Breast cancer

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Lynch Syndrome in Ireland: An opportunity for cancer prevention?

English: The island of Ireland, showing intern...Lynch Syndrome is an inherited cancer syndrome which causes up to 1 in 20 cases of bowel cancer in Ireland, that is equivalent to over 100 cases annually in the Republic of Ireland alone.  It is also an important cause of multiple cancers outside the bowel including endometrial, ovarian, and urinary tract cancers.

Prevention of cancer in people at high risk depends on the accurate identification of families with this condition. However it is estimated that over 90% of families remain unidentified. Currently there are two clinical genetics centres in Ireland, in Dublin and Belfast. Unfortunately there is only limited access to genetic testing particularly in the Republic of Ireland where testing for Lynch Syndrome may only be requested from within the genetics department in Dublin.  Thus it may be argued that much more could be done to improve the management of this condition in Ireland.

Some published data indicates that Lynch Syndrome may account for up to 5% of colorectal cancer in Ireland, thus this has a highly clinically significant impact.


1. Irish Cancer Society Factsheet

2. National Centre for Medical Genetics Information

A series of published abstracts from international medical conferences have been reproduced below which summarise the available academic work on Lynch Syndrome in Ireland.

Screening an Irish cohort with colorectal cancer for Lynch Syndrome using immunohistochemistry for mismatch repair proteins

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 10547 © 2007 American Society of Clinical Oncology. D. G. Power, M. P. Farrell, C. B. Muldoon, E. Fitzpatrick, C. Stuart, D. Flannery, M. J. Kennedy, R. B. Stephens and P. A. Daly St James’s Hospital, Dublin, Ireland Background: Large-scale screening for germ-line mutations that lead to the onset of disease in adulthood is possible owing to recent technical advances. The care of those with inherited predisposition to breast and ovarian cancer is now becoming a mainstream component of medical care. It is more difficult to identify those with Lynch Syndrome (LS) as various criteria (Amsterdam and Bethesda) have not proved definitive. An important development is the examination of tumor tissue to detect mismatch repair (MMR) protein loss using immunohistochemical (IHC) techniques. When coupled with family history those at risk of harbouring a mutation for LS can be identified. Once a mutation is identified predictive testing can be offered to family members, risk-reduction measures applied and mortality from colorectal cancer reduced. Methods: Screening for MMR protein expression (MLH1, MSH2, MSH6, PMS2) was planned on all colorectal cancer (CRC) cases using IHC on formalin-fixed tumor tissue from January 1st 2002. Local ethics committee approval was obtained and then written informed-consent from patients. Family history data was gathered from the index case or an appropriate relative. An aliquot of blood was stored from index cases for subsequent genetic screening if indicated by IHC analysis and genetic counseling. Results: 108 cases with CRC (62 male, 46 female, median age 59 years) from a potential total of 612 have been screened for MMR protein expression by a gastrointestinal pathologist and independently validated. Turn-around time for IHC analysis was 9 weeks. 5 patients (4.6%) had loss of MMR proteins, MSH2/MSH6- 2 cases, MSH6 alone- 1 case and MLH1/PMS2- 2 cases. All 5 have opted for genetic counselling and sequencing of relevant genes. Conclusion: These early results in an Irish cohort with CRC showing MMR loss in 4–5% of cases is consistent with other population findings. Microsatellite instability analysis is difficult, expensive and relatively unavailable. IHC, however, is an established technique in pathology departments and can be the cheapest and most reproducible approach to identify LS cases. IHC results along with robust family data can guide the genetic counseling process towards preventing deaths from CRC and other LS-associated cancers. Published on Meeting Library (

Investigating parent of origin effects (POE) and anticipation in Irish Lynch syndrome kindreds. 

