Evidence map›Paper›PMID 36612224›Full record

ArticleCancers2022

Large Cancer Pedigree Involving Multiple Cancer Genes including Likely Digenic

Ingrid P Vogelaar, Stephanie Greer, Fan Wang, GiWon Shin, Billy Lau, Yajing Hu, Sigurdis Haraldsdottir, Rocio Alvarez, Dennis Hazelett, Peter Nguyen and 8 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancers, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.4field-weighted citation impact, top 36% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 4 citations in OpenAlex.

  1. Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 6 institutions in 3 countries.

Ingrid P VogelaarDepartment of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Stephanie GreerDepartment of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Fan WangDepartment of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.ORCID 0000-0002-9869-9504
GiWon ShinDepartment of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Billy LauDepartment of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Yajing HuDepartment of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Sigurdis HaraldsdottirDepartment of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Rocio AlvarezBioinformatics and Functional Genomics Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.ORCID 0000-0002-9659-0679
Dennis HazelettBioinformatics and Functional Genomics Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Peter NguyenBioinformatics and Functional Genomics Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Francesca P AguirreBioinformatics and Functional Genomics Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Maha GuindiDepartment of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Andrew HendifarSamuel Oschin Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Jessica BalcomDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.
Anna LeiningerMinnesota Oncology, Woodbury, MN 55125, USA.
Beth FairbankLynch Syndrome Australia, The Summit, QLD 4377, Australia.
Hanlee JiDepartment of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Megan P HitchinsDepartment of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.ORCID 0000-0002-3603-2309
Cedars-Sinai Medical Center · USStanford University · USHarbin Medical University · CNMayo Clinic · USMinnesota Oncology · USNew York Genome Center · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Lynch syndrome (LS), caused by heterozygous pathogenic variants affecting one of the mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2), confers moderate to high risks for colorectal, endometrial, and other cancers. We describe a four-generation, 13-branched pedigree in which multiple LS branches carry the MSH2 pathogenic variant c.2006G>T (p.Gly669Val), one branch has this and an additional novel MSH6 variant c.3936_4001+8dup (intronic), and other non-LS branches carry variants within other cancer-relevant genes (NBN, MC1R, PTPRJ). Both MSH2 c.2006G>T and MSH6 c.3936_4001+8dup caused aberrant RNA splicing in carriers, including out-of-frame exon-skipping, providing functional evidence of their pathogenicity. MSH2 and MSH6 are co-located on Chr2p21, but the two variants segregated independently (mapped in trans) within the digenic branch, with carriers of either or both variants. Thus, MSH2 c.2006G>T and MSH6 c.3936_4001+8dup independently confer LS with differing cancer risks among family members in the same branch. Carriers of both variants have near 100% risk of transmitting either one to offspring. Nevertheless, a female carrier of both variants did not transmit either to one son, due to a germline recombination within the intervening region. Genetic diagnosis, risk stratification, and counseling for cancer and inheritance were highly individualized in this family. The finding of multiple cancer-associated variants in this pedigree illustrates a need to consider offering multicancer gene panel testing, as opposed to targeted cascade testing, as additional cancer variants may be uncovered in relatives.

Indexed as

Lynch syndromemulticancer gene panel testsplice variants

Identifiers

PMID36612224
PMCPMC9818763
OpenAlexW4313361155

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.