Marilena Melas

Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer

Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.

Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges

PurposeMutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management.Patients and MethodsThis cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were...

Erratum: Genome-wide association study of colorectal cancer identifies six new susceptibility loci (Nature Communications 6:7138)

Corrigendum: Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome

Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is caused by mismatch repair (MMR) gene mutations. However, data about MMR mutations in Hispanics are limited. This study aims to describe the spectrum of MMR mutations in Hispanics with LS and explore ancestral origins. This case series involved an IRB-approved retrospective chart review of self-identified Hispanic patients (n = 397) seen for genetic cancer risk assessment at four collaborating academic institutions in California, Texas, and Puerto Rico who were evaluated by MMR genotyping and/or tumor analysis. A literature review was conducted for all mutations identified. Of those who underwent clinical genetic testing (n = 176), 71 had MMR gene mutations. Nine mutations were observed more than once. One third (3/9) of recurrent mutations and two additional mutations (seen only once) were previously reported in Spain, confirming the influence of Spanish ancestry on MMR mutations in Hispanic populations. The recurrent mutations identified (n = 9) included both previously reported mutations as well as unique mutations not in the literature. This is the largest report of Hispanic MMR mutations in North America; however, a larger sample and haplotype analyses are needed to better understand recurrent MMR mutations in Hispanic populations.

Abstract 2745: Exome sequencing analysis of 41 patients with Familial Colorectal Cancer Type X (FCCTX)

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Colorectal cancer (CRC) is the second most common cancer. About 10% of CRC are hereditary including familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC), and rare syndromes. While genetics of FAP and rare syndromes is well studied (APC, STK11, AXIN2), only ∼40-50% of HNPCC have identifiable DNA mismatch-repair gene defects. CRC cases fulfilling Amsterdam Criteria I for HNPCC with normal DNA mismatch repair and elevated risk of microsatellite-stable CRC are called Familial Colorectal Cancer Type X (FCCTX). Compared to HNPCC, FCCTX patients are older, with left-sided CRC, and frequent polyps. We hypothesize that FCCTX is a dominant Mendelian cancer syndrome with incomplete penetrance caused by rare, family-specific mutations in oncogenes and tumor suppressors. To identify novel mutations and genes involved in FCCTX, we performed germline exome sequencing of microsatellite-stable familial CRC from Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based, case-control CRC study in Northern Israel. We selected 41 patients from 38 FCCTX families with extensive family history of microsatellite stable (MSS) or microsatellite instable low (MSI-Low) CRC. Patients were Ashkenazi Jewish, Sephardi Jewish, Europeans, Druze, and Arabs. Similar to previous studies, stomach cancer was second most common in the families, and left-sided CRC was more prevalent. Exome sequencing of all patients generated 52,722 variants. Stepwise filtering analysis was applied to identify candidate variants and genes. We selected all novel and rare (minor allele frequency <0.001) functional variants in cancer-related genes from literature and cancer databases (COSMIC and TCGA). In line with dominant inheritance, only heterozygous variants predicted to be deleterious by multiple bioinformatic tools were selected. We identified 627 variants in 387 genes. Gene enrichment analysis showed regulation of apoptosis and cell cycle, DNA repair, cell adhesion, and cell surface receptor linked signal transduction. As expected, we found APC*I1307K founder mutation in three Ashkenazi Jewish patients, one novel APC mutation (p.1289_1291del) in a non-Jewish European patient, and found a mutation in MSH6. We identified three promising candidate genes and performed segregation analysis in families. Our preliminary data suggest several novel candidate genes for FCCTX, although older age at onset and incomplete penetrance complicate the interpretation of the results. Further population-based and family-based studies are being conducted to confirm our findings. Citation Format: Marilena Melas, Hung N. Luu, Gad Rennert, Flavio Lejbkowicz, Stephen B. Gruber, Georgia L. Wiesner, Leon Raskin. Exome sequencing analysis of 41 patients with Familial Colorectal Cancer Type X (FCCTX). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2745. doi:10.1158/1538-7445.AM2015-2745

Abstract 491: Elucidatingde novoPATRR-mediated t(3;8) balanced translocation and clear cell renal cell carcinoma

