paywalled: Individuals at high-risk for pancreatic cancer development: Management options and the role of surgery (Lynch Syndrome, breast/ovarian BRCA 2....)

 Blogger's Note: while full access is by subscription only, key words indicate 'high risk' categories not limited to Lynch Syndrome, BRCA 2;  BRCA 2 - blogger's assumption based on genetics in absence of full text acccess)

Individuals at high-risk for pancreatic cancer development: Management options and the role of surgery

Abstract 

Pancreatic cancer (PC) is a highly lethal disease. Despite advances regarding the safety and long-term results of pancreatectomies, early diagnosis remains the only hope for cure. This necessitates the implementation of an intensive screening program (based mainly on modern imaging), which – given the incidence of PC – is not cost effective for the general population. However, this screening program is recommended for individuals at high-risk for PC development.

Indications for screening include the following three clinical settings: hereditary cancer predisposition syndromes associated with PC, hereditary pancreatitis and familial pancreatic cancer syndrome. The aim of this strategy is to identify pre-invasive (precursor) lesions, which are curable. Surgery is recommended in the presence of recognizable lesion on imaging lesions. Partial (anatomic) pancreatectomy – depending on the location of the suspicious lesion – is the most widely accepted type of surgical intervention in this setting; occasionally, however, total pancreatectomy may be required, in carefully selected patients. Despite that experience still remains limited, there is evidence that this aggressive strategy allows early detection of neoplastic lesions, thereby improving the effectiveness of surgery and prognosis.

Keywords: Pancreas, Surgery, Cancer, PanIN, MCN, IPMN, Pancreatectomy, Total pancreatectomy, Screening

Abbreviations: PanIN, pancreatic intraepithelial neoplasia, IPMN, intraductal papillary mucinous neoplasm, MCN, mucinous cystic neoplasm, PJS, Peutz–Jeghers syndrome, FAMMM syndrome, familial atypical multiple mole melanoma syndrome, HNPCC, hereditary non-polyposis colon cancer (Lynch syndrome), HOBC, hereditary ovarian and breast cancer, VHL, von Hippel–Lindau, PD, pancreatoduodenectomy

Commentary: Does aspirin really reduce the risk of colon cancer? : The Lancet

Does aspirin really reduce the risk of colon cancer? : The Lancet

Does aspirin really reduce the risk of colon cancer?

The study by John Burn and colleagues1 is unquestionably a superb piece of work that opens the door to formalised chemoprevention in young carriers of Lynch syndrome. However, setting aside the fact that the primary intention-to-treat analysis was not significant, there is a need to address whether these data are applicable to others at need of chemoprevention.

Specifically, the study included a predominantly young population with a mean age at recruitment in the early 40s and a mean follow-up of 5 years. Therefore the current age of participants is about 50 years. At this age, the frequency and severity of aspirin complications is very low.2 Indeed the number of adverse events quoted in the paper's appendix is only 21 in more than 400 aspirin-taking patients. Moreover, Rothwell and colleagues3 have indicated that, for the general public or those at risk of more common cancers, taking aspirin before 55 years of age will not have a significant benefit. Furthermore, the mean period of treatment is just more than 2 years and although this suggests an impressive effect, it means that the long-term safety is unknown.4

In conclusion, although this study is excellent news for patients with Lynch syndrome, we need data from other large and long-term randomised trials with cancer endpoints such as the AspECT trial to assess the safety of aspirin in an older and more general population.5

abstract: Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression

 http://cancerres.aacrjournals.org/content/early/2012/04/17/0008-5472.CAN-11-2619.abstract
  
Abstract

Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell cycle regulators. However, epidemiologic studies evaluating hormone therapy (HT) use and colorectal cancer risk by the status of cell cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between HT use and colorectal cancer risk differs by the molecular pathological status of microsatellite instability (MSI) and expression of cell cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between HT use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105520 postmenopausal women. We found a difference between HT use and colorectal cancer risk according to CDKN1A expression (p-value for heterogeneity=0.01). Current HT use was associated with a reduced risk for CDKN1A-nonexpressed (multivariate relative risk (RR)=0.61, 95% confidence interval (CI), 0.46-0.82), but not for CDKN1A-expressed (RR=1.32, 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A-nonexpressed, but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between HT use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular epidemiology findings suggest a preventive effect of HT against colorectal carcinogenesis which depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.

abstract: Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature.

Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature.

Hum Pathol. 2012 Apr 17;


Abstract

Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair-deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum.

Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families.

As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome.

Pinterest: Lynch Syndrome

Lynch Syndrome

Health Imaging: Uptick in colorectal cancer among under-50 crowd poses questions for researchers (Lynch Syndrome....)

Uptick in colorectal cancer among under-50 crowd poses questions for researchers

 ....Whatever the cause, the rate of colorectal cancer in young adults has increased to the point where nearly 10 percent of new diagnoses are in patients younger than 50. Most of these patients were diagnosed in their forties, but the disease has been found in patients in their twenties and thirties.......Another troubling recent finding is that when colorectal cancers are diagnosed in younger patients, they are more likely to be at an advanced stage of the disease. A study published Feb. 13 online in Archives of Internal Medicine found 63 percent of colon cancers and 57 percent of rectal cancers are stage III or IV at diagnosis......“The important thing for radiologists would be the notion that certain individuals, because of their age, may be denied radiology procedures by insurance companies,” she said.......

open access: Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome

ScienceDirect.com - Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome

 "....While endometrial cancer diagnosed under the age of 50 is not included in the Revised Bethesda Guideline, evidence suggests that these individuals should be evaluated for Lynch syndrome (Resnick et al., 2009). The patient presented was diagnosed with endometrial cancer at the age of 41 and genetic testing revealed triple heterozygosity for BRCA2, MLH1 and MSH6 mutations."

 Introduction

Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant cancer susceptibility syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, MLH1, MSH2, and less frequently MSH6 and PMS2. MMR mutation carriers are predisposed primarily to colorectal cancer and endometrial cancer, with an increased frequency of stomach, ovary, pancreas, upper urinary tract, brain, small bowel, and skin consistently reported. This hereditary syndrome accounts for approximately 2–3% of colorectal cancers and 1–4% of endometrial cancers in the United States (Lynch and de la Chapelle, 2003). Depending on the MMR gene involved, women with Lynch syndrome can have up to an 80% lifetime risk of developing colorectal cancer, and a 20–60% risk of endometrial cancer.

Germline mutations in BRCA1 or BRCA2 (BRCA1/2) cause hereditary breast ovarian cancer syndrome. Female carriers of BRCA1/2 mutations have excessive risks for both breast and ovarian cancer, with lifetime breast cancer estimates ranging from 45% to 84%, and lifetime ovarian cancer estimates ranging from 11% to 62%, depending upon the population studied. BRCA1/2 kindreds are also noted to have an increased frequency of prostate cancer, and in BRCA2 kindreds, increased frequencies of pancreatic cancer and melanoma are observed. The frequency of BRCA1 or BRCA2 mutations in the general population is estimated to be 1 in 300 to 1 in 800, respectively (King et al., 2003).

While there are kindreds with more than one cancer susceptibility syndrome and/or mutation reported in the literature ( [Thiffault et al., 2004] and [Smith et al., 2008]), they are not often encountered in routine clinical settings........

Highlights

► Endometrial cancer with BRCA2 mutation and double heterozygosity for Lynch syndrome.
► Loss of MLH1 and PMS2 by immunohistochemical stain.
► MSH1 and MSH6 gene mutations by genomic sequencing.

abstract: Uroepithelial (bladder/ureter) and kidney carcinoma in Lynch syndrome (MSH2)

Uroepithelial and kidney carcinoma in Lynch syndrome [Fam Cancer. 2012] - PubMed - NCBI
 

Fam Cancer. 2012 Apr 4

Abstract

Increased risk for urological tumors has been observed in mutation carriers with Lynch syndrome (LS). In this study, we evaluated the clinical features of uroepithelial (bladder and ureter) and kidney cancers in 974 Finnish mutation carriers. Altogether 30 patients had a total of 34 urological tumors: 12 ureter, 12 bladder, and 10 kidney cancers. Urological tumor was the only tumor in 9 (30 %) patients, and metachronous other tumor occurred in 21 (70 %). The occurrence of uroepithelial cancers was significantly higher in MSH2 mutation carriers (6 %) than in MLH1 carriers (2 %) and MSH6 mutation carriers (0 %).

