Cancer Treatment

Testing the family members for BRCA

Ly Summary:It often makes sense to test teh family member with the cancer first but many insurers object.

The common approach among those suspected of BRCA testing is to test a family member who is already diagnosed with breat or ovarian cancer. If a particular mutation si identified, a search for that mutation is indicated and sequencing of common variants or the entire gene is not necessary. A negattive test decreases the possibility that a family member carries BRCA. It will not completely obviate the need for BRCA testing if there si high suspiction of it in a family member but makes it less likely and necessary.

Most often, the first person that is tested in a family for BRCA-1 and BRCA-2 mutations is one who developed breast or ovarian cancer since this determines if the cancer in the family is associated with a BRCA mutation. If a mutation is found, it becomes a simple matter to test other blood relatives for the same mutation. If a mutation is not found in the family member who has or had cancer, the test is not informative and would not provide helpful information to other family members. If no family members with cancer are living or available for testing, testing options are generally considered on a case-by-case basis for each family.
There are no guidelines that recommend this approach and no studies. In addition, the benefit is to the family member and coverage for that is the family mebmer's responsibility and that of her plan.

U.S. Preventive Services Task Force (USPSTF). Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005 Sep 6;143(5):355-61.

http://www.cdc.gov/genomics/training/perspectives/factshts/breastcancer.htm#Ref11

CHEK2, P53, PTEN for breast cancer genetic testing

Despite a negative (normal) genetic test for mutations in the BRCA1 and BRCA2 genes, about 12 percent of breast cancer patients from high-risk families carried previously undetected cancer-associated mutations. Risks for young women with inherited BRCA1 or BRCA2 mutations are particularly increased. Among white women in the U.S., 5 percent to 10 percent of breast cancer cases are due to inherited mutations in BRCA1 and BRCA2. Inherited mutations in other genes, including CHEK2, TP53 and PTEN, can also influence risk of breast cancer.  BART and PTEN mutationa are reviewed as a separate entry.

There is currently no clear understanding how these other factors can be used in planning therapy or genetic counselling and there are no guidelines to advise physicians.

Tom Walsh, PhD; Silvia Casadei, PhD; Kathryn Hale Coats, BS; Elizabeth Swisher, MD; Sunday M. Stray, BS; Jake Higgins, BS; Kevin C. Roach, BS; Jessica Mandell, MS, CGC; Ming K. Lee, PhD; Sona Ciernikova, PhD; Lenka Foretova, MD, PhD; Pavel Soucek, PhD; Mary-Claire King, PhD Spectrum of Mutations in BRCA1, BRCA2, CHEK2, and TP53 in Families at High Risk of Breast Cancer

JAMA. 2006;295:1379-1388

Pancreatic cancer treatment based on BRCA mutations status

The concept of individualized therapy is beint tesed in clincial trial. One such trial  in patients with pancreatic cancer is being run by researchers at Johns Hopkins University. The trial will enroll patients with previously untreated, advanced or recurrent pancreatic cancer and a mutation in the BRCA2 gene. The BRCA2 gene confers greatly increased risk of breast and ovarian cancer in addition to a substantial increase in pancreatic cancer risk. Previous studies showed that pancreatic tumors from patients with a BRCA2 gene mutation were approximately 1,000 times more sensitive to mitomycin-C than were tumors from patients without the BRCA2 gene mutation. If this study confirms these data, then a diagnostic test to determine the BRCA2 status of the pancreatic cancer patients may be indicated to determine the appropriate chemotherapy prior to initiating treatment in pancreatic cancer. The clinical trial now underway is designed to determine whether the extreme sensitivity of the pancreatic cancer to mitomycin-C holds true in humans as it did in earlier studies. A total of 35 patients with BRCA2 mutations will be enrolled for treatment with mitomycin-C during the course of the study. The study will compare the six-month survival rate of treated patients with the current survival rates from standard of care therapy to determine the potential benefit of using mitomycin-C for people with BRCA2 gene mutations. Previous study results led the researchers to expect a substantial improvement in the six-month survival time of pancreatic cancer patients.Mitomycin-C is one member of an important class of DNA damaging agents used to treat cancer. BRCA2 is part of the DNA repair process. When mitomycin-C damages the DNA in a patient's cancer cells, the damage would normally be repaired with the help of BRCA2. If there is no BRCA2 to fix the DNA, because of a BRCA2 gene mutation, the mitomycin-C damage is not repaired, the cancer cells die and the drug is more effective.