J Clin Oncol 30: 2012 (suppl 34; abstr 431) Author(s): Michael P. Farrell, David J. Hughes, Jasmin Schmid, Philip S. Boonstra, Bhramar Mukherjee, Margaret B. Walshe, Padraic M. Mac Mathuna, David J. Gallagher; Mater Private and Mater Misericordiae University Hospital, Dublin, Ireland; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Biostatistics, University of Michigan, Ann Arbor, MI; High Risk Colorectal Family Clinic, Mater Misericordiae University Hospital, Dublin, Ireland; Mater Private Hospital and Mater Misericordiae University Hospital, Dublin, Ireland

Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. Previous studies have provided limited evidence for and against both POE effect and anticipation in Lynch syndrome. We sought evidence for a specific POE effect and anticipation in Irish Lynch syndrome families. Methods: Affected parent-child pairs (APCPs) (N = 53) were evaluated from kindreds (N = 20) from two hospital-based registries of MMR mutation carriers. POE were investigated by studying the ages at diagnosis in the offspring of affected parent-child pairs. Anticipation was assessed using the bivariate Huang and Vieland model. Results: Paired t-test revealed anticipation with children developing cancer mean 11.8 years earlier than parents, and 12.7 years using the Veiland and Huang bivariate model (p < 0.001). Conclusions: These data demonstrate a similar age at diagnosis among all offspring of affected mothers that was indistinguishable from affected fathers. Affected sons of affected mothers were diagnosed with cancer almost 3 years younger than female offspring; however, this finding failed to reach statistical significance. Genetic anticipation was present in this cohort of LS families, emphasizing the importance of early-onset screening. An additional 60 LS kindreds are under review and updated data will be presented at the meeting. POE effect: comparison in age at diagnosis in 53 affected parent-child pairs with Lynch syndrome associated malignancies. Affected mothers Affected fathers P value Unique parent N = 14 N = 13 0.28 Mean = 48.8 Mean = 53.6 Range = 27-73 Range = 36-85 All offspring N = 24 N = 30 0.67 Mean = 40.4 Mean = 41.6 Range = 23-72 Range = 23-60 Female offspring N = 6 N = 15 0.75 Mean = 42.5 Mean = 41.06 Range = 31-64 Range = 27-58 Male offspring N = 18 N = 15 0.94 Mean = 39.77 Mean = 40.07 Range 23-72 Range = 20-60 P value female vs male offspring 0.604 0.95 ________________________________________ Source URL: Published on Meeting Library ( Home > 88749-115 ________________________________________ 88749-115

Breast cancer in Irish families with Lynch syndrome.

J Clin Oncol 30, 2012 (suppl 4; abstr 413) Author(s): E. J. Jordan, M. P. Farrell, R. M. Clarke, M. R. Kell, J. A. McCaffrey, E. M. Connolly, T. Boyle, M. J. Kennedy, P. J. Morrison, D. J. Gallagher; Mater University Hospital, Dublin, Ireland; St. James Hospital, Dublin, Ireland; Mater University Hospital , Dublin , Ireland; Belfast City Hospital HSCTrust, Belfast, Northern Ireland Background: Breast cancer is not a recognised malignant manifestation of Lynch Syndrome which includes colorectal, endometrial, gastric, ovarian and upper urinary tract tumours. In this study we report the prevalence of breast cancer in Irish Lynch Syndrome families and determine immunohistochemical expression of mismatch repair proteins (MMR) in available breast cancer tissue. Methods: Breast cancer prevalence was determined among Lynch Syndrome kindreds from two institutions in Ireland, and a genotype phenotype correlation was investigated. One kindred was omitted due to the presence of a biallelic MMR and BRCA1 mutation. The clinicopathological data that was collected on breast cancer cases included age of onset, morphology, and hormone receptor status. Immunohistochemical staining was performed for MLH1, MSH2, MSH6, and PMS2 on all available breast cancer tissue from affected individuals. Results: The distribution of MMR mutations seen in 16 pedigrees was as follows; MLH1 (n=5), MSH2 (7), MSH6 (3), PMS2 (1). Sixty cases of colorectal cancer and 14 cases of endometrial cancer were seen. Seven breast cancers (5 invasive ductal and 2 invasive lobular cancers) and 1 case of ductal carcinoma in situ were reported in 7 pedigrees. This compared with 4 cases of prostate cancer. Six MSH2 mutations and 1 MSH6 mutation were identified in the 7 Lynch syndrome kindreds. Median age of breast cancer diagnosis was 49 years (range 38-57). Hormone receptor status is available on 3 breast cancer cases at time of abstract submission; all were ER positive and HER 2 negative. All cases had grade 2 or 3 tumours. Final results of immunohistochemistry for mismatch repair protein expression on breast cancer samples are pending and will be reported at the meeting. One breast cancer has been tested to date and demonstrated loss of MSH2 protein expression in an individual carrying an MSH2 mutation. Conclusions: Breast cancer occurred at an early age and was more common than prostate cancer in Irish Lynch Syndrome pedigrees. All reported breast cancer cases were in kindreds with MSH2 or MSH6 mutations. Enhanced breast cancer screening may be warranted in certain Lynch Syndrome kindreds. ________________________________________ Source URL:

Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome.

Fam Cancer. 2012 Sep;11(3):509-18. doi: 10.1007/s10689-012-9544-4.Farrell MP, Hughes DJ, Berry IR, Gallagher DJ, Glogowski EA, Payne SJ, Kennedy MJ, Clarke RM, White SA, Muldoon CB, Macdonald F, Rehal P, Crompton D, Roring S, Duke ST, McDevitt T, Barton DE, Hodgson SV, Green AJ, Daly PA. Source Department of Cancer Genetics, Mater Private Hospital, Dublin 7, Ireland.

Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic. PMID: 22773173 [PubMed – indexed for MEDLINE]

Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than Hereditary Non Polyposis Colorectal Cancer cohorts

Ulster Med J. 2008 January; 77(1): 25–30. PMCID: PMC2397009 Lisa A Devlin,1 Colin A Graham,1 John H Price,2 and Patrick J Morrison1

Objective To determine and compare the prevalence of MSH6 (a mismatch repair gene) mutations in a cohort of families with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), and in an unselected cohort of endometrial cancer patients (EC). Design Two patient cohorts participated in the study. A cohort of HNPCC families who were known to the Regional Medical Genetics department, and an unselected cohort of patients with a history of EC. All participants received genetic counselling on the implications of molecular testing, and blood was taken for DNA extraction with consent. All samples underwent sequencing and Multiple Ligation probe analysis (MLPA) for mutations in MSH6. Populations DNA from one hundred and forty-three probands from HNPCC families and 125 patients with EC were included in the study. Methods Molecular analysis of DNA in all participants from both cohorts for mutations in MSH6. Outcome measures Prevalence of pathogenic mutations in MSH6. Results A truncating mutation in MSH6 was identified in 3.8% (95% CI 1.0–9.5%) of patients in the endometrial cancer cohort, and 2.6% (95% CI 0.5–7.4%) of patients in the HNPCC cohort. A missense mutation was identified in 2.9% and 4.4% of the same cohorts respectively. No genomic rearrangements in MSH6 were identified. Conclusion MSH6 mutations are more common in EC patients than HNPCC families. Genomic rearrangements do not contribute to a significant proportion of mutations in MSH6, but missense variants are relatively common and their pathogenicity can be uncertain. HNPCC families may be ascertained through an individual presenting with EC, and recognition of these families is important so that appropriate cancer surveillance can be put in place. Keywords: Endometrial, Cancer, MSH6, HNPCC


Awareness of symptoms could eliminate 5600 late cancer diagnoses in England each year

BMJ 2012; 345 doi: (Published 13 November 2012)

Cite this as: BMJ 2012;345:e7669

by Zosia Kmietowicz

Age, sex, and income as well as the type of cancer influence the stage at which patients’ cancer is diagnosed, a study has found.

