Phenotypic heterogeneity in hereditary non-polyposis colorectal cancer: identical germline mutations associated with variable tumour morphology and immunohistochemical expression

Abstract

Background: Hereditary non-polyposis colorectal cancer (HNPCC) is associated with high risks for colorectal and endometrial cancer, young age at onset and an increased risk of multiple primary tumours. Colorectal cancer in HNPCC is characterised by poor tumour differentiation, an expanding growth pattern, and a pronounced lymphocytic reaction with tumour-infiltrating lymphocytes. Aims and Methods: The mutation spectrum in HNPCC is diverse and in order to clarify whether the HNPCC tumour phenotype is influenced by the underlying genetic alteration, 29 colorectal cancers and 12 adenomas from 24 individuals in two HNPCC families were morphologically and immunohistochemically characterised. Results: The tumour morphology as well as the immunohistochemical expression of b-catenin varied extensively within the families as well as between synchronous/metachronous colorectal cancers from the same individual. Poor tumour differentiation, an expanding growth pattern, and tumour-infiltrating lymphocytes occurred at higher frequencies in proximal tumours, whereas distal colorectal cancers often lacked distinct HNPCC-associated morphological features. Conclusions: The clinical, morphological and immunohistochemical variability observed within these families indicates that other mechanisms than the underlying germline mutation influence the HNPCC phenotype. Since morphological features linked to HNPCC are less frequent in distal cancers, it may be particularly relevant to obtain family history and age of onset in these tumours in order to identify individuals with HNPCC.

Characterization of ETS gene aberrations in select histologic variants of prostate carcinoma

“…Similarly to BCR:ABL1 fusion leukemias, 22 microsatellite unstable colon carcinomas 23 or breast carcinomas with BRCA mutations, 24 ETS gene fusions in prostate carcinoma have been reported to be associated with certain morphological features, which predict underlying genetic association. Mosquera et al25 identified blue-tinged mucin, cribriform growth pattern, macronucleoli, intraductal tumor spread, and signet-ring cell features to be significantly associated with TMPRSS2:ERG fusion status.…”

Deranged Wnt signaling is frequent in hereditary nonpolyposis colorectal cancer

“…HNPCC confers a high risk of colorectal cancer with a predilection for poorly differentiated, mucin-containing tumors with abundant lymphocytic reactions [4][5][6][7]. The HNPCC-associated cancers are generally characterized by diploid tumor genomes and few gross genetic abnormalities, but show wide-spread microsatellite instability, which reflects the underlying MMR defect.…”

Predicting neuroendocrine tumor (carcinoid) neoplasia using gene expression profiling and supervised machine learning

“…Current classification frameworks, however, are not validated and are unable to accurately discriminate among tumors with similar histopathologic features, which may vary substantially in clinical course and in response to treatment 3. This reflects either incorrect classification or the fact that an individual lesion may evolve into a different type of NET pattern or that there may exist within one tumor more than one phenotype 4. The recognition of these limitations has led to an interest in modifying the basis of tumor classification from a purely morphologic stratification to a system that includes molecular parameters predictive of biological behavior.…”