Spectrum of Germline Mutations Within Fanconi Anemia–Associated Genes Across Populations of Varying Ancestry

Abstract Background Fanconi anemia (FA) is a rare genetic disorder associated with hematological disorders and solid tumor predisposition. Owing to phenotypic heterogeneity, some patients remain undetected until adulthood, usually following cancer diagnoses. The uneven prevalence of FA cases with different underlying FA gene mutations worldwide suggests variable genetic distribution across populations. Here, we aim to assess the genetic spectrum of FA-associated genes across populations of varying ancestries and explore potential genotype–phenotype associations in cancer. Methods Carrier frequency and variant spectrum of potentially pathogenic germline variants in 17 FA genes (excluding BRCA1/FANCS, BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO) were evaluated in 3523 Singaporeans and 7 populations encompassing Asian, European, African, and admixed ancestries from the Genome Aggregation Database. Germline and somatic variants of 17 FA genes in 7 cancer cohorts from The Cancer Genome Atlas were assessed to explore genotype–phenotype associations. Results Germline variants in FANCA were consistently more frequent in all populations. Similar trends in carrier frequency and variant spectrum were detected in Singaporeans and East Asians, both distinct from other ancestry groups, particularly in the lack of recurrent variants. Our exploration of The Cancer Genome Atlas dataset suggested higher germline and somatic mutation burden between FANCA and FANCC with head and neck and lung squamous cell carcinomas as well as FANCI and SLX4/FANCP with uterine cancer, but the analysis was insufficiently powered to detect any statistical significance. Conclusion Our findings highlight the diverse genetic spectrum of FA-associated genes across populations of varying ancestries, emphasizing the need to include all known FA-related genes for accurate molecular diagnosis of FA.

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Detecting oncogenic selection through biased allele retention in The Cancer Genome Atlas

10.1101/2020.07.03.186593 ◽

2020 ◽

Author(s):

Juliet Luft ◽

Robert S. Young ◽

Alison M. Meynert ◽

Martin S. Taylor

Keyword(s):

Association Studies ◽

Strand Break ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Genome Wide Association Studies ◽

Sequencing Data ◽

Germline Variants ◽

A Genome ◽

Cancer Genome Atlas ◽

Genome Atlas

AbstractBackgroundThe loss of genetic diversity in segments over a genome (loss-of-heterozygosity, LOH) is a common occurrence in many types of cancer. By analysing patterns of preferential allelic retention during LOH in approximately 10,000 cancer samples from The Cancer Genome Atlas (TCGA), we sought to systematically identify genetic polymorphisms currently segregating in the human population that are preferentially selected for, or against during cancer development.ResultsExperimental batch effects and cross-sample contamination were found to be substantial confounders in this widely used and well studied dataset. To mitigate these we developed a generally applicable classifier (GenomeArtiFinder) to quantify contamination and other abnormalities. We provide these results as a resource to aid further analysis of TCGA whole exome sequencing data. In total, 1,678 pairs of samples (14.7%) were found to be contaminated or affected by systematic experimental error. After filtering, our analysis of LOH revealed an overall trend for biased retention of cancer-associated risk alleles previously identified by genome wide association studies. Analysis of predicted damaging germline variants identified highly significant oncogenic selection for recessive tumour suppressor alleles. These are enriched for biological pathways involved in genome maintenance and stability.ConclusionsOur results identified predicted damaging germline variants in genes responsible for the repair of DNA strand breaks and homologous repair as the most common targets of allele biased LOH. This suggests a ratchet-like process where heterozygous germline mutations in these genes reduce the efficacy of DNA double-strand break repair, increasing the likelihood of a second hit at the locus removing the wild-type allele and triggering an oncogenic mutator phenotype.

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Special Report: The Cancer Genome Atlas Begins with 3-Year, $100 Million Pilot

PsycEXTRA Dataset ◽

10.1037/e481292006-009 ◽

2005 ◽

Author(s):

Keyword(s):

Cancer Genome ◽

The Cancer Genome Atlas ◽

Special Report ◽

Cancer Genome Atlas ◽

Genome Atlas

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Differences in endometrial cancer molecular portraits based on ethnicity in The Cancer Genome Atlas

10.26226/morressier.59ba7298d462b80296ca20c6 ◽

2017 ◽

Author(s):

David Guttery

Keyword(s):

Endometrial Cancer ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Cancer Genome Atlas ◽

Genome Atlas

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Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1

JCO Precision Oncology ◽

10.1200/po.16.00015 ◽

2017 ◽

pp. 1-12

Author(s):

Manish R. Sharma ◽

James T. Auman ◽

Nirali M. Patel ◽

Juneko E. Grilley-Olson ◽

Xiaobei Zhao ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Somatic Mutation ◽

Mutation Rate ◽

Germ Line ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Response To Chemotherapy ◽

Cancer Genome Atlas ◽

Genome Atlas

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

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