At this time, the strategy of diagnosing BRCA in order to provide individualized therapy remains investigational.

NCCN.ORG. Pancreatic Cancer

Julia B Greer, David C Whitcomb et al, Role of BRCA1 and BRCA2 mutations in pancreatic cancer Gut 2007;56:601-605

P53 in breast cancer

Whereas BRCA testing is well estblished, p53 testing as a single factor is not. P53 is a tumor suppressor gene. Normally, the p53 protein, coded for by the p53 gene stops cells with DNA damage from multiplying until the DNA is repaired naturally or sends the defective cell into programmed cell death. When the p53 gene becomes damaged or mutated, the protein becomes nonfunctional and loses its checkpoint control, allowing cancerous cells to replicate more readily.
A recent study published in the conducted by Dr. Ayman Linjawi of the Royal Victoria Hospital in Montreal, Quebec, Canada reveals that women with early-stage breast cancer who test positive for the mutated p53 tumor suppressor tend to have a poorer breast cancer prognosis than women who do not carry the mutated p53. Dr. Linjawi and colleagues found that the Stage I breast cancer patients with the mutant p53 had an average survival rate of 74% after five years compared with a survival rate of 83% who did not have the mutant p53. p53 mutation testing is available to high-risk women at specialized centers. However, according to the American Cancer Society, this testing has not been shown to be helpful in determining current patients' treatment at this point. Further research on p53 genetic testing is needed to determine whether it may one day have value in helping physicians choose a breast cancer patient's best course of treatment.

Westhof G, Olbrecht M, Wolff M, Schiermeier S, Zimmermann RC, Hatzmann W:
Testing of Functional Integrity of p53 Protein in Primary Breast Cancer by a Rapid Quantitative p53-p21WAF1 Double Assay May Improve the Clinical Value of p53.
Tumor Biol 2006;27:252-260

B. L. Sprague, A. Trentham-Dietz, M. Garcia-Closas, P. A. Newcomb, L. Titus-Ernstoff, J. M. Hampton, S. J. Chanock, J. L. Haines, and K. M. Egan
Genetic variation in TP53 and risk of breast cancer in a population-based case control study
Carcinogenesis, August 1, 2007; 28(8): 1680 - 1686.

BART and BRCA Testing

Lay Summary: BART testing is a new twist on BRCA testing.

BART stands for BRACAnalysis® Rearrangement Test, which detects large DNA rearrangements in the BRCA1 and BRCA2 genes, which the pcr for BRCA does not detect. Myriad's postion is that BART testing is appropriate for women who have had full sequence analysis for Frye, L. A.BRCA1/2, have tested negative and are at very high baseline risk. Myriad quotes the following statistics: when baseline risk of BRCA is 30%, BART will be _ in 2-3% or women. however, if you look at all + tests results, 10% of them are in the form of BART. Based on clinical and family history criteria, 1,035 patients were identified as severe-risk during the initial months of clinical BART analysis at Myriad Genetic Laboratories. All patients were initially tested for Comprehensive BRACAnalysis which includes BRCA1 and BRCA2 full gene sequencing plus large rearrangement panel testing for 5 recurrent BRCA1 mutations. Among severe-risk patients, 302 (29.2%) were positive for a BRCA1 or BRCA2 mutation by sequencing, 9 (0.9%) were positive by large rearrangement panel testing and an additional 27(2.6%) tested positive by BART for large genomic rearrangements. The total detection rate for deleterious mutations in severe-risk individuals was therefore 32.7%. As of August 1, 2006, Myriad conducst the BRACAnalysis Rearrangement Test on patient samples where the individual's personal and family history is indicative of an exceptionally high level of risk, but the sample tests negative for BRACAnalysis. The Rearrangement test will be performed, when indicated, at no additional charge, and is also available for order independently for a fee of $650.