Eliminating these demographic inequalities would help improve the chances of a cure for up to 5600 patients in England with seven common cancers each year, the researchers have estimated.

For the study, published in the Annals of Oncology, researchers from the University of Cambridge and the Eastern Cancer Registration and Information Centre examined data on the stage at diagnosis of nearly 100 000 patients with any of 10 different cancers, including the five most common (lung, breast, prostate, colon, and rectal cancers) and also bladder, kidney, ovarian, and endometrial cancers and melanoma.1

They found that melanoma and prostate, endometrial, and breast cancers in patients in the most deprived socioeconomic groups were more likely than those in the least deprived to be diagnosed in advanced stages. The increase in risk of late diagnosis according to deprivation ranged from more than double for melanoma (odds ratio 2.24 (1.66 to 3.03) to a third more for breast cancer (1.31 (1.15 to 1.49)).

For other cancers age and sex were important determinants of late diagnosis. Men with melanoma and those with lung cancer were more likely to have their cancer diagnosed at an advanced stage than were women with the same cancer.

The researchers also found that for melanoma and breast, prostate, and endometrial cancers older patients were more likely to be given a diagnosis at an advanced stage. But for lung, bladder, and renal cancers the opposite was true, with diagnosis at an advanced stage being less likely among older patients. This may be because older patients had more tests than younger patients, say the researchers.

During the study period, 2006-10, there were no notable social inequalities in the risk of diagnosis at an advanced stage among patients with bowel cancer and among women with ovarian cancer.

Because melanoma and breast and endometrial cancers are easy to diagnose, delays in detecting these cancers are probably because of patients’ lack of awareness of symptoms, say the researchers.

The lead author, Georgios Lyratzopoulos, a researcher at the University of Cambridge, said, “We know that earlier stage diagnosis of cancer is important: it dramatically improves the effectiveness of treatment and survival for many cancers. This study documents the importance of awareness of cancer symptoms and signs by patients of all social groups. It provides clear evidence about which patient groups would benefit most from targeted campaigns to raise awareness of different cancers.”

The findings could help target publicity about cancer at groups at high risk of late diagnosis, say the researchers. For example, older men from deprived groups would benefit from information about melanoma, while older women could be targeted with material on breast and endometrial cancers.


Cite this as: BMJ 2012;345:e7669


Lyratzopoulos G, Abel GA, Brown CH, Rous BA, Vernon SA, Roland M, et al. Socio-demographic inequalities in stage of cancer diagnosis: evidence from patients with female breast, lung, colon, rectal, prostate, renal, bladder, melanoma, ovarian and endometrial cancer. Ann Oncol2012, doi:10.1093/annonc/mds526.

Genetic testing: NHS ‘must back revolution’

BBCGenetic testing: NHS ‘must back revolution’

By James Gallagher, Health and science reporter, BBC News Jan 2012

Genetic code The cost of working out a patient’s genetic code is falling

Related Stories

Putting genetic testing at the heart of the NHS could herald a “revolution” in diagnosing, treating and preventing disease, according to the government’s genetics adviser.

Prof Sir John Bell has been presenting a report on how the NHS should prepare for advances in the field.

He said missing out would come at a high cost to patients.

Health Secretary Andrew Lansley has announced plans to speed up the introduction of genetic cancer tests.

One of the problems with modern medicine is that some of the definitions of disease are too broad.

Prof Bell told the BBC: “Breast cancer has always been defined because it is a tumour in the breast.

“But if you look at the molecular detail of those cancers, some are much more similar to ovarian cancers than they are to other breast cancers, in molecular terms and in terms of their response to therapy.”

Target treatment

Cancer drugs are generally effective in fewer than one in three patients who take them, the report says.

“Innovation in any setting has to deliver a much better product or lower cost, or both, and I think genetics may be one of the things that does both”

Prof Sir John Bell Chair of Human Genomics Strategy Group

The theory is that by looking at which genes are active inside a tumour, it will be possible to pick the correct treatment.