Palindromic AT-Rich Repeat (PATRR) - mediated translocations entail exchange across chromosomes at sites enriched in palindromic repeats of the nucleotides adenine (A) and thymine (T). Their precise embryologic origin and associated pathobiology with clear cell renal cell carcinoma (ccRCC) remain incompletely described. In the present study we document an individual with familial non-VHL ccRCC (7 primary renal tumors) who harbors a germline de novo PATRR mediated balanced translocation involving chromosomes 3 and 8 [t(3;8)] validated by spectral karyotyping (SKY). Using translocation specific PCR and DNA sequencing we determined the chromosome 3 breakpoint to be located in an AT-rich palindromic sequence in the third intron of the FHIT gene (chr3p14.2) and the chromosome 8 breakpoint in the first intron of the TRC8 gene (chr8q24.1). Genotyping analysis, using a high density custom exomechip array by Illumina, revealed a loss of the entire aberrant chromosome 8 carrying the 3p segment [der(8)] in all renal tumors tested. We also determined that the [46, XY, t(3;8), (p14.2, q24.1)] translocation was paternally derived by performing a genotypic assessment of the regions that differ between the parental alleles and then establishing which haplotypes are associated with the translocation. The somatic mutational landscape was assessed by Whole Exome sequencing of the renal tumors and the proband’s germline DNA. No germline or somatic deleterious mutations were detected in VHL gene suggesting that the ccRCC phenotype is not associated with Von Hippel-Lindau disease. Furthermore, we measured the transcriptomic profiles of the renal tumors and matched normal tissues employing barcoded probe hybridization technology (NanoString) and RNASeq to fully characterize differential gene expression and define gene ontology networks that are dysregulated. Most significantly, no difference in expression of the VHL gene was detected between tumors and normal counterparts. Aberrant regulation was detected in members of WNT signaling pathway, TGF-beta and MAPK pathways, in addition to NOTCH signaling pathway genes and members of the VEGF family. In summary, in this study we employed advanced genomic and transcriptomic techniques, to delineate the embryologic origin and deleterious biological consequences of the PATRR-mediated t(3;8) balanced translocation associated with clear cell renal cell carcinoma. Citation Format: Marilena Melas, Kevin J. McDonnell, Christopher K. Edlund, Sarah J. Tash, Duveen Y. Sturgeon, Chenxu Qu, Charalampos Lazaris, Peter J. Gruber, Thomas W. Glover, Beverly S. Emanuel, Stephen B. Gruber. Elucidating de novo PATRR-mediated t(3;8) balanced translocation and clear cell renal cell carcinoma [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 491. doi:10.1158/1538-7445.AM2017-491

Abstract A17: Molecular and clinicopathological features of native Nigerian colorectal cancer

Colorectal cancer (CRC) needs no introduction in Africa; once a rare cancer type, it is now the 3rd or 4th most common cancer. However, there are significant differences in the incidence rates, tumor biology, and clinical behavior in comparison to other populations. While the total incidence rates are about one-tenth of those in the developed world, Nigerian CRC occurs at a younger age and rapidly metastasizes. Molecular pathology and genetics of African CRC have not been comprehensively studied. In addition to better understanding of the biology of African CRC, analysis of genetic and molecular biomarkers, including microsatellite instability (MSI), is aimed at improving CRC diagnosis, treatment, and prognosis in Africa. We obtained 83 CRC paraffin-embedded blocks from the University of Ibadan and private pathology laboratories in Ibadan collected in the period from 2007 to 2014. Median age of the cases was 56±14.6 years with equal number of males and females. More than 60% of the patients had stage III and IV CRC. The majority were adenocarcinomas (76%) with a relatively high prevalence of mucinous adenocarcinoma (10%) and signet ring carcinoma (4%). Of all patients, 66% had rectal cancer. Poorly differentiated tumors were observed in 34% of all cases. We found a high prevalence of MSI CRC (43%, 15/35) in the tested Nigerian samples. There were no significant differences in clinicopathological features, including tumor location, between MSI and microsatellite stable (MSS) CRC. Our results are in line with our previous report that found a high prevalence (41%) of MSI CRC in Ghanaian patients. These findings raise important questions about the role of genetic and environmental factors in CRC development in West Africa. Citation Format: David O. Irabor, Marilena Melas, Stephen B. Gruber, Chanjuan Shi, Leon Raskin. Molecular and clinicopathological features of native Nigerian colorectal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A17.