R. Wenstrup, T. Judkins, K. Eliason, J. Schoenberger, S. Rajamani, C. A. A. Frye, L. A. Burbidge, J. T. Trost, A. M. Deffenbaugh, B. B. Ro Molecular genetic testing for large genomic deletion and duplication mutations in the BRCA1 and BRCA2 genes for hereditary breast and ovarian cancer. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 10513

 
Wendy Rubinstein  Roles and responsibilities of a medical geneticist.  Fam Cancer. 2007 Jul 12; : 17624600

Personal history of breast cancer and BRCA

Lay Summary: Personal history of breast cancer at young age is an indication for BRCA testing.

The risk of baseline prevalence of BRCA mutations has been best established in the setting of family history. Most guidelines that address this question focus on the family history, on defining its importance and prognostic models. Less, is known about personal history but it is generally assumed that age at diagnosis of breast cancer below 50 increases probability of a baseline BRCA mutation.  This is less well attested to in guideline statements than family history but several guidelines do mention this factor. They include the ACS Guideline cited below. Some guidelines, such as NICE and UPTFS, skirt this issue by deliberately noting that they do not address women with breast cancer at a young age. Nevertheless, BRCA screening is usually considered to be indicated in such cases.

Full DNA screening is required when there is no pre-existing identification of BRCA mutation in a relative.

Robert A. Smith, PhD, Debbie Saslow, PhD, Kimberly Andrews Sawyer, Wylie Burke, MD, PhD (for the High-Risk Work Group), Mary E. Costanza, MD (for The Screening Older Women Work Group), W. Phil Evans, III, MD (for The Mammography Work Group), Roger S. Foster, Jr., MD (for The Physical Examination Work Group), Edward Hendrick, PhD (for the New Technologies Work Group), Harmon J. Eyre, MD and Steven Sener, MD (for The Breast Cancer Advisory Group)American Cancer Society Guidelines for Breast Cancer Screening: Update 2003  CA Cancer J Clin 2003; 53:141-169

Niels Kroman Factors influencing the effect of age on prognosis in breast cancer: population based study BMJ 2000;320:474-479 ( 19 February )

Tuya Pal et al, BRCA1 and BRCA2 Mutations in a Study of African American Breast Cancer Patients Cancer Epidemiology Biomarkers & Prevention Vol. 13, 1794-1799, November 2004

K. E. Malone, J. R. Daling, D. R. Doody, L. Hsu, L. Bernstein, R. J. Coates, P. A. Marchbanks, M. S. Simon, J. A. McDonald, S. A. Norman, B. L. Strom, R. T. Burkman, G. Ursin, D. Deapen, L. K. Weiss, S. Folger, J. J. Madeoy, D. M. Friedrichsen, N. M. Suter, M. C. ########, R. Spirtas, and E. A. Ostrander
Prevalence and Predictors of BRCA1 and BRCA2 Mutations in a Population-Based Study of Breast Cancer in White and Black American Women Ages 35 to 64 Years
Cancer Res., August 15, 2006; 66(16): 8297 - 8308.

http://guidance.nice.org.uk/page.aspx?o=30600

BRCA with and without personal history

Lay Summary: I discuss the guidelines for BRCA testing.

The most recent guidelines for BRCA testing is the USPTF. in 2005. The USPSTF recommends against routine referral for genetic counseling or routine breast cancer susceptibility genes (BRCA) testing for women whose family history is not associated with an increased risk for deleterious mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA).

The USPSTF found fair evidence that women without certain specific family history patterns, termed here "increased risk family history" have a low risk for developing breast or ovarian cancer associated with BRCA1 or 2 mutations. Thus, any benefit to routine screening of these women for BRCA1 or 2 mutations, or routine referral for genetic counseling, would be small or zero. The USPSTF found fair evidence regarding important adverse ethical, legal, and social consequences that could result from routine referral and testing of these women. Interventions such as prophylactic surgery, chemoprevention, or intensive screening have known harms. The USPSTF estimated that the magnitude of these potential harms is small or greater. The USPSTF concluded that the potential harms of routine referral for genetic counseling or BRCA testing in these women outweigh the benefits.

The USPSTF found fair evidence that women with certain specific family history patterns ("increased risk family history") have an increased risk for developing breast or ovarian cancer associated with BRCA1 or 2 mutations. The USPSTF determined that these women would benefit from genetic counseling that allows informed decision-making about testing and further prophylactic treatment. This counseling should be done by suitably trained health care providers. There is insufficient evidence to determine the benefits of chemoprevention or intensive screening in improving health outcomes in these women if they test positive for deleterious BRCA1 or 2 mutations. However, there is fair evidence that prophylactic surgery for these women significantly decreases breast and ovarian cancer incidence. Thus, the potential benefits of referral and discussion of testing and prophylactic treatment for these women may be substantial.

The USPSTF concluded that the benefits of referring women with an increased risk family history to suitably trained healthcare providers outweigh the harms.

This recommendation applies to women who have not been diagnosed with either breast or ovarian cancer. It does not apply to women with a family history of breast or ovarian cancer that includes a relative with a known deleterious mutation in BRCA1 or BRCA2 genes; these women should be referred for genetic counseling. This recommendation does not apply to men.
While there currently are no standardized referral criteria, women with an increased risk family history (see below) should be considered for genetic counseling to further evaluate their potential risks.
Certain specific family history patterns are associated with an increased risk for deleterious mutations in BRCA1 or 2 genes. Both maternal and paternal family histories are important. For non-Ashkenazi Jewish women, these patterns include:
Two first-degree relatives with breast cancer, one of whom was diagnosed at age 50 or younger
A combination of 3 or more first- or second-degree relatives with breast cancer, regardless of age of diagnosis
A combination of both breast and ovarian cancer among first- and second- degree relatives
A first-degree relative with bilateral breast cancer
A combination of 2 or more first- or second-degree relatives with ovarian cancer, regardless of age of diagnosis
A first- or second-degree relative with both breast and ovarian cancer, at any age
A history of breast cancer in a male relative
For women of Ashkenazi Jewish heritage, an increased risk family history includes any first-degree relative (or 2 second-degree relatives on the same side of the family) with breast or ovarian cancer.
About 2% of adult women in the general population have an increased risk family history as defined above. Women without one of these family history patterns have a low probability of having a deleterious mutation in BRCA1 or BRCA2 genes.
Computational tools are available to predict the risk for clinically important BRCA mutations (i.e., BRCA mutations associated with the presence of breast and/or ovarian cancer), but these tools have not been verified in the general population. There is no empirical evidence concerning what level of risk for a BRCA mutation merits referral for genetic counseling.
Not all women with a potentially deleterious BRCA mutation will develop breast or ovarian cancer. The probability of developing breast or ovarian cancer by the age of 70 in a woman who has a clinically important BRCA mutation is estimated to be 35% to 84% for breast cancer and 10% to 50% for ovarian cancer.
Appropriate genetic counseling helps women make informed decisions and can improve their knowledge and perception of absolute risk for breast and ovarian cancer and often reduce anxiety. Genetic counseling includes elements of counseling, risk assessment, pedigree analysis, and, in some cases, recommendations for testing for BRCA mutations in affected family members and/or the presenting patient. It is best delivered by a suitably trained healthcare provider.
Ordering a BRCA test typically is done by a physician. When done in concert with genetic counseling, the test assures the linkage of testing with appropriate management decisions. Genetic testing may lead to potential adverse ethical, legal, and social consequences, such as insurance and employment discrimination; these issues should be discussed in the context of genetic counseling and evaluation for testing.
Among women with BRCA1 or 2 mutations, prophylactic mastectomy or oophorectomy decreases the incidence of breast and ovarian cancer; there is inadequate evidence for mortality benefits. Chemoprevention with selective estrogen receptor modulators (SERMs) may decrease breast cancer incidence of estrogen receptor-positive cancers; however, it is also associated with adverse effects such pulmonary embolism, deep vein thrombosis, and endometrial cancer. Most breast cancers associated with BRCA1 mutations are estrogen-receptor negative and thus not prevented by tamoxifen. Intensive screening with mammography has poor sensitivity, and there is no evidence of benefit of intensive screening for women with BRCA1 or BRCA2 gene mutations; magnetic resonance imaging (MRI) may detect more cancers, but the effect on mortality is not clear.
Women with an increased risk family history are at risk not only for deleterious BRCA1 or BRCA2 mutations, but potentially for other unknown mutations as well. Women with an increased risk family history who test negative for BRCA1 and BRCA2 mutations may also benefit from surgical prophylaxis.

