Putative Cancer Susceptibility Gene Research Articles

More reliable breast cancer risk assessment for every woman.

Using large, unbiased cohorts, two studies in The New England Journal of Medicine assessed the associations between germline variants in putative cancer susceptibility genes and the risk of breast cancer. They consistently identified a small set of genes as being the most informative for risk prediction, helping select high-risk women in the general population, and developing effective cancer prevention strategies.

Abstract 4281: Identification of putative cancer susceptibility genes through whole exome sequencing of a family presenting hereditary colorectal cancer

Abstract Germline mutations in known colorectal cancer (CRC) predisposing genes accounts for less than half of the genetic cause of hereditary CRC cases. The absence of mutations in the remaining patients suggests that other yet unknown CRC predisposing genes might exist. However, recently studies with large cohorts probably discounts the existence of major unknown genes and it is thought that rare or even family private variants and genes may contribute to familial CRC. Thus, the aim of our study was to identify novel CRC susceptibility genes by whole exome sequencing (WES) of a family presenting hereditary CRC. The studied family fulfilled Amsterdam I criteria and appears to segregate a dominant cancer syndrome with a high risk of colon and rectal cancer, with four affected members in three generations. The index patient’s tumor was microsatellite stable and positive for the four mismatch repair proteins at immunohistochemistry. Genetic testing of the proband was negative for the following genes: MLH1, MSH2, MSH6, PMS2, PMS1, TP53, CHEK2. We performed WES in three family members: two with rectal cancer (onset 26 and 56 years) and one with colon cancer (onset 63 years). Using a functional-based variant prioritization, we identified six novel or very rare (MAF<0.002) candidate variants segregating with the phenotype. Two variants were loss-of-function stop codon variants in LSG1 and RRH genes. Three variants were missense (ARID1A, MC1R and SPEN), and three were synonymous (KIT, POLE and XAB2), all occurring in cancer-related genes. The identified KIT variant (c.1983C>A) is located 8 base pairs from the 3’ end of exon 13, and is predicted it to disrupt an exonic splicing enhancer by in silico tools (ESR finder and Human Splice Finder), possibly affecting the splice of this gene. Pyrosequencing of the KIT variant in tumor cDNA revealed an allelic imbalance between mutated and wild type alleles, with the mutated allele being three times more expressed. Transcript analysis using a customized heteroduplex enrichment-based method identified a novel KIT transcript in the index patient’s tumor, presenting an exon skipping event of exon 12. The resulting transcript (c.1775_1879del) is predicted to produce an in-frame deletion of 35 amino acids (p.Gly592_Pro627delinsAla) at the beginning of the protein kinase domain. The functional impact of this transcript and its relevance for CRC predisposition will be further evaluated. Moreover, experiments evaluating allelic imbalance, loss of heterozygosity and alternative spliced transcripts for the other identified variants are ongoing. Our results provide a set of putative CRC predisposing genes and underpin that WES of highly informative CRC families, ascertained on the basis of highly selected phenotypes and followed by functional validation, are likely to continue to prove an effective strategy for gene discovery. Citation Format: Giovana T. Torrezan, Anna Smirnova, Felipe C. Silva, Erika M. Santos, Renan Valieris, Jorge E. de Souza, Samuel Aguiar, Benedito M. Rossi, Sandro J. de Souza, Dirce M. Carraro. Identification of putative cancer susceptibility genes through whole exome sequencing of a family presenting hereditary colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4281. doi:10.1158/1538-7445.AM2017-4281

POU5F1P1, a putative cancer susceptibility gene, is overexpressed in prostatic carcinoma

Association between genetic variants located on human chromosome 8q24.21 with an increased risk for prostatic carcinoma has been well established. POU5F1P1, a processed pseudogene homologous to the pluripotency factor OCT4, is the only sequence with coding capacity in this region. The objective of this study was to investigate the POU5F1P1 expression in prostatic carcinoma and carcinoma surrounding prostatic tissue. RT-PCR and real-time PCR was used to measure the expression of POU5F1P1 relative to the expression of HPRT1 in cell lines, prostatic carcinoma and carcinoma surrounding prostatic tissue. The structure of the POU5F1P1 mRNA and the promoter sequence were elucidated by 5'-RACE experiments. The POU5F1P1 protein was shown with immunohistochemistry on prostate tissue. POU5F1P1 was found to be the only member of the POU5F1 family to be expressed in prostate with over-expression in prostatic carcinoma compared to surrounding prostatic tissue probably because of an increased density of expressing cells. The POU5F1P1 expression is driven by a variety of promoter structures scattered over a genomic region of 860 kB. The over-expression of POU5F1P1 in prostatic carcinoma in addition to its genomic location and the putative function of its gene product render POU5F1P1 a good candidate to harbour functional genetic variants which modulate prostatic cancer susceptibility.

Analysis of HPC1, HPCX, and PCaP in Icelandic hereditary prostate cancer.

Putative prostate cancer susceptibility loci have recently been identified by genetic linkage analysis on chromosomes 1q24-25 (HPC1). 1q44.243 (PCaP), and Xq27-28 (HPCX). In order to estimate the genetic linkage in Icelandic prostate cancer families, we genotyped 241 samples from 87 families with eleven markers in the HPC1 region, six markers at PCaP, and eight at HPCX. Concurrently, we assessed allelic imbalance at the HPC1 and PCaP loci in selected tumors from the patients. For each of the candidate regions, the combined parametric and non-parametric LOD scores were strongly negative. Evidence for linkage allowing for genetic heterogeneity was also insignificant for all the regions. The results were negative irrespective of whether calculations were performed for the whole material or for a selected set of early age at onset families. The prevalence of allelic imbalance was relatively low in both the HPC1 (0%-9%) and PCaP (5%-20%) regions and was not elevated in tumors from positively linked families. Our studies indicate that the putative cancer susceptibility genes at chromosomes 1q24-25, 1q44.2-43, and Xq27-28 are unlikely to contribute significantly to hereditary prostate cancer in Iceland and that selective loss of the HPC1 and PCaP loci is a relatively rare somatic event in prostate cancers.