A clinical and genetic analysis of multiple primary cancer referrals to genetics services

Abstract

Multiple primary malignant tumours (MPMT) are frequently taken as an indicator of potential inherited cancer susceptibility and occur at appreciable frequency both among unselected cancer patients and, particularly, among referrals to cancer genetics services. However, there is a paucity of information on the clinical genetic evaluation of cohorts of MPMT patients representing a variety of tumour types. We ascertained a referral-based series of MPMT cases and describe the patterns of tumours observed. Service-based molecular genetic testing had demonstrated a pathogenic germline variant in an inherited cancer gene in fewer than one in four unselected referrals. To assess for evidence of thus far unidentified variants in those who tested negative, comparisons were made with those who tested positive. This revealed considerable overlap between the two groups with respect to clinical characteristics indicative of an inherited cancer syndrome. We therefore proceeded to test a subset of unexplained MPMT cases (n ¼ 62) for pathogenic germline variants in TP53 and PTEN but none were detected. Individuals with MPMT may receive negative genetic test results for a number of reasons, which are discussed. Many of these may be addressed by the increasing application of next generation sequencing techniques such as inherited cancer gene panels.

Germline genetic variants in men with prostate cancer and one or more additional cancers

“…17,18 In addition, a retrospective study of individuals with multiple primary malignancies who were referred for clinical genetic testing found that 44 of 111 individuals (39.6%) carried a variant in 1 cancer predisposition genes, with DNA mismatch repair genes among the most frequently mutated. 19 Although the presence of certain constellations of MPMNs in a single individual is considered to be one indication for referral for genetic risk assessment, to the best of our knowledge the percentage of individuals with MPMNs who are referred for genetic assessment and the outcomes of clinical genetics referrals in these patients with multiple primary cancers has not been extensively described.…”

Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review

“…No statistically significant correlation was identified for younger age at first tumor diagnosis, PGL, renal oncocytoma or malignant PGL, and the identification of a genetic mutation ( P > 0.05 for all associations). The mean MTS ( 11 ) value in group A patients with a mutation was 3.6 compared with 1.8 in those without a mutation ( P = 0.09).…”

“…Although the literature review identified patients with non-VHL RAPTAS and a germline mutation had relatively young-onset PC/PGL/HNPGL (mean, 31.8. years; RCC, 41.4 years) in the case series, there was no clear relationship between age at tumor diagnosis and presence/absence of a mutation. Although the difference in MTS ( 11 ) between mutation-positive and mutation-negative cases did not reach statistical significance, further studies are required to determine MTS utility in group A RAPTAS cases. Although RAPTAS might in some cases arise coincidentally, we note in two SDHB mutation-positive cases in our series (probands 9 and 18), age at tumor diagnosis was 60 years or older.…”

Automated Detection of Cancer Associated Genes Using a Combined Fuzzy-Rough-Set-Based F-Information and Water Swirl Algorithm of Human Gene Expression Data

“…During gene expression-based cancer diagnosis, in addition to finding the subset of potential genes causing the cancer, the researcher is expected to trace out the physiognomies of the causative genes in terms of their part in multiple cancer classes [57]. The GO Sim package in the R platform [22] was used to compute the similarity value for the genes identified in the GCM_RM dataset using the GO terms.…”