This is already happening in some cases. Bowel cancer patients with the defective gene K-RAS do not respond to some drugs, while the breast cancer drug herceptin works only if patients have a specific mutation, HER2.

One of the driving forces behind genetics in medicine is the plummeting cost of working out a patient’s genetic code. To sequence one patient’s genome once cost millions of pounds but it now costs thousands, and Prof Bell argues that in the future, the “cost could be essentially nothing”.

Prof Bell has previously accused the NHS of being “completely unprepared” for advances in the field of genetics. He has called for ministers to develop a strategy which would see the NHS adopting genetic tools, and training current and new staff in genetics.

He also wants a national centre which could store genetic information about patients who were sequenced. It would allow doctors to compare mutations in the genetic code with other patients who had the same mutation, to help plan treatment.

“We want to make sure that all patients can benefit from these tests”

Andrew Lansley Health Secretary

Prof Bell acknowledged that reforming the healthcare system to take greater account of genetics would require investment, but he added: “Innovation in any setting has to deliver a much better product or lower cost, or both, and I think genetics may be one of the things that does both.”

More testing

The government has yet to formally respond to the recommendations. However, Mr Lansley has announced plans to develop a new way of introducing and funding genetic tests for cancer.

“We want to make sure that all patients can benefit from these tests – as soon as the tests are recommended by NICE (the National Institute for Health and Clinical Excellence),” he said.

He compared the genetic code to a treasure map, saying the Xs were starting to appear, and that the promise of the field was “immense”.

The chief medical officer for England, Prof Dame Sally Davies, said genetics was “terrifically exciting” and would have an “increasingly important role” in areas such as cancer screening.

However, she said she was “quite worried” about some of the consequences, such the possibility that telling patients they had a low risk of developing lung cancer would give them a licence to smoke.


Hereditary Breast and Colorectal Cancer – what is the genetic link?

The association between breast and colorectal cancer in not clear.  There is an increased incidence of breast cancer and colorectal hamartomas which may lead to colorectal cancer in PTEN-mutation spectrum disorders such as Cowden’s Syndrome, and in Peutz-Jeghers Syndrome.  Data from genome-wide association studies demonstrates association of a common but low penetrance (weak) risk locus at chromosome 8q24.

Lynch Syndrome
The link between Lynch Syndrome has been controversial, but two recent studies have added weight to Lynch Syndrome as a risk factor for breast cancer.  A recent study in JNCI (Win et al 2012) suggests that amongst Lynch Syndrome patients the risk of breast cancer as a second cancer after a diagnosis of colorectal cancer may be increased by about 76%.  An earlier study this year suggests that their is molecular evidence for this association (Buerki et al Genes Chromosomes Cancer 2012).


Some studies in Li-Fraumeni Syndrome families identified mutations in CHEK2 as possible cause for this condition (Bell et al Science 1999).  This link has not been reproducible but the variant 1100 may be a population variant which increases risk in Ashkenazi Jewish populations.

Families with Li-Fraumeni Syndrome and CHEK2 mutations

Evidence demonstrates that a subset of families with hereditary breast and colon cancer may have a cancer family syndrome caused by a mutation in the CHEK2 gene. Although the penetrance of CHEK2 mutations is clearly less than 100%, additional studies are needed to determine the risk of breast, colon, and other cancers associated with CHEK2 germline mutations. One large study showed that truncating mutations in CHEK2 were not significantly associated with CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR], 1.5; 95% CI, 1.2–3.0) of CRC.

Similar results were obtained in another study conducted in Poland. In this study, 463 probands from LS and LS–related families and 5,496 controls were genotyped for four CHEK2 mutations, including I157T. The missense I157T allele was associated with LS–related cancer only for MMR mutation-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating mutations. Further studies are needed to confirm this finding and to determine whether they are related to familial CRC type X.

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