The mean ages of patients at the time of diagnosis were: bladder cancer, 57 years; ureter cancer, 58 years; and kidney cancer, 64 years. Overall 5-year survival rates were 70 % in bladder cancer, 81 %  in ureter cancer, and 75 % in kidney cancer.

Cancer-specific 5-year survival rates were 70 %  in bladder cancer, 91 %  in ureter cancer, and 100 % in kidney cancer.

In conclusion, early age of onset was observed in patients with uroepithelial tumors, but not in patients with kidney cancer. The frequency of uroepithelial tumors was significantly higher in MSH2 mutation carriers than in MLH1 carriers. Further studies with larger numbers of patients, however, are needed to evaluate the potential benefit of surveillance of urological tumors in LS.

abstract: Microsatellite Instability in Saliva from Patients with Hereditary Non-polyposis Colon Cancer (HNPCC/Lynch Syndrome) and Siblings Carrying Germline Mismatch Repair Gene Mutations

Microsatellite Instability in Saliva from Patients with Hereditary Non-polyposis Colon Cancer and Siblings Carrying Germline Mismatch Repair Gene Mutations

"Saliva testing, a less-invasive procedure than PBL ( peripheral blood lymphocytes) testing, is more sensitive and appears to be a viable alternative for identifying MSI in carriers with MMR mutations."

open access: Microsatellite Instability and DNA Mismatch Repair Protein Deficiency in Lynch Syndrome Colorectal Polyps - multinational study

Blogger's Note: as determined by the title, focus is on colorectal cancer in Lynch Syndrome; see also prior posting Diagnosing Lynch Syndrome: More Light at the End of the Tunnel which gives a more comprehensive overall view of Lynch Syndrome

                           ~~~~~~~~~~~~~~~~~

Microsatellite Instability and DNA Mismatch Repair Protein Deficiency in Lynch Syndrome Colorectal Polyps

"Lynch syndrome results from germline mutations in one
of the genes involved with DNA mismatch repair (MMR):
MLH1, MSH2, MSH6, PMS2, or EPCAM/TACSTD."

"The aim of this study was to determine the prevalence
of MSI and loss of MMR protein expression by immunohistochemistry
in colorectal polyps from patients with genetically confirmed Lynch syndrome."

open access: Perspectives - Diagnosing Lynch Syndrome: More Light at the End of the Tunnel

Diagnosing Lynch Syndrome: More Light at the End of the Tunnel

"Lynch syndrome is one of the most commonly inherited
cancer conditions, accounting for 2% to 4% of colorectal
cancer (CRC) cases. The population frequency of Lynch
syndrome is slightly more than one in 500 individuals (1).
In addition to a 50% to 80% lifetime risk of CRC, patients
with Lynch syndrome have a 40% to 60% risk of uterine
cancer and an elevated risk of ovarian, pancreatic, gastric,
upper-urinary tract, renal, biliary, small bowel, and central
nervous system (CNS) malignancies.

"Colorectal surveillance of persons with this condition leads to greatly reduced CRC incidence and mortality. Appropriately timed hysterectomy and ovarectomy likewise results in a reduced incidence of malignancies in these organs. The diagnosis of Lynch syndrome is thus critical to the prevention and early detection of cancer in affected persons and families, notwithstanding that the effectiveness of screening patients with Lynch syndrome for non colorectal and non uterine malignancies remains uncertain. As will be discussed later, the article by Yurgelun and colleagues in this issue of the journal provides an important new tool for the diagnosis of Lynch syndrome (2).
The major issue in Lynch syndrome remains failure to
diagnose for a variety of reasons......."