I did not discuss personal history of breat cancer, as addressed by other guidelines, two of which are referenced. In addition, there are guidelines by NICE, ACHG, PDQ, NCCN and other authoritative bodies.

Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005 Sep 6;143(5):355-61

http://www.asco.org/asco/downloads/Genetic_Testing.pdf

http://www.breastsurgeons.org/brca.shtml

Screening for hereditary pancreatic cancer

The U.S. Preventive Services Task Force (USPSTF) recommends against routine screening for pancreatic cancer in asymptomatic adults using abdominal palpation, ultrasonography, or serologic markers. The USPSTF found no evidence that screening for pancreatic cancer is effective in reducing mortality. There is a potential for significant harm due to the very low prevalence of pancreatic cancer, limited accuracy of available screening tests, the invasive nature of diagnostic tests, and the poor outcomes of treatment. As a result, the USPSTF concluded that the harms of screening for pancreatic cancer exceed any potential benefits.

There are some special groups in which screening may be reasonable. These include hereditary pancreatitism chronic pancreatitits and thos with a strong family history.

An individual's risk of developing pancreatic cancer increases with the number of affected first-degree relatives, and it is estimated that hereditary factors account for at least 5% of pancreatic cancers.2 Familial pancreatic cancer (FPC) is inherited in an autosomal dominant manner, with variable penetrance. In order to diagnose FPC, it is necessary to obtain an accurate and thorough family history with particular emphasis on the oncologic history. While it is important to ascertain any family history of pancreatic cancer, it is also important to screen for a personal and family history of extrapancreatic malignancies, and to obtain a family cancer history beyond first-degree relatives, if possible. The family history allows the clinician to determine if prior cases of pancreatic cancer in relatives are more likely to be familial or sporadic.

If a diagnosis of FPC is made in conjunction with a family history of extrapancreatic malignancies, consideration should also be given to a syndromic FPC. Hereditary pancreatic cancer has been associated with colorectal cancer in the Lynch syndrome II variety of hereditary nonpolyposis colorectal cancer (HNPCC), with breast and ovarian cancer (breast–ovarian cancer syndrome), Peutz–Jeghers syndrome, and melanomas in the familial atypical multiple mole melanoma (FAMMM) syndrome. A family history of early pancreatitis suggestive of hereditary pancreatitis is also an important risk factor for subsequent pancreatic adenocarcinoma.

Although there are no consensus guidelines on what defines FPC, an assessment of the risk of developing pancreatic cancer according to the number of affected relatives is useful in clinical practice. Genetic testing might be a useful adjunct in the management of a patient with FPC, but should be performed only after appropriate genetic counseling. Many important genes that have at least a partial role in FPC, both syndrome-associated and nonsyndromic, have been identified. In a multicenter study, 40% of patients with a history of hereditary pancreatitis developed pancreatic adenocarcinoma by 70 years of age.6 Testing for the cationic trypsinogen gene (PRSS1), which is associated with hereditary pancreatitis, is available. The FAMMM syndrome, described in 1975, is associated with a germline mutation of the p16 tumor suppressor gene (CDKN2A). Testing for p16 mutations helps identify those patients at risk for pancreatic malignancy in families with a history of melanomas and pancreatic cancer. The majority of FPC cases, however, are nonsyndromic.

