archives

Archive for

DNA polymerase proofreading associated-polyposis (PPAP): A new syndrome


An external file that holds a picture, illustration, etc. Object name is emss-53122-f0001.jpg

PAP family

Polymerase proofreading associated polyposis
(PPAP) is the suggested name for the condition predisposed by pathogenic mutations in the exoncuclease/proof reading domain of the POLE and POLD1 genes. This leads to a heritable susceptibility to developing multiple adenomas and/or early onset colorectal cancer.  The phenotype of PPAP is similar to that seen with MutYH associated polyposis (multiple adenomas) or Lynch syndrome (large adenomas or early onset carcinoma). Mutations in POLD1 are also associated with development of endometrial carcinoma.  Tumours tend to be microsatellite stable.

Mutations in related DNA polymerase genes POLE and POLD1 were described in families with oligopolyposis and endometrial cancer by Ian Tomlinson’s group in Oxford. An elegant approach was employed using whole-genome sequencing in 15 selected patients with more than ten adenomas before age 60 years. Several had a close relative with at least five adenomas who could also have whole-genome sequencing performed. All tested patients had CRC or a first-degree relative with CRC. All had negative APC, MYH, and MMR gene mutation test results. No variants were found to be in common among the evaluated families. In one family, however, linkage had established shared regions, in which one shared variant was found (POLE p.Leu424Val; c.1270C>G), with a predicted major derangement in protein structure and function. In a validation phase, nearly 4,000 affected cases enriched for the presence of multiple adenomas were tested for this variant and compared with nearly 7,000 controls. In this exercise, 12 additional unrelated cases were found to have the L424V variant, with none of the controls having the variant. In the affected families, inheritance of multiple-adenoma risk appeared to be autosomal dominant. Somatic mutations in tumors were generally consistent with the otherwise typical chromosome instability (CIN) pathway, as opposed to MSI or CIMP. No extracolonic manifestations were seen. A similar approach, whole-genome testing for shared variants, with further “filtering” by linkage analysis identified a variant in the POLD1 gene, p.Ser478Asn alteration, c.1433G>A). This S478N variant was identified in two of the originally evaluated families, suggesting evidence of common ancestry. The validation exercise showed one patient with polyps with the variant but no controls with the variant. Somatic mutation patterns were similar to the POLE variant. Several cases of early-onset endometrial cancer were seen. The mechanism underlying adenoma and carcinoma formation resulting from the POLE L424V variant appeared to be a decrease in the fidelity of replication-associated polymerase proofreading. This in turn appeared to lead to mutations related to base substitution.

 

The study authors recommend consideration of POLE and POLD1 testing in patients with multiple or large adenomas in whom alternatives mutation testing is uninformative and surveillance akin to that afforded patients with LS or MAP. POLE and POLD1 mutation testing is being incorporated into the new multigene CRC susceptibility panels.

Inherited Colorectal Cancer Course for the Multidisciplinary Team, London 15th January 2015


 

Date: January 15th, 2015

Venue: St Mark’s Hospital, London

Click here for more information

Target Audience:  All members of the Colorectal Cancer MDT (nurse specialists, oncologists, gastroenterologists, colorectal surgeons, pathologists), Geneticists, genetics counsellors

Learning Style: Lectures and case discussions

Learning Outcomes: On completion of this course, attendees will:

  • Appreciate the contribution of inheritance to colorectal cancer
  • Be able to assess family history and associated risk
  • Understand how to manage individuals at moderate risk of colorectal cancer
  • Understand the basic features and management of polyposis syndromes
  • Understand the diagnosis and management of Lynch syndrome

Course Fees:

£150.00 – Consultants
£75.00 – Nurses, Trainees and other Healthcare Professionals

To apply, complete the application form and send to nwlh-tr.StMarksAcademicInstitute@nhs.net.

For further information, view the programme and brochure for the course. If you have any questions, please feel free to contact the Academic Institute.

Genetic testing of young bowel cancer patients could save lives


Autosomal dominant pedigree chart. In Autosoma...

Lynch Syndrome  (LS), formerly known as Hereditary non-polyposis colorectal cancer (HNPCC) is a familial cancer syndrome; affected individuals have disease-associated mutations in one of a number of key genes involved in normal DNA repair processes (most commonly the MLH1, MSH2, MSH6  and PMS2 genes). This results in a significantly increased risk of developing certain forms of cancer, notably colorectal (bowel) cancer but also endometrial and ovarian cancers and a number of others.

Teenager Stephen Sutton, who raised millions of pounds for cancer research, had a family history of the syndrome.  The test for this condition is used in some UK hospitals but has not been rolled out nationally. It is offered to all bowel cancer patients in Denmark, and to patients under the age of 70 in Norway and the Netherlands.

New research published as a formal Heath Technology Assessment has examined the efficacy and cost-effectiveness of alternative strategies to diagnose LS in patients with early-onset colorectal cancer – those younger than 50, 60 or 70 years of age.

Identifying LS has important health benefits for the patients – allowing appropriate close monitoring or preventative treatments for different forms of cancer as well as recurrences of colorectal cancer; for example, removal of the womb or ovaries in women. Moreover, cascade testing of close relatives can also identify family members at high risk of the same cancers who would benefit from risk reduction strategies.

The researchers compared the alternative approaches of microsatellite instability (MSI) testing or immunohistochemistry (IHC), including economic data. Analysis of the available evidence showed that testing for LS newly-diagnosed colorectal cancer patients aged under 70 years is indeed cost-effective. No specific method emerged as a clear ‘gold-standard’ for testing but the most cost-effective approach was found to be the use of MSI and BRAF mutation testing; cascade testing of at-risk family members was recommended for all strategies.

Efforts to review the alternative techniques and develop a consensus optimal strategy for national implementation have been in progress for many years.

The new HTA findings, combined with a new clinical classification scheme for genetic variants associated with LS released by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) earlier this year, should underpin policy changes that will increase the numbers of people identified with LS and prevent cancers.

Dr Ian Frayling of Cardiff University‘s Institute of Medical Genetics, one of the researchers, told the BBC: “Now the cost of genetic testing is coming down there is a good argument for younger bowel cancer patients to be screened. It will save lives and save money for the NHS”.

Looking further ahead, he and colleagues recommended new research into the cost-effectiveness of testing for LS in younger patients with newly diagnosed endometrial or ovarian cancer, and of the value of treatment with aspirin to reduce the risk of future cancers.

Deborah Alsina, chief executive of Bowel Cancer UK, said while bowel cancer is relatively rare in people under 50, 550 people in this age group lose their lives to the cancer each year.

“It’s critical that more lives are saved by ensuring people gain access to the screening surveillance they need, so that bowel cancer can be ruled out first, not last, in younger patients.”

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,302 other followers

Live twitter feed

RSS CRUK Bowel Cancer Blog

  • An error has occurred; the feed is probably down. Try again later.

RSS Familial Cancer

  • An error has occurred; the feed is probably down. Try again later.

Categories

Google Plus

%d bloggers like this: