk of Colorectal Precursor Lesions Among Patients with Type 2 Diabetes Undergoing Surveillance Colonoscopy.

BACKGROUND: The incidence rate of colorectal cancer (CRC) in young adults is rising in parallel with type 2 diabetes (T2D). The majority of CRC develop through two main subtypes of precursor lesions; adenomas and serrated lesions. The associations between age and T2D on development of precursor lesions remain uncertain. OBJECTIVES: We studied the association of T2D with the development of adenomas and serrated lesions in individuals <50 versus ≥50 years of age, in a population undergoing long-term regular surveillance colonoscopy due to an elevated risk of CRC. METHODS: A case-control study was conducted on patients who were enrolled in a surveillance colonoscopy program between 2010-2020. Findings at colonoscopy, clinical and demographic features were collected. Adjusted and unadjusted binary logistic regression assessed the association of age, T2D, sex, and other medical conditions and lifestyle-related factors with different subtypes of precursor lesions diagnosed at colonoscopy. Cox proportional hazards model analysis determined the association of T2D and other confounders with development time for precursor lesions. RESULTS: Cases included 412 patients <50y [mean age 38.7 (range, 24-49y)] and 824 sex-matched controls ≥50y [62.1 (50-75y)]. Individuals <50y were less likely to have been diagnosed with T2D than those ≥50y (7% vs 22%, P-value<0.001). During the follow-up period, there was no significant association between T2D and diagnosis of any precursor lesions, but when considering development time, individuals with T2D developed non-significant adenomas earlier than those without T2D (HR =1.46; 95% CI: 1.14-1.87; P-value=0.003). However, this was not independent of age or findings at index colonoscopy. CONCLUSIONS: T2D does not further increase the incidence of adenomas or serrated lesions in either a young or older cohort undergoing long-term surveillance colonoscopy.

Appendiceal neoplasm incidence and mortality rates are on the rise in Australia.

OBJECTIVES: The study aimed to examine the incidence and mortality rates of appendiceal neoplasms (ANs) in Australia. METHODS: A retrospective analysis was performed on national data obtained from the Australian Institute of Health and Welfare (AIHW) from 1982 to 2013. Changes to the incidence, and the cancer-specific mortality following the diagnosis of ANs were analyzed over this time period, with stratification performed for histological subtype, gender, and age groups (<50y and ≥50y). RESULTS: Incidence and mortality rates of ANs increased significantly across both genders and age groups. Incidence rates increased by 415%, from 0.40/100 000 population in 1982 to 2.06/100 000 in 2013. Overall mortality rates increased by 130%, from 0.057/100 000 during 1982-1985 to 0.131/100 000 during 2010-2013. Controlling for age group and gender, the incidence rates increased by 20% every four years (Incidence rate ratio (IRR) = 1.20, 95% confidence interval (CI): 1.17, 1.23, global P value<0.0001), and controlling for age, the mortality rates increased by 8% every four years (IRR = 1.08, 95% CI: 1.00, 1.17, global P-value = 0.0401). CONCLUSION: The increasing use of CT scanning, improvements in pathological assessment of the appendix, and the growing aging population may have contributed in part to the apparent rise in the incidence of ANs.

Young-onset colorectal cancer is associated with a personal history of type 2 diabetes.

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.