CT scanning, while critical in the management of pancreatic adenocarcinoma, has not proven to be of definitive benefit in screening for pancreatic malignancy in FPC, mainly because of a lack of adequate resolution to detect dysplasia. For CT scanning to exert a benefit in terms of mortality, it must detect either premalignant changes or early malignancy, so that curative surgery can be performed.

In cocnlusion, genetic counselling should presecede radiological screening, an attempt to better define a familial syndrome should be made before screening, and there is no evidence that any screening is supror to another or to no screening at all. There is little evidence for CT scan based screening.

U.S. Preventive Services Task Force (USPSTF). Screening for pancreatic cancer: recommendation statement. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); 2004 Feb. 3 p. [4 references]

Ulrich CD; Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology.Pancreatic cancer in hereditary pancreatitis: consensus guidelines for prevention, screening and treatment.Pancreatology. 2001;1(5):416-22

Ellis I, Lerch MM, Whitcomb DC; Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology.  Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues.
Pancreatology. 2001;1(5):405-15

Rajesh N Keswani, Amy Noffsinger and Irving Waxman A family history of pancreatic cancer, Nature Clinical Practice Gastroenterology & Hepatology (2006) 3, 586-591

Hereditary Colon Cancer tests

Lay Summary: Testing for the colon cancer gene and its role and approopriate use is described.

Hereditary nonpolyposis colorectal cancer (HNPCC) usually occurs in patients younger than age 45 and can result in the development of cancers in a variety of tissues, such as the colon, rectum, endometrium, stomach, ovaries, brain, and skin. A major genetic characteristic of HNPCC tumors is microsatellite instability (MSI). Microsatellites are short repeated sequences of DNA, and MSI results when mutations in genes that are responsible for repairing damaged DNA cause microsatellites to become longer or shorter. Cancers that exhibit MSI account for about 15% of all colorectal cancers. Myriad Genetic's Colaris test is an MSI test.

Because HNPCC results from inherited mutations, it is possible that family members of patients with HNPCC also have the genetic characteristics that put them at an increased risk for cancers associated with a particular mutation. The Amsterdam criteria were the first diagnostic guidelines to be developed, and the aim of these was to determine whether a family should be classified as having HNPCC. All of the following criteria had to be met to diagnose HNPCC: at least three members of the family should have colorectal cancer and at least one should be a first-degree relative of the other two; at least two generations of the family should have colorectal cancer; and one of the cases of colorectal cancer should have been diagnosed before the individual was age 50 years.

Revised Amsterdam Criteria
In response to criticism that the Amsterdam criteria were too stringent, the revised Amsterdam criteria (Amsterdam II criteria) were developed in 1998 to include extracolonic HNPCC-associated cancers — colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis — that are also quite common in HNPCC. This revision prevents some individuals and families from being left out of the classification. The original Amsterdam criteria were also modified so that very small families can be considered as having HNPCC. These families must have two diagnosed colorectal cancers in first-degree relatives, which involve at least two generations. One of these individuals must have been diagnosed by the age of 55. The presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is considered sufficient to classify the family as meeting the Amsterdam II criteria.