".....It seems that MSI or immunohistochemical
testing in uterine cancers may be as effective as in
CRCs and therefore should also be considered in evaluating
persons and families for Lynch syndrome (17, 18). Whether
tumor testing in other (nonuterine or noncolorectal)
Lynch-associated malignancies would be as effective is
unclear....."

"............Next generation sequencing also may soon
be available for individual testing at reasonable costs.
Such new testing developments may well make direct-to-genetic
testing based on risk increasingly attractive. At
some point, general testing for an inherited syndrome
without regard to risk may even become a reality, which would get the diagnosis of Lynch syndrome out of the tunnel altogether."

abstract: Role of the Msh2 gene (Lynch Syndrome) in genome maintenance and development in mouse fetuses.

Role of the Msh2 gene in genome maintenance and development in mouse fetuses

These results indicate that elevated mutation levels have little effect on the development of the fetus, even if a mutator phenotype appears at the organogenesis stage.

 Abstract
In an attempt to evaluate the roles of the mismatch repair gene Msh2 in genome maintenance and in development during the fetal stage, spontaneous mutations and several developmental indices were studied in Msh2-deficient lacZ-transgenic mouse fetuses.

abstract: Insertion of an SVA element, a non-autonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.

Insertion of an SVA element, a non-autonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.:

Hum Mutat. 2012 Mar 27;


Abstract

Heterozygous germline mutations in the mismatch repair gene PMS2 predispose carriers for Lynch syndrome, an autosomal dominant predisposition to cancer. Here, we present a LINE-1-mediated retrotranspositional insertion in PMS2 as a novel mutation type for Lynch syndrome. This insertion, detected with Southern blot analysis in the genomic DNA of the patient, is characterized as a 2.2 kb long 5' truncated SVA_F element. The insertion is not detectable by current diagnostic testing limited to MLPA and direct Sanger sequencing on genomic DNA. The molecular nature of this insertion could only be resolved in RNA from cultured lymphocytes in which nonsense-mediated RNA decay was inhibited. Our report illustrates the technical problems encountered in the detection of this mutation type. Especially large heterozygous insertions will remain unnoticed because of preferential amplification of the smaller wild-type allele in genomic DNA, and are probably underreported in the mutation spectra of autosomal dominant disorders.

press release: Myriad Study Finds High Prevalence of Mutations in the PMS2 Gene (Lynch syndrome)

Myriad Study Finds High Prevalence of Mutations in the PMS2 Gene

"This study demonstrates the importance of the analyzing the PMS2 gene to fully comprehend a patient's Lynch syndrome status."

open access - Revie: Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine (references to Lynch Syndrome/Familial Melanoma)

Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine

pdf file

Genetic variants associated with breast cancer risk for BRCA1 mutations carriers

Genetic variants associated with breast cancer risk for BRCA2 mutations carriers

Patterns of association and tumour characteristics

Genetic modifiers of ovarian cancer risk

Environmental, hormonal and reproductive modifiers of risk

Common alleles and cancer risks for mutation carriers

Future challenges     "Over the past 5 years, there has been substantial progress in our understanding of genetic factors that modify breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. This was made possible to a great extent because of the availability of large numbers of mutation carriers from the CIMBA consortium and GWAS data. However, the five loci described in this review that are associated with breast cancer risk for BRCA1 mutation carriers are estimated to explain only approximately 3% of the genetic variability in breast cancer risk for BRCA1 mutation carriers. Similarly, the 11 SNPs associated with breast cancer risk for BRCA2 mutation carriers are estimated to account for approximately 6% of the genetic variability in breast cancer risk for BRCA2 mutation carriers. Therefore, the majority of the genetic variability in breast cancer risk for mutation carriers still remains unexplained. Several more breast and ovarian cancer susceptibility alleles have been identified through GWAS in the general population, but have not yet been investigated in mutation carriers [61, 63, 72, 75]. Given the observed association patterns in mutation carriers with previously identified loci, it is expected that at least a subset of these will also be associated with breast or ovarian cancer risk for mutation carriers. Additional genetic modifiers of risk may also be identified through not only the ongoing GWAS in BRCA1 and BRCA2 mutation carriers but also other GWAS from the general population or by GWAS focusing on specific cancer subtypes such as oestrogen-receptor-negative or triple-negative breast cancers, or serous ovarian cancer. However, it is likely that several of the alleles identified through population-based GWAS may be associated with modest relative risks in the range of 1.05–1.10. Despite sample sizes of approximately 15 000 BRCA1 and 10 000 BRCA2 mutation carriers, CIMBA would still be underpowered to detect modifying polymorphisms conferring such modest relative risks. Given the rarity of BRCA1 and BRCA2 mutations, increasing sample sizes is currently only possible through increased collaboration between studies and through continued recruitment of mutation carriers........

Conclusions

As more cost-effective mutation screening techniques become available, the number of identified BRCA1 and BRCA2 mutation carriers in the population is likely to increase. Therefore, it will be important that all mutation carriers are provided with accurate information on their risk of developing breast and ovarian cancer, so that informed decisions on clinical management are made. Our understanding of factors influencing cancer risk variability in mutation carriers has increased over the last few years and is likely to improve further in the near future. Therefore, we are getting closer to the goal of being able to provide more individualized clinical management. Understanding how cancer risks are modified in BRCA1 and BRCA2 mutation carriers will also provide further insights for studying the biological mechanisms of cancer development in mutation carriers. These may lead to the development of novel therapies and more accurate prediction of breast and ovarian cancer progression in mutation carriers.

Studying genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has provided useful insights in study design, analytical methodology and applications, which could be used for studying modifiers of disease in carriers of other high-risk mutations such as the mismatch repair genes MSH2, MLH1, MSH6, PMS2 in colorectal cancer (Lynch Syndrome) and CDKN2A in melanoma but also other noncancer-related diseases.

 

 

 

 

 

 

open access: Apr 2012 -Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) - Journal of Internal Medicine (BRCA, Lynch, high/low penetrance mutations....)

Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) -  Journal of Internal Medicine

open access pdf file


 "In this article, we review the current knowledge of the inherited genetics of epithelial ovarian cancer (EOC) susceptibility and clinical outcome. We focus on recent developments in identifying low-penetrance susceptibility genes and the role of the ovarian cancer association consortium (OCAC) in these discoveries. The OCAC was established to facilitate large-scale replication analyses for reported genetic associations for EOC. Since its inception, the OCAC has conducted both candidate gene and genome-wide association studies (GWAS); the latter has identified six established loci for EOC susceptibility, most of which showed stronger association with the serous histological subtype. Future GWAS and sequencing studies are likely to result in the discovery of additional susceptibility loci and may result in established associations with clinical outcome. Additional rare and uncommon ovarian cancer loci will likely be uncovered from high-throughput next-generation sequencing studies. Applying these novel findings to establish improved preventative and clinical intervention strategies will be one of the major challenges of future work....

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.:

Abstract
Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. .........................We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.

abstract: DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome (eg. BRCA2, MSH3 (polymorphisms)...)

DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome:

Source:Cancer Epidemiology, Volume 36, Issue 2


DNA repair plays a pivotal role in maintaining genomic integrity with over 130 genes involved in various repair pathways that include base excision repair, nucleotide excision repair, double strand break repair and DNA mismatch repair. Polymorphisms within genes that are involved in these processes have been widely reported to be associated with cancer susceptibility in an extensive range of malignancies that include colorectal cancer (CRC).

Lynch syndrome is caused by inherited germline mutations in DNA mismatch repair genes, predominantly in MLH1 and MSH2, that predispose to a variety of epithelial malignancies, most notably CRC. Despite being a relatively well understood hereditary cancer syndrome there remain several questions in relation to genetic influences on disease expression. Since Lynch syndrome is associated with a breakdown in DNA mismatch repair variation in other DNA repair genes may influence disease expression.

