HNPCC

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HNPCC

• Grand Rounds
• 3/18/05
• Warren Brenner M.D.

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Colon cancer age 55
Died colon cancer
Died colon cancer age 83
Died age 46 esophageal cancer
Paternal half sister Died age 40 metastatic
cancer of unknown origin
Paternal half brother Died age 43 from TCC
Multiple keratoacanthomas Colon cancer - age
36 Breast cancer age 44 Synchronous colon
cancer age 50 Endometrial cancer - age 51
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CA Cancer J Clin 2005 55 10-30
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Lynch Cancer100, No1,2004
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HNPCC

• First described by Aldred Warthin in 1895 and
  reported in 1913
• Lynch described 2 Midwestern kindred's as having
  a cancer family syndrome in 1966
• Germline mutation in DNA mismatch repair genes
  resulting in microsatellite instability
• Inherited in AD manner
• Accounts for 1-3 of all cases of CRC (based on
  detection of germline mutations)

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Clinical Presentation

• Earlier than average age of onset mean 45
• Pattern of primary cancers segregating in family
• Distinguishing pathological features
• CRC usually involves the proximal colon
• Increased incidence of synchronous and
  metachronous CRC
• Survival rate for CRC appears better than that of
  its sporadic variant
• Extra colonic cancers (Lynch II)

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Pathology

• Poorly differentiated, mucinous and increased
  incidence of signet cells
• Diploid, peritumoral lymphocyte infiltration and
  Crohns like reaction
• Adenomas found in 20 of colons in HNPCC patients
  with CRC
• Colonic adenomas tend to occur earlier, are
  larger and more often villous with more high
  grade dysplasia
• Accelerated rate of adenoma to carcinoma

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Lifetime risk of cancer development
ChungAnnals of Int Med2003,vol 138,2003
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Molecular Biology

• Fearson and Vogelstein described the molecular
  basis of sporadic colon cancer as a multistep
  model of carcinogenesis with accumulation of
  genetic events ultimately resulting in clonal
  tumor development
• Oncogenes involved include RAS, SRC, APC and TSG
  include P53 mutations and DCC genes on chromosome
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• These cancers develop from the chromosomal
  instability (microsatellite stable) pathway and
  are characterized by aneuploidy, allelic losses,
  amplifications and translocations and have no
  site predilection

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LynchNEJM 348 2003, 919
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Microsatellite Instability Pathway

• Various repair mechanisms are available to
  correct any errors occurring during DNA
  replication
• One type of error called slippage can occur
  during the replication of microsatellite
  sequences by DNA polymerase
• Microsatellite DNA sequences are defined as short
  dinucleotide or mononucleotide repeats
• These sequences are usually within non coding
  regions although some genes contain
  microsatellites within coding regions (e.g.,
  TGF-ß receptor II, Insulin like growth factor II
  receptor, regulators of the cell cycle e.g. E2F4,
  regulators of apoptosis e.g. BAX and even the MMR
  genes themselves)

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Slippage during DNA replication
Chung, D. C. et. al. Ann Intern Med
2003138560-570
ChungAnnals of Int Med2003,vol 138,2003
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DNA Mismatch repair system

• Primary function of the MMR system is to
  eliminate these mismatches and insertion-deletion
  loops
• At least 6 different MMR proteins
• mutS hMSH2, hMSH3, hMSH6
• mutL hMLH1, hMLH3, hPMS1 and hPMS2
• Mutations in hMSH2 or hMLH1 usually results in
  high MSI
• Mutations in genes such as hMSH6 result in low
  levels of MSI

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Genes Associated with the Hereditary Nonpolyposis
Colorectal Cancer Syndrome
ChungAnnals of Int Med2003,vol 138,2003
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LynchNEJM 348 2003, 919
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Components of the DNA mismatch repair system
Chung, D. C. et. al. Ann Intern Med
2003138560-570
ChungAnnals of Int Med2003,vol 138,2003
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Microsatellite Instability

• Defined according to an NCI panel of markers
• MSI-H gt instability at 2 or more of 5 loci
• MSI-L is defined as 1 loci showing instability
• MSI is identified in about 15 of all sporadic
  cancers
• These tumors have similar pathological and
  clinical features to classic HNPCC tumors
• Sporadic MSI-H tumors usually occur due to
  transcriptional silencing by methylation of the
  promotor of the hMLH1 gene

UmarJNCI, vol96,2004, 261
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What to do when HNPCC is suspected

• First step is usually to test tumors for MSI-H
  phenotype
• Germline testing if positive
• Alternative is to prescreen tumors with
  immunostaining for MSH2 or MLH1 protein which is
  cheaper and technically easier
• Pathogenic mutations in a MMR gene usually lead
  to absence of any detectable gene product by IHC

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Overall strategy for genetic testing of an
affected proband from a suspected hereditary
nonpolyposis colorectal cancer kindred
Chung, D. C. et. al. Ann Intern Med
2003138560-570
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Do patients with MSI have a more favorable
prognosis than MSS patients?
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• A number of studies have reported better survival
  for patients whose tumors have MSI
• Population based series of 607 patients
• 17 had MSI
• MSI tumors were associated with a significant
  survival advantage independent of all standard
  prognostic factors (including stage) and also had
  a decreased likelihood of metastasizing to
  regional lymph nodes or distant organs

Gryfe et al NEJM, 342, 69
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Do tumors with MSI benefit from chemotherapy ?
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• Specimens were obtained from 570 patients with
  CRC previously enrolled in 5 phase III trials of
  adjuvant chemotherapy
• 16.7 showed MSI-H
• 10.5 showed MSI-L

Ribic NEJM 349, 2003, 247
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• In a review of 7000 colon cancer patients in
  published studies which analyzed survival and
  stratified cases by MSI status 1300 had MSI
• Based on pooled findings, MSI was associated with
  a 15 or better prognosis compared with MSS
  tumors
• Data from this analysis also showed that these
  tumors may be resistant to FU
• In vitro data has shown a survival benefit for
  MMR deficient colon cancer cell lines treated
  with FU
• Cell cycle arrest does not appear to occur in
  these cells in response to FU

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• These results contrast with other smaller non
  randomized study populations and a larger
  selected case series of patients which showed
  that patients with MSI had an increased duration
  of OS if receiving adjuvant chemotherapy
• One small retrospective study showed that
  patients with MSI-H tumors were more likely to
  respond to irinotecan based therapy than those
  with MSI-S tumors.

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Screening

• Colonoscopy starting age 25 repeated every 1-2
  years
• Upper endoscopy in families with history of
  gastric cancer or who reside in high risk
  incidence areas
• Urine cytology/ultrasound
• Annual transvaginal U/S and endoscopic aspiration
  with cytology starting age 30 for endometrial
  cancer screening
• Transvaginal U/S and CA-125 screening starting
  age 30 annually for ovarian cancer screening
• ?role of prophylactic surgery

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Controlled Trial of Screening in HNPCC

• 252 at risk members of 22 families with HNPCC
  followed for 15 years
• 133 agreed to screening
• 119 refused
• Of those screened there were 62 fewer cancers
  and 65 fewer deaths
• There were 0 CRC deaths vs. 9 in the unscreened
  group

Jarvinen.Gastroenterology,118829,2000
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