Bethesda Guidelines
The need for a set of guidelines for genetic diagnosis of HNPCC became obvious in the mid-1990s. The use of the Amsterdam criteria was achieving their original purpose; however, their limited sensitivity hampered decisions of choosing which patients should undergo genetic testing. The Bethesda guidelines (or criteria) were therefore developed with a different objective to the Amsterdam criteria[31] — they mainly aid in the decision process for whether individuals with cancer in families that do not fulfill Amsterdam criteria should undergo genetic testing. The Bethesda guidelines include additional criteria such as pathological evaluation of the Amsterdam-criteria-positive individuals (BOX 3), which allows less stringent criteria. Individuals with two HNPCC-related cancers — including synchronous (two or more tumours are present at the same time) and metachronous (first tumour is followed by a second one at a later date) cancers — or associated extracolonic cancers, or individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal adenoma are considered to fulfill the Bethesda criteria. Alternatively, individuals are considered to fulfill the Bethesda guidelines if one of the cancers is diagnosed by 45 years and the adenoma is diagnosed by 40 years; if colorectal cancer or endometrial cancer is diagnosed by 45 years; if right-sided colorectal cancer with an undifferentiated pattern (solid/cribiform) on histopathology is diagnosed by 45 years; or if signet-ring-cell-type colorectal cancer is diagnosed by 45 years.

Revised Bethesda Guidelines
Although the Bethesda guidelines are considered to be a useful tool for making decisions about whether genetic testing and/or MSI testing of the tumours from individuals with HNPCC should be performed, data that has been accumulated over the past five years on both genetics and IHC characterization indicate that these criteria should be updated. An international group of HNPCC researchers and clinicians unanimously decided to revise these guidelines. In the revised Bethesda guidelines, changes were undertaken for several reasons: to identify patients who were at risk for hereditary cancer, to include a complete spectrum of colonic and extracolonic cancers, and to identify MSH2 and MLH1 germline-mutation carriers in patients with cancers who might or might not fulfill the Amsterdam II criteria. First, the Amsterdam and then the Amsterdam II criteria can be used to assess cases that can be subjected to the revised Bethesda guidelines. Next, cancers from these cases can be analysed for MSI or the absence of MSH2 or MLH1 — by IHC — based on the availability of either test or the cost effectiveness in a particular situation. The final decision is whether genetic testing of the main HNPCC genes, MSH2 and MLH1, should be performed. If individuals are found to have disease-related mutations, they are confirmed as having HNPCC.

It was decided that individuals who meet one of the following criteria fulfilled the revised Bethesda guidelines and should be recommended to undergo genetic testing. Those diagnosed with colorectal cancer before the age of 50 years; who had synchronous or metachronous colorectal or other HNPCC-associated tumours, regardless of age; who had MSI-H under the age of 60 years; who had one or more first-degree relatives with colorectal cancer or other HNPCC-related tumour, with one of the cancers diagnosed by the age of 50 years (including adenoma by the age of 40 years); or who had colorectal cancer with two or more relatives with colorectal cancer or other HNPCC-related tumours, regardless of age.

Although Bethesda criteria differ in their original purpose to the Amsterdam criteria, several studies show that the Bethesda criteria are the most sensitive (94%), followed by the Amsterdam II criteria (72%) and then the Amsterdam criteria (61%). Now, with further refinements in the Bethesda guidelines (revised Bethesda guidelines), it is hoped that the clinical-research community will accept these new guidelines to make decisions in patients with familial cancer and to decide whether determination of precise gene mutation in MMR genes should be performed.

In summary, the revised criteria suggest that tumors from patients with colorectal cancer should be tested for MSI and subsequent genetic testing to confirm a mutation in one of the genes responsible for HNPCC in the following situations:

1. The patient is younger than age 50.
2. The patient has multiple HNPCC-associated tumors in the colon or in other areas known to be caused by the same mutations, either at the same time or occurring over a period of time.
3. A patient younger than age 60 has colorectal cancer that has microscopic characteristics that are often indicative of MSI.
4. A patient has one or more first-degree relatives who had an HNPCC-related tumor at age 50 or younger.
5. A patient has two or more first- or second-degree relatives who had HNPCC-related tumors at any age.

Syngal, S., Fox, E. A., Eng, C., Kolodner, R. D. & Garber, J. E. Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J. Med. Genet. 37, 641-645 (2000).

Cai, S. J. et al. Clinical characteristics and diagnosis of patients with hereditary nonpolyposis colorectal cancer. World J. Gastroenterol. 9, 284-287 (2003).

Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96;2004:261-8.