Akademiliv

Sahlgrenska akademins nyheter

På Svenska
University of Gothenburg Logotype
  • News
  • Notices
  • Calendar
  • Grants
  • About Akademiliv
Jonas Nilsson presenterar arbetet för medarbetare på Sahlgrenska Cancer Center.

Difficult cancer case solved with new analytical methods and animal model tailored to the individual

28 August, 2018

NEW STUDY. Through multidisciplinary collaboration, cancer researchers at Sahlgrenska Academy and doctors at Sahlgrenska University Hospital have solved a case that was difficult to diagnose. The analytical methods employed probably can be used almost immediately for patients lacking a correct cancer diagnosis.

A patient sought care at Sahlgrenska University Hospital for lung cancer. Despite various treatments in several hospitals, the tumor kept coming back. Before dying of cancer, the patient contributed several biopsies to research, which now probably will increase the chances of receiving a diagnosis for those with cancers that are difficult to diagnose. The research has led to a new diagnostic tool, which is expected to help patients with intractable cancer get the right diagnosis and thereby better treatment.

Surprising results

Joakim Karlsson, Roger Olofsson Bagge, and Akif Demir are joint co-lead authors for the article that the research collaboration led to.

Through good multidisciplinary collaboration, researchers and doctors together were able to shed new light on the patient’s cancer. The researchers are working with what is known as a patient-derived xenograft (PDX) model, which requires very carefully managed tumor samples. A biopsy of the tumor, extracted by surgeon Roger Olofsson Bagge, was placed under the skin of an immunodeficient mouse lacking the ability to recognize human cells. Simultaneously pathologist Akif Demir, working with another part of the biopsy, analyzed different immunostainings. In addition, another part of the biopsy was used to extract nucleic acids for whole genome and RNA sequencing at SciLifeLab, and a chromosome analysis called CGH by cancer researcher Göran Stenman’s lab.

Unusual characteristics

Many surprises followed from the analyses, notes cancer researcher Jonas Nilsson, who is leading work on PDX models at Sahlgrenska Cancer Center:

“First of all, the pathological examination showed that the tumor most resembled a neuroendocrine cancer and not an adenocarcinoma of the lung. However, the tumor grew very well in the mouse, which is unusual for neuroendocrine tumors.”

The cancer was also found to have a mutation in a specific cancer gene called BRAF.

“What is most remarkable about this finding is that it meant the patient could be treated with BRAF inhibitors, which were effective and led to a shrinking of the patient’s tumor. The tumor in the mouse also grew more slowly when the mouse was treated with BRAF inhibitors. Unfortunately, the tumor recurred after half a year, and the patient died,” Jonas Nilsson says.

Upon extended analysis of the mutations in the patient, researchers found a mutation in another gene (MEK1), which results in a poorer response to BRAF inhibitors.

“This probably explains the relatively weak effect BRAF inhibitors had in the mouse and why the patient’s tumor came back so quickly. We thought the case still was interesting and submitted our analyses to a journal for publication,” Jonas says.

Skin cancer in the lung

The Journal of Clinical Oncology – Precision Oncology also thought the case was interesting, but one of the reviewers was skeptical of the diagnosis. The special neuroendocrine type of tumor proposed as a diagnosis rarely or never has the clinical manifestation observed in the patient nor does it ever grow in mice, and it lacks the mutations in BRAF described in this case. To try to disprove their own hypothesis – that it involved a neuroendocrine tumor – Akif Demir and Ola Nilsson Wassen then analyzed additional markers, but these stainings could not disprove the diagnosis.

Further genetic analyses by bioinformatician Joakim Karlsson, who is a doctoral student of Erik Lekholm, indicated that the reviewer had a right to be skeptical. A mutation signature analysis revealed that the first biopsy, the PDX tumor, and the last biopsy taken before the patient died must have come from the skin.

Joakim Karlsson

“When ultraviolet rays from the sun strike skin cells, a very characteristic mutational pattern occurs during the repair of ultraviolet-induced DNA damage,” says Joakim Karlsson. He adds:
“All biopsies from the patient we analyzed had this pattern.”

Strong resemblance to malignant melanoma

Joakim’s supervisor, Erik Lekholm, previously had access to RNA sequencing data from 9,000 tumors in The Cancer Genome Atlas (TCGA) database. He decided to compare the biopsies’ RNA sequencing data with the entire TCGA data set. The analysis reinforced the mutation signature analysis: there was a 90 percent correlation with the malignant melanoma type of skin cancer.

“We chose to send back the results to the same journal and added our analyses as well as a re-examination of the case by a Dutch expert pathologist in neuroendocrine types of cancers,” Jonas explains.

Hope for cancers difficult to diagnose

This version of the manuscript was appreciated and accepted for publication, after an additional peer review that focused on the genetic analyses (bioinformatics).

