Observational study

Pathogenic Germline Variants in 10,389 Adult Cancers

Cell · 201810,389 cancer cases from 33 cancer types

Huang Kl, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, et al. Cell. 2018. 173:355-370.e14

Study type: Observational study
Study name: Pan-Cancer Germline
Design: Large-scale pan-cancer genomic analysis to identify germline cancer-predisposition variants
Sample size: 10,389 cancer cases from 33 cancer types
Source: Cell · 2018

In plain words

In this very large study, the genes of 10,389 patients with 33 types of cancer were examined, and in about 8% of them inherited genetic changes were found that raise the chance of developing cancer. The researchers showed that these changes often disrupt the work of genes that normally hold cancer back. The results may help genetic tests be interpreted better in the future. If you have a family history of cancer, talk to your doctor or a genetic counsellor about whether genetic testing is right for you.

Key results

853 variants in 8% of 10,389 cases

Pathogenic or likely pathogenic variants

33 cancer types

21 genes

Genes with single-cancer or cross-cancer associations

Including novel associations of SDHA in melanoma and PALB2 in gastric adenocarcinoma

659 variants and 18 additional large deletions

Predisposition variants in tumour suppressor genes

Including ATM, BRCA1 and NF1; low gene expression and loss of heterozygosity or biallelic two-hit events in 43%

33 variants

Predisposition variants in oncogenes

Including MET, RET and PTPN11 missense variants with high gene expression

47 variants

Additional predisposition variants nominated from prioritised VUSs

Based on multiple lines of evidence: case–control frequency, LOH, effect on expression, and co-localisation with mutations and altered residues

Study population

10,389 adult cancer cases from 33 cancer types. Details of inclusion criteria are in the full text of the paper.

Endpoints

Identification of germline pathogenic or likely pathogenic variants and their association with cancer types; assessment of the functional consequences of these variants (gene expression, loss of heterozygosity and two-hit events); and nomination of variants of uncertain significance (VUS) with multiple lines of supporting evidence. Exact endpoint details are not stated in the abstract.

Safety and side effects

The study was not interventional and has no safety data.

Clinical significance and place in guidelines

Based on the abstract, this study provides evidence linking rare germline variants with functional consequences and could guide future variant classification and germline genetic testing in cancer. The abstract does not comment on direct changes to clinical practice or guideline endorsement; the current status of guidelines should be checked separately.

Limitations

The abstract does not describe limitations; their details are in the full text of the paper. The variants of uncertain significance (VUS) nominated in this study are "candidates" and need further evidence before clinical use.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.