In this report we have genotyped 424 Australian and Polish Lynch syndrome participants for eight common DNA repair gene polymorphisms to assess any association with the age of CRC onset.

 The DNA repair gene SNPs included in the study were: BRCA2 (rs11571653), MSH3 (rs26279), Lig4 (rs1805386), OGG1 (rs1052133), XRCC1 (rs25487), XRCC2 (rs3218536 and rs1799793) and XRCC3 (rs861539). Cox multi-variant regression modelling failed to provide any convincing evidence of an effect in any of the polymorphisms analysed. The data suggest that polymorphisms in DNA repair genes do not contribute to cancer risk in a population of CRC patients who are at increased risk of disease as a result in a deficiency of DNA mismatch repair.

abstract: (Lynch Syndrome) Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study [Epidemiology] multi-national study

 Blogger's Note: some stats deleted for ease of reading, see abstract (or paid subscription for full details; interesting stat on female breast cancer


Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study [Epidemiology]:

Purpose
To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population.

Patients and Methods
We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.
Results
Over a median follow-up of 5 years, mutation carriers had an increased risk of

colorectal cancer (20.48),
endometrial cancer (30.62),  
ovarian cancer (18.81),
renal cancer (11.22),
pancreatic cancer ( 10.68), 
gastric cancer (9.78),  
urinary bladder cancer (9.51), and  
female breast cancer ( 3.95;).

We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (1.02).

Conclusion 
 We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.

Lynch Syndrome: Don't Miss It (Transcript including slides))

Blogger's Opinion/Note:
guidelines indicate varying ages of screening depending on organ assuming there are screening mechanisms (eg. ovarian cancer has no screening for the general population however increased surveillance is possible for those at high risk,  albeit, ineffective; generally 25 yrs +;  'averages' are not helpful and therefore the urging of family history taking by primary/family care physicians, see NCCN guidelines for Lynch Syndrome which includes gene-specific details (eg. MLH1, MSH2/6, PMS2.....)

Lynch Syndrome: Don't Miss It (Transcript)

Clinical Implications

"Lynch syndrome is a genetic defect that has significant implications on the clinical side. A patient whose genetic testing is positive for Lynch syndrome has a likelihood of developing colon cancer that approaches 70% over his or her lifetime. The risk for uterine cancer is similar or a bit higher, and the risk for ovarian cancer is13%-15%. Almost certainly, these patients will have some type of cancer during their lifetime.

Metachronous cancers occur in 7%-10% of patients with Lynch syndrome. These patients present with one cancer, and typically in the course of a short period of time, another cancer develops. In patients with Lynch syndrome who have colon cancer, if you don't perform a subtotal colectomy because you didn't recognize that it was Lynch syndrome, the likelihood that the patient will develop a repeat colon cancer over 30 years (even in patients who are being screened) approaches 65%. This is not uncommon. A lot of these diagnoses are missed, and a secondary cancer develops."

"You need to start thinking about syndromic cancers because the relative risk is quite high. You need to be thinking about this in patients with early cancers -- not just colon cancer, but in uterine cancer and ovarian cancer as well." (Blogger's Note: and others including pancreatic, stomach, ureter, renal, bilary tract, gallbladder.....see slides)

" If you look at colon cancer in Lynch syndrome, the average age of onset is earlier (45 years) and some patients may be in their 20s. For sporadic uterine cancer, the average age is approximately 60 years, but in Lynch syndrome, it is shifted by a decade, to 50 years. When you see these cancers in a younger patient, the bell should go off and you should start thinking about Lynch syndrome and doing the appropriate testing."

"It is important to think about extracolonic cancers in these patients and to start to put the dots together because we are missing the boat on a lot of these syndromic cancers. It's not a zebra; it's 2%-3% of the patients who are presenting with cancer. We need to think outside the box. Even if you are not a gastroenterologist, include the colon when you see syndromic related cancers of the uterus, ovary, small bowel, or stomach."