“In the last version of the manuscript, we could also demonstrate that three lung tumors in the TCGA database itself probably also were incorrectly diagnosed,” Joakim Karlsson recounts.

In anticipation of the article’s publication, the multidisciplinary team has continued its efforts to see how robust the analysis is for accurately diagnosing patient tumors.

Akif Demir

“There is a group of patients known as CUP, Cancer of Unknown Primary, and they would benefit from these analyses,” says Akif Demir, who is a pathologist at Sahlgrenska University Hospital.

The disadvantage is that the analyses require RNA, which is sensitive to how the biopsy is handled in the clinic. This will be the next step to resolve so that patients get the right diagnosis.

Roger Olofsson Bagge

“Since many treatments are approved by the Medical Products Agency Sweden for a certain diagnosis, but not for another, a correction of a diagnosis can mean that the patient suddenly has access to a particular treatment,” says Roger Olofsson Bagge, a surgeon at Sahlgrenska University Hospital.

The article with three co-lead authors (Olofsson Bagge, Demir and Karlsson) is available online at: http://ascopubs.org/doi/10.1200/PO.18.00002

TEXT AND PHOTO: ELIN LINDSTRÖM CLAESSEN

 

By: Elin Lindström

Add your own events in the Akademiliv Calendar

No newsletter during the sports holiday – Wednesday, February 15

Information from Sahlgrenska Academy Research Support Office

[UPDATED JAN 24]
The Sahlgrenska Academy Research Support Office provides an overview of upcoming and current calls, nominations and events in an information letter. This letter is updated approximately four times per semester.

’20 minutes for researchers’ is back – see full spring program

During 20 minutes over Zoom, the Biomedical Library gives tips on tools and services that can facilitate your research everyday life.

We are building at Medicinareberget

You will now find comprehensive information on construction projects that affect the Sahlgrenska Academy in the Staff Portal.

Lunch menus

Café Anatomen
Menu not available on website.

Café Annedal
Menu not available on website.

Lunchen.nu

Lustgården på Änggårdsbacken
Take away for external guests between 11.00-12.30 weekdays.

Lyktan

Mersmak Mölndal

Mersmak Sahlgrenska

Mersmak Östra

Salt & Syra

More news

New thesis: Higher risk of future accidental bowel leakage after sphincter injury

3 February, 2023

THESIS. A study that was part of a recent doctoral thesis at the Institute of Clinical Sciences reports a significantly higher risk of developing …  

Formal ceremony for Zealous and Devoted Service

3 February, 2023

ACADEMIC CEREMONIES. On Wednesday, January 25, the University invited a 68 staff members to a ceremony to receive their Zealous and Devoted …  

Nominations for Honorary Doctors 2023 is open

2 February, 2023

HONORARY DOCTOR. All staff at Sahlgrenska Academy may nominate honorary doctorates. The appointments are evidence of the faculty’s appreciation, a …  

Depression and low quality of life 30 years after chemical attack

27 January, 2023

NEW STUDY. Mustard gas harms the vision, skin and breathing. Three decades on, however, the predominant effect is mental ill-health. At a time …  

Testing a immunological drug as a new treatment for early type 1 diabetes

26 January, 2023

CLINICAL STUDY. A large clinical study is now beginning on an approved drug for treating psoriasis. The drug will be tested on patients who were …  

Emma Eckernäs: GU now surveying doctoral students’ work environment too

25 January, 2023

COLUMN. For the first time, the work environment survey (ARK) at the University of Gothenburg (GU) now contains a sub-survey aimed specifically …  

Nominate for the award “PhD Thesis of the Year”

24 January, 2023

AWARD. Do you know of a really good thesis that was defended last year? Until February 7, you can nominate for the Sahlgrenska Academy's PhD …  

New legislation for clinical trials of medicinal products

24 January, 2023

RESEARCH RESOURCES. New EU legislation for clinical trials of medicinal products will be phased in over the coming years. All new applications …  

Joining forces for research on asthma, allergy, and airways

24 January, 2023

RESEARCH CONDITIONS. "Breathe Sweden", a digital platform for researchers who collect studies on diseases and disorders of the respiratory tract, …  

Fewer surgically treated ankle fractures with a clear-cut treatment routine

24 January, 2023

DOCTORAL THESIS. It has been shown that the percentage of ankle fractures that undergo surgery could be substantially reduced, from more than 30 …  

More news...

Sahlgrenska Academy

© University of Gothenburg
PO-Box 100, S-405 30 Gothenburg, Sweden
Phone: 00 46 31 786 0000

About the website

Elin Lindström is editor for Akademiliv.
Please feel free to send your ideas and comments to akademiliv@gu.se

Sign up for the Akademiliv newsletter:

Send you tips to Akademiliv

Do you have a suggestion for news, grants, seminars or an education?
Send an email to Elin Lindström Claessen